Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[C@H:4]([CH2:28][S:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[NH:5][C:6](=[O:27])[C@H:7]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10](O)=[O:11].[NH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:37])[C@H:4]([CH2:28][S:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[NH:5][C:6](=[O:27])[C@H:7]([CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:8][C@H:9]([C:10]([NH:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1)=[O:11])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)[C@H](CSCc1ccccc1)NC(=O)[C@H](Cc1ccccc1)C[C@@H](Cc1ccccc1)C(=O)O
Reactant: Nc1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@H](CSCc1ccccc1)NC(=O)[C@H](Cc1ccccc1)C[C@@H](Cc1ccccc1)C(=O)Nc1ccccn1

Procedure:
A solution of 2.1 g of N-[(S,S)-2,4-dibenzyl-4-carboxybutyryl]-S-benzyl-(L)-cysteine methyl ester, 0.60 g of 2-aminopyridine and 1.2 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 25 ml of methylene chloride is stirred at room temperature overnight. The mixture is concentrated, ethyl acetate is added and washed with water, sodium bicarbonate, dried (Na2SO4), filtered and concentrated. The residue is chromatographed on silica gel eluting with ethyl acetatemethylene chloride (1:9) to give N-[4-(2-pyridylamino-carbonyl)-(S,S)-2,4-dibenzylbutyryl]-S-benzyl-(L)-cysteine methyl ester (oil).
Reaction SMILES: C(O)C.[CH3:4][N:5]([CH3:24])[CH:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[C:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(O)[CH2:7]1.N.[Na]>O1CCCC1>[CH3:4][N:5]([CH3:24])[CH:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[CH:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:7]1
Reactant: CN(C)C1CCc2ccccc2C(O)(c2ccccc2)C1
Agent: N
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCO
Product: CN(C)C1CCc2ccccc2C(c2ccccc2)C1
Temperature: -40 °C
Reaction time: 0.33 h

Procedure:
12.4 ml of ethanol and then a solution of 12 g of 7-dimethylamino-5ξ-phenyl-5ξ-hydroxy-6,7,8,9-tetrahydro [5H] benzocycloheptene in 200 ml of tetrahydrofuran were added to 600 ml of condensed ammonia and then 2.46 of sodium were added at -40° C. The mixture was stirred at -40° C for 20 minutes and the ammonia and tetrahydrofuran were evaporated. The residue was dissolved in ethyl acetate and the solution was washed with water, dried and evaporated to dryness. The residue was chromatographed over silica gel and eluted with a 9-1-1 cyclohexane-ethyl acetate-triethylamine mixture to obtain 3.2 g of isomer A (equatorial 5-H) and 6.5 g of isomer B (axial 5-H) of 7-dimethylamino-5-phenyl-6,7,8,9-tetrahydro [5H] benzocycloheptene.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[C:9](CCCCBr)[CH:10]=[CH:11][C:6]=2[O:5][CH2:4][C:3]1=[O:17].[I-].[K+]>CO.C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:10][CH2:11][CH2:6][CH2:7][NH2:2])=[CH:11][C:6]=2[O:5][CH2:4][C:3]1=[O:17]
Reactant: CN1C(=O)COc2ccc(CCCCBr)cc21
Agent: [I-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CN1C(=O)COc2cc(CCCCN)ccc21
Reaction time: 72 h

Procedure:
In a 250 cm3 ground-necked flask, 8.1 g (0.03 mol) of 4-methyl-6-(4-bromobutyl)2,3-dihydro-3-oxo-1,4-benzoxazine and 0.9 g of potassium iodide are dissolved in 120 cm3 of methanol and 30 cm3 of chloroform. A stream of gaseous ammonia is bubbled into the solution to the point of saturation, equivalent to approximately 2.6 g of ammonia, and a reflux condenser is then fitted. The temperature is stabilized at 50° C. with an oil bath and the mixture is left stirring magnetically for 72 hours. After cooling, the reaction mixture is evaporated on a water bath under vacuum. The residue is ground with distilled water acidified with 5% HCl solution, and then drained. The filtrate is recovered, washed with ethyl acetate and then alkalinized with 10% sodium hydroxide solution. It is extracted with chloroform, leaving the 2 phases agitating for 1/2 hour, and the organic phase is washed with distilled water and then dried over calcium chloride. The organic phase is evaporated on a water bath under vacuum, the residue is then taken up in absolute ethanol, a stream of gaseous HCl is bubbled through and the mixture is then evaporated to dryness on a water bath under vacuum. The product is dried and then recrystallized in absolute ethanol.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[S:3]([C:6]1[C:7]([F:17])=[C:8]([F:16])[C:9]([F:15])=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12])(=[O:5])=[O:4].[CH3:19]O>C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:19][O:12][C:11](=[O:13])[C:10]1[CH:14]=[C:6]([S:3](=[O:4])(=[O:5])[N:2]([CH3:18])[CH3:1])[C:7]([F:17])=[C:8]([F:16])[C:9]=1[F:15]
Reactant: CO
Reactant: CN(C)S(=O)(=O)c1cc(C(=O)O)c(F)c(F)c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COC(=O)c1cc(S(=O)(=O)N(C)C)c(F)c(F)c1F
Yield: 10 %

Procedure:
The solid 5-dimethylsulfamoyl-2,3,4-trifluoro-benzoic acid (1.47 g, 0.00519 mol) and p-toluenesulfonic acid catalyst (17.1 mg) were dissolved in methanol (125 ml). The stirring mixture was brought to reflux under a nitrogen atmosphere for 51 hours. The reaction mixture was concentrated in vacuo to give a solid. The product was partitioned between diethyl ether (200 ml) and saturated aqueous potassium carbonate (75 ml). The layers were separated and the organic phase was washed with water (75 ml), brine (75 ml), was dried over anhydrous potassium carbonate, and was concentrated in vacuo to afford 0.15 g of an off-white solid; 10% yield; 1H-NMR (400 MHz; CDCl3) δ 8.23-8.19 (m, 1H), 3.92 (s, 3H), 2.83 (s, 6H); 19F-NMR (376 MHz; CDCl3) δ 120.79 to −121.02 (m), −153.69 to −153.80.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[Br:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]=[O:9].Cl>O1CCCC1>[Br:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]([OH:9])[CH2:1][CH3:2]
Reactant: CC[Mg]Br
Reactant: O=Cc1ccccc1Br
Agent: Cl
Solvent: C1CCOC1
Product: CCC(O)c1ccccc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A solution (1 mol/L, 60 mL) of ethylmagnesium bromide in tetrahydrofuran was added to a solution (200 mL) of 2-bromobenzaldehyde (5.55 g, 3.0 mmol) in tetrahydrofuran under ice-cooling, followed by stirring for 1 hour while gradually heating the mixture to room temperature. Next, the reaction solution was poured into ice water, and this mixture was neutralized with hydrochloric acid (1 mol/L) and then extracted with ethyl acetate. After the extract was washed with a saturated brine and then dried over sodium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developed with ethyl acetate/hexane=1/4) to give 1-(2-bromophenyl)-1-propanol (4.5 g, yield 70%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](SC)[N:5]2[C:10]([C:13]3[O:14][CH:15]=[CH:16][CH:17]=3)=[N:11][N:12]=[C:4]2[CH:3]=1.C1CCN2C(=NCCC2)CC1.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:34][NH2:35]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:35][CH2:34][C:33]2[CH:36]=[CH:37][C:38]([O:39][CH3:40])=[C:31]([O:30][CH3:29])[CH:32]=2)[N:12]2[N:11]=[C:10]([C:13]3[O:14][CH:15]=[CH:16][CH:17]=3)[N:5]=[C:4]2[CH:3]=1
Reactant: COc1ccc(CN)cc1OC
Reactant: CSc1nc(Cl)cc2nnc(-c3ccco3)n12
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(CNc2nc(Cl)cc3nc(-c4ccco4)nn23)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.3 %

Procedure:
Into 600 mL of THF, 50.0 g (188 mmol) of Compound B was dissolved, and 42.0 mL (280 mmol) of DBU was added thereto, followed by stirring at room temperature for about 30 minutes. During the period, crystals were precipitated from the reaction solution. Next, 94 g (563 mmol) of 3,4-dimethoxybenzylamine was added thereto, followed by stirring at 60° C. for about 2 hours. After completion of the reaction, the solvent was evaporated, the residue was diluted with chloroform and washed with water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was triturated with ethyl acetate to obtain 53.2 g of Compound D as a white solid (yield: 74%). The residue obtained by concentrating the solution part present after trituration was purified by silica gel column chromatography (hexane/ethyl acetate=7/3) to additionally recover Compound D in about 10% yield.
Reaction SMILES: O1C2([CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[C:15]([OH:17])[N:14]4[N:18]=[CH:19][CH:20]=[C:13]4[N:12]=3)[CH2:7][CH2:6]2)OCC1.C(OC(=O)CC(C1CC[N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])CC1)=O)C.O=C(C1CCC2(OCCO2)CC1)CC(OCC)=O>>[OH:17][C:15]1[N:14]2[N:18]=[CH:19][CH:20]=[C:13]2[N:12]=[C:11]([CH:8]2[CH2:7][CH2:6][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:10][CH2:9]2)[CH:16]=1
Reactant: CCOC(=O)CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Oc1cc(C2CCC3(CC2)OCCO3)nc2ccnn12
Agent: CCOC(=O)CC(=O)C1CCC2(CC1)OCCO2
Product: CC(C)(C)OC(=O)N1CCC(c2cc(O)n3nccc3n2)CC1

Procedure:
tert-Butyl 4-(7-hydroxypyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate was synthesized in a manner similar to the synthesis of 5-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazolo[1,5-a]pyrimidin-7-ol, but with tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate substituted for ethyl 3-oxo-3-(1,4-dioxaspiro[4.5]decan-8-yl)propanoate.
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[N:17]([CH3:18])[CH:16]=[N:15][C:14]=1[C:19]([NH2:21])=[O:20])=[S:11])(=O)C1C=CC=CC=1.CC(C)=O.CO.C(=O)([O-])[O-].[K+].[K+]>O.C(O)(=O)C>[CH3:18][N:17]1[C:13]([NH:12][C:10](=[S:11])[NH2:9])=[C:14]([C:19]([NH2:21])=[O:20])[N:15]=[CH:16]1
Reactant: Cn1cnc(C(N)=O)c1NC(=S)NC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: Cn1cnc(C(N)=O)c1NC(N)=S
Yield: 96.9 %

Procedure:
5-(N'-benzoylthiocarbamoyl)amino-1-methyl-1H-imidazole-4-carboxamide (12.1 g, 40 mM) was added to a mixture of acetone and methanol (1:1) (200 ml). Potassium carbonate 2.8 g, 20 mM) dissolved in water (12 ml) was added. The reaction mixture was refluxed under N2 for 6 hours whereafter acetic acid (2.9 g, 48 mM) was added. After stirring in an ice bath the product was filtered off, washed and dried. Hereby was isolated 7.7 g (96%) of the title compound as a white powder, mp. 270°-274° C. (dec.) (the conversion begins at about 220° C.).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[N:39]1([CH2:45][CH2:46][CH:47]([OH:50])[CH2:48][OH:49])[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:42]3[CH2:41][CH2:40][N:39]([CH2:45][CH2:46][CH:47]([OH:50])[CH2:48][OH:49])[CH2:44][CH2:43]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: OCC(O)CCN1CCNCC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCC(O)CO)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 4-piperazin-1-yl-butane-1,2-diol hydrochloride to give the title compound. HR-MS (ES, m/z) calculated for C37H48Cl2N5O4 [(M+H)+] 696.3078, observed 696.3074.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([C:25](=[O:27])[CH3:26])[CH2:7][C:8]3[CH:15]=[CH:14][C:13](B4OC(C)(C)C(C)(C)O4)=[CH:12][C:9]=3[CH2:10][CH2:11][C:4]=2[CH:3]=1.Br[C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33]([NH2:35])=[O:34].C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:25]([N:6]1[CH2:7][C:8]2[CH:15]=[CH:14][C:13]([C:31]3[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=3[C:33]([NH2:35])=[O:34])=[CH:12][C:9]=2[CH2:10][CH2:11][C:4]2[CH:3]=[C:2]([Cl:1])[CH:29]=[CH:28][C:5]1=2)(=[O:27])[CH3:26]
Reactant: NC(=O)c1ccccc1Br
Reactant: CC(=O)N1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2CCc2cc(Cl)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(=O)N1Cc2ccc(-c3ccccc3C(N)=O)cc2CCc2cc(Cl)ccc21
Temperature: 80 °C
Yield: 57.6 %

Procedure:
A 2 mL conical vial was charged with Example 22B (10 mg, 0.024 mmol), 2-bromo-benzamide (7 mg, 0.036 mmol) and Pd(PPh3)4 (3 mg). The vial was evacuated and purged with argon. EtOH (0.5 mL) and toluene (0.5 mL) were added, followed by 2M aqueous Na2CO3 (0.036 mL, 0.072 mmol). The reaction was heated to 80° C. until disappearance of the starting material was noted. The reaction was cooled to room temperature and concentrated. The product was purified by reversed-phase HPLC to afford 2-(5-Acetyl-2-chloro-5,6,11,12-tetrahydro-dibenzo[b,f]azocin-9-yl)-benzamide (5.6 mg, 58%). HPLC Rt=1.62(b) min. m/z=405 (M+H+).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].Cl[C:7]1[S:8][C:9]([N+:13]([O-:15])=[O:14])=[C:10]([Cl:12])[N:11]=1>O1CCOCC1>[CH2:1]([N:3]([CH2:4][CH3:5])[C:7]1[S:8][C:9]([N+:13]([O-:15])=[O:14])=[C:10]([Cl:12])[N:11]=1)[CH3:2]
Reactant: CCNCC
Reactant: O=[N+]([O-])c1sc(Cl)nc1Cl
Solvent: C1COCCO1
Product: CCN(CC)c1nc(Cl)c([N+](=O)[O-])s1
Reaction time: 8 h
Yield: 91.6 %

Procedure:
146 g (2 mols) of diethylamine are added dropwise to a solution of 199 g (1 mol) of 2,4-dichloro-5-nitrothiazole in 1 l of dioxane at 20° C. to 30° C. in the course of about 2 hours. After the mixture has been left to stand overnight at room temperature, it is stirred in 8 l of icewater and the precipitate is filtered off, washed with water and dried. 216 g (91.7% of theory) of 2-diethylamino-4-chloro-5-nitrothiazole of melting point 85° C. (from cyclohexane) are obtained.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([O:19][C:20]([C:22]1[C:26]([CH2:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[C:25]([CH:37]=O)[NH:24][C:23]=1[CH3:39])=[O:21])[CH3:18].N1CCCCC1>C(O)C>[CH2:17]([O:19][C:20]([C:22]1[C:26]([CH2:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[C:25]([CH:37]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[NH:11][C:10]2=[O:16])[NH:24][C:23]=1[CH3:39])=[O:21])[CH3:18]
Reactant: CCOC(=O)c1c(C)[nH]c(C=O)c1CCCN1CCN(C)CC1
Reactant: O=C1Cc2c(cccc2-c2ccccc2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4ccccc4)c32)c1CCCN1CCN(C)CC1
Temperature: 70 °C
Yield: 29.3 %

Procedure:
To a solution of 4-phenyl-1,3-dihydro-indol-2-one (41.9 mg, 0.20 mmol) and 5-formyl-2-methyl-4-[3-(4-methyl-piperazin-1-yl)-propyl]-1H-pyrrole-3-carboxylic acid ethyl ester (64.2 mg, 0.20 mmol) in ethanol (1 mL) was added piperidine (0.1 mL). The reaction mixture was stirred at 70° C. for over-night. The solvent was evaporated and the residue was purified on a silica gel column eluting with MeOH—CH2CL2 1:9 to provide 2-methyl-4-[3-(4-methyl-piperazin-1-yl)-propyl]-5-(2-oxo-4-phenyl-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrole-3-carboxylic acid ethyl ester as a yellow solid (30 mg, 29%).
Reaction SMILES: [C:1]([C:5]1[C:6]([N+:19]([O-])=O)=[CH:7][C:8]([N+]([O-])=O)=[C:9](/[CH:11]=[CH:12]/[N:13](C)C)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].O.O.[Sn](Cl)Cl>C(O)C>[C:1]([C:5]1[CH:10]=[C:9]2[C:8](=[CH:7][C:6]=1[NH2:19])[NH:13][CH:12]=[CH:11]2)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)/C=C/c1cc(C(C)(C)C)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc2cc[nH]c2cc1N
Temperature: 25 °C
Yield: 11.8 %

Procedure:
A solution of (E)-2-(5-tert-butyl-2,4-dinitrophenyl)-N,N-dimethylethenamine (5.3 g, 18 mmol) and tin (II) chloride dihydrate (37 g, 0.18 mol) in ethanol (200 mL) was heated at reflux overnight. The mixture was cooled to room temperature and the solvent was removed under vacuum. The residual slurry was diluted with water (500 mL) and was basifed with 10% aq. Na2CO3 to pH 8. The resulting suspension was extracted with ethyl acetate (3×100 mL). The ethyl acetate extract was washed with water and brine, dried over Na2SO4, and concentrated. The residual solid was washed with CH2Cl2 to afford a yellow powder, which was purified by column chromatography to give 5-tert-butyl-1H-indol-6-amine (0.40 g, 12%). 1H NMR (DMSO, d6) δ 10.34 (br s, 1H), 7.23 (s, 1H), 6.92 (s, 1H), 6.65 (s, 1H), 6.14 (s, 1H), 4.43 (br s, 2H), 2.48 (s, 9H); MS (ESI) m/e (M+H+) 189.1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][O:7]2)[CH2:3][CH2:2]1.[CH:15]12[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH:16]1[N:25]=[C:26]=[O:27])[CH2:22]2>>[CH:17]12[CH2:23][CH:21]3[CH2:20][CH:19]([CH2:24][CH:15]([CH2:22]3)[CH:16]1[NH:25][C:26]([N:1]1[CH2:6][CH2:5][C:4]3([C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH2:8][O:7]3)[CH2:3][CH2:2]1)=[O:27])[CH2:18]2
Reactant: O=C=NC1C2CC3CC(C2)CC1C3
Reactant: c1ccc2c(c1)COC21CCNCC1
Product: O=C(NC1C2CC3CC(C2)CC1C3)N1CCC2(CC1)OCc1ccccc12

Procedure:
The title compound was prepared from 3H-spiro[isobenzofuran-1,4′-piperidine] following a procedure analogous to that described in Example 79 Step 2 using 2-adamantyl isocyanate in place of 2-adamantyl chloroformate. LC-MS Method 1 tR=2.03 min, m/z=367; 1H NMR (CDCl3) δ=1.60-2.00 (18H), 3.29 (m, 2H), 3.94 (m, 2H), 3.99 (s, 1H), 4.95 (1H), 5.08 (s, 2H), 7.05-7.35 (4H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:17](=[O:18])[NH:16][C:11]3=[N:12][CH:13]=[CH:14][N:15]=[C:10]3[C:9]=2[O:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:6][CH:5]=[C:4]([Cl:26])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:33][CH:34]([F:37])[CH2:35]Br>CN(C)C=O.C(OCC)(=O)C.O>[Cl:1][C:2]1[C:7]([C:8]2[C:17](=[O:18])[N:16]([CH2:35][CH:34]([F:37])[F:33])[C:11]3=[N:12][CH:13]=[CH:14][N:15]=[C:10]3[C:9]=2[O:19][C:20](=[O:25])[C:21]([CH3:22])([CH3:23])[CH3:24])=[CH:6][CH:5]=[C:4]([Cl:26])[N:3]=1
Reactant: FC(F)CBr
Reactant: CC(C)(C)C(=O)Oc1c(-c2ccc(Cl)nc2Cl)c(=O)[nH]c2nccnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)C(=O)Oc1c(-c2ccc(Cl)nc2Cl)c(=O)n(CC(F)F)c2nccnc12
Temperature: 120 °C

Procedure:
To s suspension of 2,2-dimethyl-propionic acid 7-(2,6-dichloro-pyrid-3-yl)-6-oxo-5,6-dihydro-pyrido[2,3-b]pyrazin-8-yl ester (Example 1.7) (0.064 g) in dry N,N-dimethylformamide (3 ml) was added successively potassium carbonate (0.068 g) and difluoro-ethyl bromide (0.063 g). The reaction mixture was heated in a microwave for 20 minutes at 120° C. The reaction mixture was cooled to ambient temperature, and then diluted with ethyl acetate and water. The phases were separated and organic phase was washed with water and brine, dried over magnesium sulfate, and concentrated to give Compound No. A16 of Table A as a pale yellow solid (0.006 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4]C(C#N)=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:22])[C:15]([O:17]C(C)(C)C)=[O:16])[C:10](=[O:23])[CH:9]=2)[CH:7]=1.[C:26](O)([C:28]([F:31])([F:30])[F:29])=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:26]([C:28]([F:31])([F:30])[F:29])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:22])[C:15]([OH:17])=[O:16])[C:10](=[O:23])[CH:9]=2)[CH:7]=1
Reactant: CC(C(=O)OC(C)(C)C)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: O=C(O)C(F)(F)F
Product: CC(C(=O)O)n1ccc(-c2cc(Cl)ccc2C(F)(F)F)cc1=O

Procedure:
2.3 g (purity 91%, 5.2 mmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoate (racemate) were hydrolysed with TFA according to General Method 6A. Yield: 2.6 g (purity 93%, quant.)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][CH:26]=[CH:25][C:4]=1[CH2:5][NH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12](/[CH:17]=[CH:18]/[C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH:13]=2)[N:8]=1.[H][H]>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][CH:26]=[CH:25][C:4]=1[CH2:5][NH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:17][CH2:18][C:19]3[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=3)[CH:13]=2)[N:8]=1
Reactant: COc1ccccc1CNc1ccc2cc(/C=C/c3ccncc3)ccc2n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1ccccc1CNc1ccc2cc(CCc3ccncc3)ccc2n1

Procedure:
(2-Methoxy-benzyl)-[6-((E)-2-pyridin-4-yl-vinyl)-quinolin-2-yl]-amine (example 2, 51 mg, 0.139 mmol) was dissolved in 20 mL ethanol. Palladium on charcoal (10%, 15 mg, 0.014 mmol) was added and the reaction mixture war hydrogenated with a hydrogen balloon overnight. The palladium was filtered off and the solvent was evaporated. The title compound was obtained as a yellow oil (40 mg, 78%), MS: m/e=370.1 (M+H+).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[CH:20][CH:19]=[CH:18]2)(=[O:11])=[O:10].N(OC(C)(C)C)=O.CC(O)=O>C1COCC1>[CH3:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[C:14]1[C:13](=[C:22]3[C:17](=[CH:16][CH:15]=1)[CH:18]=[CH:19][CH:20]=[N:21]3)[NH:12][S:9]2(=[O:10])=[O:11]
Reactant: Cc1ccc(N)c(S(=O)(=O)Nc2cccc3cccnc23)c1
Agent: CC(C)(C)ON=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)S(=O)(=O)Nc1c-2ccc2cccnc12
Yield: 13.2 %

Procedure:
In a similar fashion using route 16 general procedure 61, 2-amino-5-methyl-N-quinolin-8-yl-benzenesulfonamide (Intermediate 296) (160 mg, 0.51 mmol), t-butyl nitrite (80 mg, 0.76 mmol), AcOH (1.6 ml) and THF (1.6 ml) gave the title compound (20 mg, 13%) after purification by column chromatography with n-hexane/DCM (1:1) as the eluent.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:20])[N:9]2[C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])[N:3]=1.[NH2:28][CH:29]1[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]1>>[Cl:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:4]1[N:3]=[C:2]([NH:28][CH:29]2[CH2:30][CH2:31][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:33][CH2:34]2)[CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:20])[N:9]2[C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:19]
Reactant: O=c1ccc2c(-c3ccccc3Cl)nc(Br)cc2n1-c1c(Cl)cccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc3c(ccc(=O)n3-c3c(Cl)cccc3Cl)c(-c3ccccc3Cl)n2)CC1

Procedure:
The title compound was prepared from 50 mg of 7-bromo-5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-1,6-naphthyridin-2(1H)-one (COMPOUND HHH2) and 63 mg of tert-butyl 4-aminopiperidine-1-carboxylate by a procedure analogous to that described in COMPOUND HHH4. Mass spectrum (ESI) 599 (M+1).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[O:9][CH2:8][CH2:7][O:6]1.[C-:10]#[N:11].[Na+]>CS(C)=O>[C:10]([CH2:2][CH2:3][CH2:4][CH:5]1[O:9][CH2:8][CH2:7][O:6]1)#[N:11]
Reactant: ClCCCC1OCCO1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCCCC1OCCO1
Temperature: 80 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
In a flame dried flask fitted with a nitrogen inlet, magnetic stirrer, and oil bath was dissolved the 2-(3-chloropropyl)-1,3-dioxolane (25.4 g, 169 mmol) in 70 ml of dimethylsulfoxide. Sodium cyanide (9.1 g, 186 mmol) in 100 ml of dimethylsulfoxide was added and the mixture was heated to 80° C. for 18 hours. The reaction was cooled to room temperature then poured onto ice water and stirred for 1 hour. The mixture was extracted thoroughly with diethyl ether, testing the aqueous after each extraction by TLC for the presence of product. The ether was washed with brine, dried over sodium sulfate, and concentrated in vacuo to give a colorless oil. The oil was purified by silica gel chromatography (50/50 ethyl acetate/hexane) to give 19.2 g of product. (80.7%).