Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:13][C:12]2[CH:14]=[C:15]([N:19]3[CH2:23][CH2:22][C:21]4([CH2:27][CH2:26][N:25]([CH2:28][CH3:29])[CH2:24]4)[CH2:20]3)[CH:16]=[C:17]([CH3:18])[C:11]=2[N:10]=1.[NH2:30][CH2:31][C@H:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=1)[OH:33].CCN(CC)CC>CCO>[Cl:40][C:36]1[CH:35]=[C:34]([C@H:32]([OH:33])[CH2:31][NH:30][C:2]2[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=2[C:9]2[NH:13][C:12]3[CH:14]=[C:15]([N:19]4[CH2:23][CH2:22][C:21]5([CH2:27][CH2:26][N:25]([CH2:28][CH3:29])[CH2:24]5)[CH2:20]4)[CH:16]=[C:17]([CH3:18])[C:11]=3[N:10]=2)[CH:39]=[CH:38][CH:37]=1
Reactant: CCN1CCC2(CCN(c3cc(C)c4nc(-c5c(Cl)cc[nH]c5=O)[nH]c4c3)C2)C1
Reactant: NC[C@@H](O)c1cccc(Cl)c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCN1CCC2(CCN(c3cc(C)c4nc(-c5c(NC[C@@H](O)c6cccc(Cl)c6)cc[nH]c5=O)[nH]c4c3)C2)C1
Yield: 35.2 %

Procedure:
A solution of 4-chloro-3-[6-(7-ethyl-2,7-diaza-spiro[4.4]non-2-yl)-4-methyl-1H-benzoimidazol-2-yl]-1H-pyridin-2-one (53 mg, 0.13 mmol), (S)-2-amino-1-(3-chlorophenyl)-ethanol (27 mg, 0.156 mmol) and Et3N (26 mg, 0.26 mmol) in EtOH (0.5 mL) was heated at 80° C. for 18 h and then the reaction mixture was evaporated. The residue was purified by chromatography (150:8:1 CH2Cl2/MeOH/28% aqueous NH4OH) to afford the title compound (25 mg, 35%). 1H NMR (MeOH-d4) δ 1.16 (t, J=8 Hz, 3H), 1.80-2.02 (4H), 2.48-2.80 (4H), 2.50 (s, 3H), 3.19-3.39 (4H), 3.63 (m, 2H), 4.81 (m, 1H), 4.95 (m, 2H), 6.18 (d, J=6 Hz, 1H), 6.38 (s, 1H), 6.44 (s, 1H), 7.17-7.31 (3H), 7.38 (d, J=6 Hz, 1H), 7.55 (s, 1H). ESI-MS m/z 547 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]1[CH2:8][C@@H:7]([OH:9])[CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].Cl.[Br:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][NH:23][CH2:24]2.CCN(C(C)C)C(C)C.CN([CH:41]=[O:42])C>>[Br:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][N:23]([C:41]([O:9][C@H:7]1[CH2:6][N:5]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[C@H:4]([C:3]([O:2][CH3:1])=[O:17])[CH2:8]1)=[O:42])[CH2:24]2
Reactant: Brc1cccc2c1CNC2
Reactant: CN(C)C=O
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1C[C@@H](OC(=O)N2Cc3cccc(Br)c3C2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (2S,4R)-BOC-4-hydroxyproline methyl ester (126.3 g, 515 mmol) in DMF (960 mL) at 0° C. was added N,N′-carbonyldiimidazole (83.51 g, 515 mmol). The reaction mixture was stirred at RT for 3 hours. 4-Bromoisoindoline hydrochloride (120 g, 515 mmol) and DIPEA (96.3 mL, 540 mmol) were added, and the reaction mixture heated to 50° C. for 6 hours. The reaction mixture was then allowed to cool to RT and stirred overnight. The reaction mixture was partitioned between EtOAc (3 L) and 10% aqueous KHSO4 (6 L), the aqueous re-extracted with EtOAc (2 L) and the combined organic phases washed with 10% aqueous NaHCO3, brine, dried over Na2SO4 and solvent evaporated to a foam (239 g). LRMS (ESI) m/z 471.0 [(M+H)+; calcd for C20H26BrN2O6: 471.1].
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH:10]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=[C:25]([CH3:33])[CH:24]=3)=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:9][CH2:8][O:7][CH2:6]1)=[O:4].[C:34](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH:10]([N:11]([CH3:34])[S:12]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=[C:25]([CH3:33])[CH:24]=3)=[CH:19][CH:20]=2)(=[O:14])=[O:13])[CH2:9][CH2:8][O:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1COCCC1NS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C1COCCC1N(C)S(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Temperature: 40 °C
Yield: 68.4 %

Procedure:
To a slurry of 0.3 g (0.634 mmol) of 4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-tetrahydro-pyran-3-carboxylic acid methyl ester (Example 24, Step 1) and potassium carbonate (0.176 g, 1.27 mmol) in DMF (10 mL) was added iodomethane (0.109 g, 0.765 mmol). The reaction was heated at 40° C. for 2 h and then the reaction was allowed to cool to 25° C. over 19 h. The DMF was removed in vacuo and the resulting oil was diluted with ethyl acetate (100 mL) and then washed with water (2×30 mL) and saturated aqueous sodium chloride (30 mL). The organic layer was dried over MgSO4, filtered and concentrated to obtain a crude oil (0.170 g,). The crude product was purified by Biotage Flash 40S chromatography, eluting with 1:1 ethyl acetate:hexanes, to afford 4-{methyl-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonyl]-amino}-tetrahydro-pyran-3-carboxylic acid methyl ester as an amorphous white solid (0.210 g, 68%). MS: 485 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([O:11]COCCOC)=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[N:8]=[C:7]([CH:22]=O)[N:6]=1)([CH3:4])[CH3:3].NCCC(O)=O.COC1C=CC(/C=[C:45]2/[C:46]([NH:48][C:49]([S:51]/2)=[NH:50])=[O:47])=CC=1OC1CCCC1>>[CH3:1][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[N:8]=[C:7]([CH:22]=[C:45]2[S:51][C:49](=[NH:50])[NH:48][C:46]2=[O:47])[N:6]=1)([CH3:3])[CH3:4]
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Reactant: COCCOCOc1c(C(C)(C)C)nc(C=O)nc1C(C)(C)C
Agent: NCCC(=O)O
Product: CC(C)(C)c1nc(C=C2SC(=N)NC2=O)nc(C(C)(C)C)c1O
Yield: 11.2 %

Procedure:
4,6-Bis-(1,1-dimethylethyl)-5-[(2-methoxyethoxy)methoxy]-2-pyrimidine carboxaldehyde (0.5 g, 1.5 mmoles) is treated with β-alanine (0.27 g, 3.1 mmoles) and pseudothiohydantoin (0.21 g, 1.8 mmoles) according to the procedure of Example 6 to give 0.056 g (11%) of 5-[[4,6-bis-(1,1-dimethylethyl]-5-hydroxy pyrimidinyl]methylene]-2-imino-4-thiazolidinone. MP=278°-281° C. dec.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.CC1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][N+:10]=1[O-].[OH-].[Na+].ClCCl>O>[CH3:15][C:12]1[CH:13]=[CH:14][C:6]([CH2:5][OH:7])=[N:10][CH:11]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(C)[n+]([O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(CO)nc1
Temperature: 95 °C
Reaction time: 1.5 h

Procedure:
To acetic anhydride (1.61 L) at 90° C. was added 2,5-dimethyl-pyridine 1-oxide (1000 g) dropwise over 3 hours, maintaining a temperature between 90-100° C. The reaction was stirred at 90° C. for 1.5 hours, and then cooled with stirring overnight. The mixture was slowly poured into aqueous 25% sodium hydroxide (3 L) over 4 hours, and then dichloromethane (8 L) and water (8 L) were added, and the mixture was allowed to separate for 2 days. The aqueous layer was separated and extracted separately with dichloromethane and ethyl acetate, and the combined organic layers were concentrated to dryness. The crude material was applied to the top of a pad of silica (˜1 kg) and eluted with ethyl acetate until no product was observed in the eluant. The filtrate was concentrated under vacuum to give the desired product (320 g).
Reaction SMILES: [I:1]I.[CH2:3]([O:6][N:7]1[CH:11]=[CH:10][CH:9]=[N:8]1)[C:4]#[CH:5].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[I:1][CH:3]([O:6][N:7]1[CH:11]=[CH:10][CH:9]=[N:8]1)[C:4]#[CH:5]
Reactant: C#CCOn1cccn1
Reactant: II
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: C#CC(I)On1cccn1
Reaction time: 8 h
Yield: 98.5 %

Procedure:
41.6 g of iodine are added, a little at a time, to 20 g of 1-pyrazolyl propargyl ether and 20 g of sodium carbonate in 400 g of acetonitrile at 40° C., while stirring. Stirring is continued for 8 hours at 40° C., after which undissolved material is filtered off under suction, and the filtrate is evaporated down in a rotary evaporator at 30° C. and under 20 mbar. The residue is dissolved in 200 g of dichloromethane, the solution is extracted twice with 200 g of 10% strength aqueous sodium thiosulfate solution, and the organic phase is dried with magnesium sulfate and evaporated down. 40 g (99% of theory) of 1-pyrazolyl iodopropargyl ether are obtained as an oil (H1 --NMR, in ppm: 5.1, s, 2H; 6.2, m, 1H; 7.4, m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[N:25]=[CH:24]4)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>COCCOC.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[N:25]=[CH:24]4)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc([N+](=O)[O-])c4)nc4ccccc34)ccc21
Agent: [Pd]
Solvent: CO
Solvent: COCCOC
Product: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(N)c4)nc4ccccc34)ccc21
Reaction time: 16 h

Procedure:
A suspension of product tert-butyl 5-(2-(3-nitrophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (9.0 g, 18.65 mmole) in a mixture of DME/MeOH (300 mL/100 mL) was hydrogenated in the presence of 10% Pd/C (1.25 g) at RT using a balloon filled with hydrogen gas. The reaction was stirred for 16 h and the reaction mixture filtered through Celite™. The pad of Celite™ was washed with a 1:1 mixture of MeOH/CH2Cl2 (200 mL). The filtrate was then concentrated in vacuo and dried under high vacuum overnight to give tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate. (8.8 g, mmol, %).
Reaction SMILES: [N:1]([O-])=O.[Na+].[F:5][C:6]([F:16])([F:15])[O:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1.O.[Sn](Cl)(Cl)(Cl)Cl.[C:23]1(=[O:29])O[C:26](=[O:27])[CH:25]=[CH:24]1>O.Cl>[F:5][C:6]([F:15])([F:16])[O:7][C:8]1[CH:14]=[CH:13][C:11]([N:12]2[C:26](=[O:27])[CH:25]=[CH:24][C:23]([OH:29])=[N:1]2)=[CH:10][CH:9]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: O=N[O-]
Reactant: O=C1C=CC(=O)O1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Product: O=c1ccc(O)nn1-c1ccc(OC(F)(F)F)cc1
Temperature: 100 °C
Yield: 48.5 %

Procedure:
The substituted pyridazinones of the formula (III), to be used as starting materials for the preparation of the compounds of the formula (I), could be prepared, for example, as follows: ##STR7## A solution of 68.3 g of sodium nitrite in 135 ml of water was added dropwise, at 0°-5° C., to a solution of 133 g (0.75 mol) of 4-trifluoromethoxyaniline in 300 ml of concentrated hydrochloric acid and 300 ml of water. After the end of the addition, the reaction mixture was allowed to run, at 5°-10° C., into a solution of 450 g of tin chloride hydrate in 450 ml of hydrochloric acid. After half an hour the salt which had precipitated was filtered off and dissolved in 900 ml of hot water, and the solution was filtered. 73.5 g (0.75 mol) of maleic anhydride were then added to the filtrate at 95°-100° C. and the mixture was stirred for a further hour at 100° C. The product which had precipitated was filtered off at 80° C., rinsed with warm water and then dissolved in dilute sodium hydroxide solution. The filtered solution was acidified with hydrochloric acid and the product which had crystallized out was then filtered off and rinsed with water. 99 g (49% of theory) of 1-(4-trifluoromethoxyphenyl)-3-hydroxy-1,6-dihydropyridazin-6-one were thus obtained in the form of a beige powder of melting point 243° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:14]([C:15](=[O:17])[CH3:16])=[CH:13][NH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1>CN(C)C=O>[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][N:12]2[CH:13]=[C:14]([C:15](=[O:17])[CH3:16])[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)=[N:11]2)=[CH:28][CH:27]=1
Reactant: CC(=O)c1c[nH]nc1-c1cccc([N+](=O)[O-])c1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc(C(C)=O)c(-c3cccc([N+](=O)[O-])c3)n2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
320 mg (1.39 mmol) of 1-[3-(3-nitrophenyl)-1H-pyrazol-4-yl]ethanone were dissolved with 15 ml of dry dimethylformamide and 540 mg (1.66 mmol) of cesium carbonate and 189 μl (1.39 mmol) of p-methoxybenzyl chloride were added. The reaction mixture was maintained at 70° C. under stirring for 8 hours. The solvent was then removed under reduced pressure and the residue taken up with dichloromethane and washed with water. The organic layer was dried over sodium sulphate and evaporated. The crude was finally purified by flash-chromatography on a silica gel column (cyclohexane-ethylacetate; from 4/1 to 3/2), giving 470 mg (97%) of the title compound.
Reaction SMILES: [CH2:1]([C:5]1[CH:12]=[C:11]([CH3:13])[C:8]([C:9]#[N:10])=[C:7]([SH:14])[N:6]=1)[CH:2]([CH3:4])[CH3:3].Br[CH2:16][C:17]([NH2:19])=[O:18].[O-]CC.[Na+]>CN(C=O)C.O>[NH2:10][C:9]1[C:8]2[C:7](=[N:6][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:12][C:11]=2[CH3:13])[S:14][C:16]=1[C:17]([NH2:19])=[O:18]
Reactant: NC(=O)CBr
Reactant: Cc1cc(CC(C)C)nc(S)c1C#N
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(CC(C)C)nc2sc(C(N)=O)c(N)c12
Temperature: 70 °C

Procedure:
A mixture of the above nitrile (1.00 g, 4.85 mmol), bromoacetamide (0.67 g, 4.85 mmol), and sodium ethoxide (0.68 g, 10 mmol) in DMF (20 mL) was heated at 70° C. for 1 h before it was allowed to cool to room temperature. The resulting mixture was diluted with water, filtrated and the precipitates washed with EtOH providing the title compound (0.5 g, 39%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]([C:15]([OH:17])=O)[CH:12]=[CH:11][C:10]=1[F:18].[NH2:19][C:20]1[C:21]([N:29]2[CH2:34][C@H:33]([C:35]([F:38])([F:37])[F:36])[CH2:32][C@H:31]([NH:39]C(=O)OC(C)(C)C)[CH2:30]2)=[C:22]2[CH2:28][CH2:27][O:26][C:23]2=[N:24][CH:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:39][C@H:31]1[CH2:32][C@@H:33]([C:35]([F:37])([F:38])[F:36])[CH2:34][N:29]([C:21]2[C:20]([NH:19][C:15]([C:13]3[CH:12]=[CH:11][C:10]([F:18])=[C:9]([C:3]4[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[N:14]=3)=[O:17])=[CH:25][N:24]=[C:23]3[O:26][CH2:27][CH2:28][C:22]=23)[CH2:30]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](C(F)(F)F)CN(c2c(N)cnc3c2CCO3)C1
Reactant: O=C(O)c1ccc(F)c(-c2c(F)cccc2F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N[C@H]1C[C@@H](C(F)(F)F)CN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cccc4F)n3)cnc3c2CCO3)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 19.6 %

Procedure:
To a mixture of 6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylic acid (38.7 mg, 0.153 mmol), tert-butyl [(3S,5R)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl]carbamate (51.4 mg, 0.128 mmol) and HATU (178.7 mg, 0.4700 mmol) was added DMF (2.0 mL) followed by DIPEA (159.5 mg, 1.234 mmol). The reaction mixture was stirred at room temperature for 3 h, and then concentrated under reduced pressure. To the resulting residue was added DCM (2.0 mL), followed by TFA (2.0 mL). The mixture was stirred at room temperature for 30 min., and then concentrated under reduced pressure. The resulting residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at flow rate of 30 mL/min.) to afford the title compound as a white solid (13.5 mg, 20%). LCMS calc. for C25H22F6N5O2 (M+H)+: m/z=538.2. found 538.2.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4]([S:19]([CH3:22])(=O)=O)[N:3]=1.[CH2:23](S)C.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4]([S:19][CH2:22][CH3:23])[N:3]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccc3c(c2)OCO3)c1C#N
Reactant: CCS
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: CCSc1nc(N)nc(-c2ccc3c(c2)OCO3)c1C#N

Procedure:
From 2-amino-4-benzo[1,3]dioxol-5-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, ethyl mercaptan and DBU in DME. EI-MS m/e (%): 300 (M+, 74), 299 ([M—H]+, I100).
Reaction SMILES: C[C:2]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13]2[C:4](=[C:5]3[C:10](=[CH:11][CH:12]=2)[C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:8][C:7](C)=[N:6]3)[N:3]=1.ClN1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[C:55]([Cl:59])([Cl:58])([Cl:57])Cl.[CH:60]([Cl:63])([Cl:62])[Cl:61]>>[Cl:61][C:60]([Cl:63])([Cl:62])[C:7]1[CH:8]=[C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:10]2[C:5](=[C:4]3[C:13](=[CH:12][CH:11]=2)[C:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:15][C:2]([C:55]([Cl:59])([Cl:58])[Cl:57])=[N:3]3)[N:6]=1
Reactant: Cc1cc(-c2ccccc2)c2ccc3c(-c4ccccc4)cc(C)nc3c2n1
Reactant: ClC(Cl)Cl
Reactant: ClC(Cl)(Cl)Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Cl
Product: ClC(Cl)(Cl)c1cc(-c2ccccc2)c2ccc3c(-c4ccccc4)cc(C(Cl)(Cl)Cl)nc3c2n1
Reaction time: 6 h

Procedure:
A mixture composed of 2,9,-dimethyl-4,7-diphenyl-1,10-phenanthroline (4.0 g, 0.011 mole), N-chlorosuccinimide (9.0 g, 0.067 mole), benzoyl peroxide (0.011 g) and 96 ml carbon tetrachloride was stirred for 6 hr in an oil bath at 90°. After standing overnight at 4° C., crystals of succinimide were removed by filtration. The solvent was removed from the filtrate by vacuum evaporation to produce a light yellow solid which was then dissolved in chloroform. The organic layer was washed with saturated sodium carbonate solution and dried over anhydrous magnesium sulfate. Removal of solvent by vacuum evaporation yielded the white solid product. Yield=6.1 g (97%). Mp=286°-289°. IR 3020-3080, 1620, 1570, 1550, 1490, 1445, 1405, 1360, 1220, 1040, 930, 895, 835, 800, 780, 760, 735, 700, 620 cm-1. 60 MHz proton NMR in CDCl3 δ7.55 singlet (10 protons), δ8.05 singlet (2 protons), δ8.3 singlet (2 protons).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.C(N(CC)C(C)C)(C)C.[C:21]([O:25][C:26]([NH:28][C@@H:29]1[CH2:33][CH2:32][NH:31][CH2:30]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:31]1[CH2:32][CH2:33][C@@H:29]([NH:28][C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])[CH2:30]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc([N+](=O)[O-])cc2F)C1
Yield: 99.8 %

Procedure:
3,4-Difluoronitrobenzene (16.03 g, 0.101 M) was dissolved in acetonitrile (300 ml), and treated with N,N-diisopropylethylamine (32.63 g, 0.253 M) and (3R)-3-t-butoxycarbonylaminopyrrolidine (20.65 g, 0.111 M). The mixture was stirred and heated to reflux for 18 hours. Solvent was evaporated, and the residue treated with EtOAc (300 ml) and water (200 ml). The organic laver was washed with water (1 50 ml). citric acid solution (10% in water, 2×150 ml), and dried (magnesium sulfate). Evaporation gave the desired product as a yellow solid (32.7 g), of sufficient quality for use without purification. MS (ESP): 326 (MH+) for C15H20FN3O4.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]=O)[CH:10]=1)[NH:7][CH:6]=[CH:5]2.[NH2:13][CH2:14][CH2:15][OH:16].[H][H]>CO.[Pd]>[OH:16][CH2:15][CH2:14][NH:13][CH2:11][C:9]1[CH:10]=[C:2]([CH3:1])[CH:3]=[C:4]2[C:8]=1[NH:7][CH:6]=[CH:5]2
Reactant: NCCO
Reactant: Cc1cc(C=O)c2[nH]ccc2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1cc(CNCCO)c2[nH]ccc2c1
Reaction time: 1 h

Procedure:
Dissolve 5-Methyl-1H-indole-7-carboxaldehyde (4.036 g, 25.384 mmol) in absolute methanol (200 mL), add 2-aminoethanol (3.1 g, 50.767 mmol) and 10% palladium on carbon (0.4 g). Stir the mixture for 1 hour under nitrogen, then under 1 atmosphere of hydrogen for 3 hours. Filter, concentrate under reduced pressure, and purify by flash column chromatography (silica gel, 90/9/1, dichloromethane/methanol/ammonia) to give the title compound as a colorless oil.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].Br[CH2:20][CH:21]1[CH2:23][CH2:22]1>CN(C=O)C>[CH:21]1([CH2:20][N:1]2[C:9]3[CH:8]=[C:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[N:6]=[CH:5][C:4]=3[CH:3]=[CH:2]2)[CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)c1cc2[nH]ccc2cn1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1cc2c(ccn2CC2CC2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
To a mixture of tert-butyl 1H-pyrrolo[3,2-c]pyridine-6-carboxylate (1.0 g, 4.6 mmol) in DMF (20 ml) was added sodium hydride (60% in oil) (0.4 g, 10 mmol) and stirred at room temperature for 3 h. To the mixture, (bromomethyl)cyclopropane (1.2 g, 9.2 mmol) was added and stirred at room temperature. for 2 h. The reaction mixture was extracted with EtOAc/H2O. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The crude mixture was purified by chromatography (SiO2, hexanes:EtOAc=50:50) to give tert-butyl 1-(cyclopropylmethyl)-1H-pyrrolo[3,2-c]pyridine-6-carboxylate (2A, 1.1 g, 4.0 mmol, 88% yield) as a yellow oil. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.16-0.23 (m, 2 H) 0.44-0.51 (m, 2 H) 0.99-1.11 (m, 1H) 1.48 (s, 9 H) 3.84 (d, J=7.07 Hz, 2 H) 6.45-6.47 (m, 1 H) 7.19 (d, J=3.03 Hz, 1 H) 7.96 (s, 1 H) 8.79 (s, 1 H).
Reaction SMILES: C(Br)C.[Mg].[CH3:5][CH:6]([OH:9])[C:7]#[CH:8].[CH3:10][CH:11]([CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH3:20])[CH2:12][CH2:13][OH:14]>O1CCCC1>[CH3:10][CH:11]([CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH3:20])[CH2:12][CH:13]([OH:14])[C:8]#[C:7][CH:6]([OH:9])[CH3:5]
Reactant: C#CC(C)O
Reactant: CCC/C=C\CC(C)CCO
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCBr
Product: CCC/C=C\CC(C)CC(O)C#CC(C)O
Reaction time: 1.5 h
Yield: 81.6 %

Procedure:
A solution of 10.4 g (95.6 mmol) of ethyl bromide in 40 mL of dry tetrahydrofuran was added dropwise over a period of 30 min to a vigorously stirred suspension of 2.32 g (95.6 mmol) of magnesium turnings in 15 mL of dry tetrahydrofuran, with the reaction being initiated by occasional heating with a heat gun. After stirring the reaction mixture for 90 min under reflux, it was allowed to cool down to room temp., and a solution of 2.95 g (42.1 mmol) of but-3-yn-2-ol in 40 mL of dry tetrahydrofuran was added dropwise with stirring. The reaction mixture was then again refluxed for 3 h, the heating bath removed and a solution of 6.50 g (42.2 mmol) of (5Z)-3-methylnon-5-en-1-ol (vide supra) in 40 mL of dry tetrahydrofuran added at room temp. with stirring over a period of 30 min. The reaction mixture was refluxed with stirring overnight, allowed to cool to room temp., and quenched by pouring into 100 mL of an aqueous satd. NH4Cl solution. The organic layer was separated, and the aqueous one extracted three times with 500 mL of ether each. The combined organic extracts were dried with sodium sulphate, and concentrated to dryness in a rotary evaporator. The resulting residue (8.85 g) was purified by flash chromatography (200 g of silica gel, pentane/ether, 1:1, Rf=0.21) to furnish 7.71 g (82%) of (9Z)-7-methyltridec-9-en-3-yne-2,5-diol as a colourless oil.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([CH3:22])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[OH:15])[C@@H:9]1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)C1C=CC=CC=1.Cl.[H][H]>CN(C)C=O.[Pd]>[CH3:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][C@H:9]2[C@@H:10]([C:14]([CH3:22])([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[OH:15])[CH2:11][CH2:12][CH2:13][NH:8]2)=[CH:29][CH:28]=1
Reactant: COc1ccc(C[C@H]2[C@@H](C(C)(O)c3ccccc3)CCCN2Cc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccc(C[C@@H]2NCCC[C@@H]2C(C)(O)c2ccccc2)cc1

Procedure:
A solution 41.5 g. of cis-1-benzyl-2-(p-methoxybenzyl)-α-methyl-α-phenyl-3-piperidinemethanol in 8.3 ml. of concentrated hydrochloric acid is diluted with dimethylformamide to a volume of 400 ml. and catalytically hydrogenated under 10 atmospheres of hydrogen in the presence of palladium-on-carbon catalyst. The catalyst is removed by filtration and the solvent is evaporated from the filtrate under reduced pressure. The resulting residue is taken up in ethanol and diluted with diethyl ether to yield cis-2-(p-methoxybenzyl)-α-methyl-α-phenyl-3-piperidinemethanol.