Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C@@H:3]([C:5]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:7]([F:14])[C:6]=1[F:15])[OH:4].C([SnH](CCCC)CCCC)CCC.CC(N=NC(C#N)(C)C)(C#N)C>>[F:11][C:10]1[C:5]([C@@H:3]([OH:4])[CH3:2])=[C:6]([F:15])[C:7]([F:14])=[C:8]([F:13])[C:9]=1[F:12]
Reactant: O[C@@H](CCl)c1c(F)c(F)c(F)c(F)c1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Product: C[C@H](O)c1c(F)c(F)c(F)c(F)c1F
Temperature: 80 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
A mixture of 1.23 g of (R)-(-)-2-chloro-1-(pentafluorophenyl)ethanol obtained in Example 8, 1.60 ml of tributyltin hydride, and 16 mg of AIBN was stirred for eight hours at 80° C. After completion of reaction, the reaction mixture was purified by silica gel column chromatography to give 0.7 g of (S)-(-)-1-(pentafluorophenyl)-ethanol.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[C:4]#N.CC(C[AlH]CC(C)C)C.C1C[O:23]CC1>>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH:4]=[O:23]
Reactant: C1CCOC1
Reactant: Cc1cccc(C)c1C#N
Agent: CC(C)C[AlH]CC(C)C
Product: Cc1cccc(C)c1C=O
Reaction time: 3 h

Procedure:
To a stirred solution of 2,6-dimethylbenzonitrile (1 g, 7.6 mmol) in THF (15 mL) under argon at 0° C. a solution of DIBAL (1 M in THF, 8 mL, 8 mmol) was added dropwise over 5 minutes. After 3 hr at 0° C., the reaction mixture was brought to room temperature and stirred overnight. The reaction was quenched with 5% sulfuric acid at 0° C., extracted with ether, washed with brine and dried (MgSO4). Concentration provided 2,6-dimethylbenzaldehyde (0.9 g) which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[N:14]=[CH:15][C:16]([C:17]([OH:19])=O)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]([S:27]([NH2:30])(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1>>[S:27]([C:23]1[CH:22]=[C:21]([NH:20][C:17]([C:16]2[CH:15]=[N:14][N:11]3[CH:12]=[CH:13][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[N:9][C:10]=23)=[O:19])[CH:26]=[CH:25][CH:24]=1)(=[O:28])(=[O:29])[NH2:30]
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: O=C(O)c1cnn2ccc(-c3ccc(Cl)cc3)nc12
Product: NS(=O)(=O)c1cccc(NC(=O)c2cnn3ccc(-c4ccc(Cl)cc4)nc23)c1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.22) and 3-amino-benzenesulfonamide according to general procedure II. Pale-yellow solid. MS (ISP) 428.3 [(M+H)+]; mp 345° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@@H:6]([C:8]([OH:10])=[O:9])[CH3:7])=[O:4].[C:11]1(=[O:34])[N:15]([N:16]([C:21](=[O:32])[CH2:22][S:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:17][C:18]([O-:20])=[O:19])[C:14](=[O:33])[CH2:13][CH2:12]1>O.C(O)C>[C:14]1(=[O:33])[N:15]([N:16]([C:21](=[O:32])[CH2:22][S:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:17][C:18]([O-:20])=[O:19])[C:11](=[O:34])[CH2:12][CH2:13]1.[C:24]([S:23][CH2:22][C:21]([NH:1][CH2:2][C:3]([NH:5][C@@H:6]([C:8]([OH:10])=[O:9])[CH3:7])=[O:4])=[O:32])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C[C@@H](NC(=O)CN)C(=O)O
Agent: O=C([O-])CN(C(=O)CSC(=O)c1ccccc1)N1C(=O)CCC1=O
Solvent: O
Solvent: CCO
Product: C[C@@H](NC(=O)CNC(=O)CSC(=O)c1ccccc1)C(=O)O
Temperature: 70 °C
Yield: 31.6 %

Procedure:
Succinimidyl-N-(S-benzoylmercaptoacetyl)glycinate is prepared according to the method described by R. F. Schneider et al, Journal of Nuclear Medicine 25 (2), 223-229 (1984). Glycyl-D-alanine in an amount of 250 mg is dissolved in 15 ml of water and the mixture is heated to 70° C. on a water bath. Meanwhile, 1 g of succinimidyl-N-(S-benzoylmercaptoacetyl)glycinate is dissolved in 40 ml of ethanol and the mixture is heated to 70° C. on a water bath. The solution of glycyl-D-alanine in water is added at once to the said ethanolic solution while stirring magnetically. The mixture is then refluxed for 1 hour. After cooling, the solution is evaporated to dryness under reduced pressure. The solid residue is shaken five times with 15 ml of acetone which is each time filtered off. Benzoylmercaptoacetylglycyl-D-alanine is precipitated from the collected filtrates by the addition of diethylether. The precipiate is filtered off and dried in vacuo over phosphorous pentoxide. In this manner 174 mg (yield 31.6%) of benzoylmercaptoacetylglycyl-D-alanine are obtained as a white crystalline powder.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][N:9]([CH2:11][C:12]1[S:16][C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[C:24]([C:26]([NH2:28])=[O:27])[CH:25]=2)[NH:22][CH:21]=[C:20]3[CH:29]2[CH2:34][CH2:33][N:32]([S:35]([CH2:38][CH3:39])(=[O:37])=[O:36])[CH2:31][CH2:30]2)=[CH:14][CH:13]=1)C.CNC>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:38]([S:35]([N:32]1[CH2:31][CH2:30][CH:29]([C:20]2[C:19]3[C:23](=[C:24]([C:26]([NH2:28])=[O:27])[CH:25]=[C:17]([C:15]4[S:16][C:12]([CH2:11][NH:9][CH2:8][CH2:2][CH3:3])=[CH:13][CH:14]=4)[CH:18]=3)[NH:22][CH:21]=2)[CH2:34][CH2:33]1)(=[O:36])=[O:37])[CH3:39]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CN(C)C)s4)cc23)CC1
Agent: CNC
Solvent: O=C(O)C(F)(F)F
Product: CCCNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Yield: 16.4 %

Procedure:
The title compound was prepared according to the general procedure of 5-{5-[(dimethylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting propylamine (0.064 mL, 0.90 mmol) for 2M dimethylamine to afford 8.9 mg of the title compound (16.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[CH3:32][NH:33][C:34](=[O:42])[CH2:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:39]5[CH2:38][CH2:37][N:36]([CH2:35][C:34]([NH:33][CH3:32])=[O:42])[CH2:41][CH2:40]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:29])[F:30])[CH:3]=1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CNC(=O)CN1CCNCC1
Product: CNC(=O)CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CC1

Procedure:
2-(4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperazin-1-yl)-N-methyl-acetamide was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and N-methyl-2-piperazin-1-yl-acetamide following General Procedure C.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:8][CH2:9][CH2:10][OH:11])[C:4]([CH3:7])=[CH:5][CH:6]=1.[H-].[Na+].Cl[C:15]1[CH:20]=[C:19]([C:21]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:22])[CH:18]=[CH:17][N:16]=1>COCCOC>[CH3:1][C:2]1[N:3]([CH2:8][CH2:9][CH2:10][O:11][C:17]2[CH:18]=[C:19]([C:21]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:22])[CH:20]=[CH:15][N:16]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: Cc1ccc(C)n1CCCO
Reactant: O=C(c1ccnc(Cl)c1)N1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccc(C)n1CCCOc1cc(C(=O)N2CCCCC2)ccn1
Yield: 102.5 %

Procedure:
To a suspension of 0.047 mol of 2.5-dimethyl-1-(3-hydroxypropyl)pyrrole and 0.059 mol of 80% sodium hydride in 150 ml of 1,2-dimethoxyethane, previously heated at reflux for 15 minutes and cooled, is added 0.044 mol of 2-chloro-4-piperidino carbonylpyridine, then the reaction mixture is heated two hours with reflux and evaporated to dryness. The residue is taken up with water and extracted with ethyl acetate. The organic phase is separated and evaporated to dryness. Thus, 15.4 g of an oily product are obtained.
Reaction SMILES: CN(C)C1CC2C(=CC=C(NC(=O)C)C=2)C1.[CH3:17][N:18]([CH3:35])[CH:19]1[CH2:27][C:26]2[C:21](=[CH:22][C:23]([N+:32]([O-:34])=[O:33])=[C:24]([NH:28]C(=O)C)[CH:25]=2)[CH2:20]1.CN(C)C1CC2C(=CC=C(NC(=O)C)C=2[N+]([O-])=O)C1.C(N)(=O)C>C(O)(C(F)(F)F)=O.CCO.[CH]Cl>[CH3:17][N:18]([CH3:35])[CH:19]1[CH2:27][C:26]2[C:21](=[CH:22][C:23]([N+:32]([O-:34])=[O:33])=[C:24]([NH2:28])[CH:25]=2)[CH2:20]1
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])CC(N(C)C)C2
Agent: CC(=O)Nc1ccc2c(c1)CC(N(C)C)C2
Agent: CC(=O)Nc1ccc2c(c1[N+](=O)[O-])CC(N(C)C)C2
Agent: CC(N)=O
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C1Cc2cc(N)c([N+](=O)[O-])cc2C1
Temperature: 20 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
A solution of cHNO3 (70%, 13.4 mL, 211 mmol) in TFA (15 mL) was added dropwise to a stirred solution of acetamide 109 (15.38 g, 70.5 mmol) in TFA (120 mL) and the solution stirred at 20° C. for 16 h. The solution was poured into ice/water (1.2 L) and the pH adjusted to 10 with cNH3. The mixture was extracted with DCM (4×150 mL), the combined organic fraction dried and the solvent evaporated. The residue was filtered through a short column of silica, eluting with a gradient (0-15%) of MeOH/DCM, to give a 6:1 mixture of N-[2-(dimethylamino)-6-nitro-2,3-dihydro-1H-inden-5-yl]acetamide and N-[2-(dimethylamino)-4-nitro-2,3-dihydro-1H-inden-5-yl]acetamide (16.7 g, 90%). A solution of the acetamide mixture (16.7 g, 63.4 mmol) in EtOH (300 mL) and cHCl (70 mL) was stirred at reflux temperature for 4 h. The mixture was cooled and the EtOH evaporated. The mixture was diluted with water (200 mL) and the pH adjusted to 9 with cNH3. The precipitate was filtered, washed with water (40 mL), dried and recrystallised from EtOAc/pet. ether to give pure 6-nitroaniline 110 (8.12 g, 52%) as a red solid: mp 19-121° C.; 1H NMR δ 7.91 (s, 1H, H-7), 6.61 (s, 1H, H-4), 6.00 (br s, 2H, NH2), 2.95-3.06 (m, 3H, H-2, CH2), 2.74-2.84 (m, 2H, CH2), 2.29 [s, 6H, N(CH3)2]; 13C NMR δ 151.8, 144.4, 131.6, 131.4, 121.0, 113.6, 67.8, 43.8 (2), 37.9, 36.2. Anal. calcd for C11H15N3O2: C, 59.7; H, 6.8; N, 19.0. Found: C, 59.5; H, 6.9; N, 18.9%.
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Br[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:19][CH:18]=1>C(O)C>[CH:23](/[C:20]1[CH:19]=[CH:18][C:17]([O:16][CH2:15][CH2:14][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])=[CH:22][CH:21]=1)=[CH:24]/[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCCCCCCCC/C=C\c1ccc(OCCBr)cc1
Agent: [Na]
Solvent: CCO
Product: CCCCCCCCC/C=C\c1ccc(OCCC(C(=O)OCC)C(=O)OCC)cc1
Yield: 125.6 %

Procedure:
A solution of sodium (0.408 g, 17.7 mmol) in ethanol (50 ml) under nitrogen was treated with diethyl malonate, (2.84 g, 17.7 mmol) followed by 1-bromo-2-(4-[(Z)1-undecenyl]phenoxy)ethane, (1.30 g, 3.68 mmol). The solution was refluxed 30 h, then cooled and evaporated in vacuo to dryness. The residue was partitioned between ethyl acetate and water and the organic phase separated, washed with water, and dried, (MgSO4). Evaporation in vacuo gave 2.0 g of a yellow oil which was purified by column chromatography using silica gel, eluting with dichloromethane: n-hexane, [2:3] to yield 510 mg (32%) of the title compound as a colourless oil. νmax (film) 1510, 1570 (weak) 1608, 1735, 1753 cm-1 δ(CDCl3) 0.84 (3H, distorted t, terminal CH3), 1.25 (3H, t, J 7 Hz ester CH3), 1.25 (14H, m, (CH2 )7), 2.31 (4H, m, OCH2CH2, allylic CH2), 3.63 (1H, t, J 7 Hz, CH(CO2Et)2), 4.01 (2H, t, J 7 Hz, OCH2), 4.18 (4H, q, J 7 Hz, ester CH2), 5.54 (1H, d.t, Jd 12 Hz, Jt 7 Hz, =CH--alkyl), 6.31 (1H, d, J 12 Hz, ArCH=), 7.02 (4H, ABq, Δν 34 Hz, J 9 Hz, C6H4).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(=NC1CCCCC1)C.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[C:26]([CH3:29])[CH:27]=O)=[CH:21][CH:20]=1.[O:37]1CC[CH2:39][CH2:38]1>>[F:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[C:26]([CH3:29])[CH:27]=[CH:39][CH:38]=[O:37])=[CH:23][CH:24]=1
Reactant: C1CCOC1
Reactant: CC(C=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: CC(C)[N-]C(C)C
Agent: CC=NC1CCCCC1
Agent: [Li+]
Product: CC(C=CC=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 4 h

Procedure:
Lithium diisopropylamide (13 mL of 1.84M solution, 24 mmol) was added to N-ethylidenecyclohexanamine (12 mL of 2M solution, 24 mmol) in tetrahydrofuran at -40° C. After stirring for 30 minutes 3,3-bis(4-fluorophenyl)-2-methylpropenal (2.1 g, 8.1 mmol) was added and the solution stirred for 4 hours during which time the temperature was allowed to rise to -15° C. The solution was quenched with 2N hydrochloric acid and the mixture extracted with diethyl ether. The extracts were dried with magnesium sulfate and concentrated in vacuo. The residue was stirred for 16 hours with a mixture of 100 mL benzene, 65 mL acetic acid and 35 mL of water. The mixture was diluted to 500 mL with water and the aqueous layer was separated and extracted with diethyl ether. The combined organic solution was washed with saturated sodium bicarbonate and water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica eluting with 1% ethyl acetate in hexane to give after hexane crystallization 1.5 g of the title compound; m.p. =86°-88° C.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[S:3])[NH2:2].[F:14][C:15]([F:28])([F:27])[O:16][C:17]1[CH:26]=[CH:25][C:20]([C:21](=O)[CH2:22]Br)=[CH:19][CH:18]=1>>[F:14][C:15]([F:27])([F:28])[O:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]2[N:2]=[C:1]([C:4]3[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=3)[S:3][CH:22]=2)=[CH:25][CH:26]=1
Reactant: COC(=O)c1ccc(C(N)=S)cc1
Reactant: O=C(CBr)c1ccc(OC(F)(F)F)cc1
Product: COC(=O)c1ccc(-c2nc(-c3ccc(OC(F)(F)F)cc3)cs2)cc1
Yield: 60 %

Procedure:
In the same manner as in Example 28, methyl 4-thiocarbamoylbenzoate was reacted with 4-trifluoromethoxyphenacyl bromide to obtain methyl 4-[4-(4-trifluoromethoxyphenyl)-2-thiazolyl]benzoate. The product was recrystallized from ethanol. Yield: 60%. Pale yellow prisms. Melting point: 138 to 139° C.
Reaction SMILES: [CH:1]([C:3]1[N:4]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[N:7]=1)=[O:2].[BH4-].[Na+]>CO>[OH:2][CH2:1][C:3]1[N:4]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:17])([CH3:19])[CH3:18])[CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[N:7]=1
Reactant: COC(=O)c1cn(COCC[Si](C)(C)C)c(C=O)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cn(COCC[Si](C)(C)C)c(CO)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Into a flask containing a solution of methyl 2-formyl-1-((2-(trimethylsilyl)-ethoxy)-methyl)-1H-imidazole-4-carboxylate (3 g, 10.5 mmol) in MeOH (20 ml), NaBH4 (0.401 g, 10.5 mmol) was added in portions at 0° C. The resulting mixture was allowed to stir at 0° C. for 30 min followed by RT for 1 hour. The reaction mixture was concentrated and the crude was diluted with water and extracted with EtOAc. The organic layer was concentrated under reduced pressure. Yield 1.5 g. LC-MS: [M+1]=287.17.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:15][C@@H:14]([CH2:16][OH:17])[O:13][C:12]3=[O:18])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C(OC1C(OC(=O)C)=C(I)C=CC=1)(=[O:21])C.CC1(C)N([O])C(C)(C)CCC1.C([O-])([O-])=O.[Na+].[Na+]>CC(=O)OCC.O.CC#N>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:15][C@@H:14]([C:16]([OH:21])=[O:17])[O:13][C:12]3=[O:18])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=C1O[C@H](CO)CN1c1ccc2c(c1)OCCO2
Reactant: CC(=O)Oc1cccc(I)c1OC(C)=O
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(O)[C@@H]1CN(c2ccc3c(c2)OCCO3)C(=O)O1
Temperature: 0 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
To a solution of (S)-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-5-hydroxymethyl-oxazolidin-2-one (985 mg, 3.92 mmol) in 1:1 water/MeCN (20 mL) cooled to 0° C. was added diacetoxyiodobenzene (2.83 g, 2.2 eq.) and TEMPO (122 mg, 0.2 eq). The mixture was stirred at 0° C. for 30 min and at rt overnight. EA and sat. Na2CO3 were added and the phases were separated. The aq. layer was washed once more with EA and then carefully acidified with 1M HCl. The water phase was then extracted twice with EA. The combined org. layers were washed with brine and dried over MgSO4 and concentrated to afford the title intermediate as a colourless solid (847 mg, 81% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[C:6]([C:18]([OH:20])=O)=[CH:5]2.[NH2:21][C:22]1[CH:23]=[N:24][C:25]([N:29]([CH3:31])[CH3:30])=[C:26]([CH3:28])[CH:27]=1>>[CH3:30][N:29]([CH3:31])[C:25]1[N:24]=[CH:23][C:22]([NH:21][C:18]([C:6]2[N:7]([CH2:11][C:12]3[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=3)[C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)=[O:20])=[CH:27][C:26]=1[CH3:28]
Reactant: Cc1cc(N)cnc1N(C)C
Reactant: O=C(O)c1cc2cc(F)ccc2n1Cc1ccncc1
Product: Cc1cc(NC(=O)c2cc3cc(F)ccc3n2Cc2ccncc2)cnc1N(C)C

Procedure:
Compound No. 19 is prepared from 5-fluoro-1-(pyridin-4-ylmethyl)-1H-indole-2-carboxylic acid, synthesized in stage 5.1, and 3-amino-5-methyl-6-(dimethylamino)pyridine (GB 870 027) according to a process similar to that described in example No. 3.
Reaction SMILES: I[C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]([CH3:11])[C:3]=1[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1.[Cl-].[NH4+]>C1(C)C=CC=CC=1.C(O)C>[CH3:11][N:4]1[C:5]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[C:2]([C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([C:25]([F:36])([F:35])[F:24])[CH:31]=2)=[C:3]1[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: Cn1c(-c2ccncc2)c(I)c2ncccc21
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cn1c(-c2ccncc2)c(-c2cccc(C(F)(F)F)c2)c2ncccc21
Temperature: 80 °C
Yield: 50.8 %

Procedure:
To a solution of 130 mg (0.39 mmoles) of 3-Iodo-1-methyl-2-pyridin-4-yl-1H-pyrrolo[3,2-b]pyridine in 5 mL of toluene under nitrogen is added a 1 mL of a 2N solution of sodium carbonate, 78 mg (0.4 mmole) of 3-trifluoromethyl phenylboronic acid and 1 mL of ethanol. To the reaction mixture is finally added 24 mg of tetrakistriphenylphosphine palladium before heating at 80° C. for 10 hours. The cooled reaction mixture is then poured into ammonium chloride solution and extracted with ethyl acetate. The organic phase is washed with water and dried over magnesium sulfate. The solid residue after concentration is recrystallized into hexane to afford 70 mg of 1-Methyl-2-pyridin-4-yl-3-(3-trifluoromethyl-phenyl)-1H-pyrrolo[3,2-b]pyridine as white crystals.
Reaction SMILES: [CH3:1][NH:2][C:3]1([C:6]([O:8][CH3:9])=[O:7])[CH2:5][CH2:4]1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[C:27]1([CH2:33][O:34][C:35]([NH:37][CH2:38][C:39](O)=[O:40])=[O:36])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:1][N:2]([C:39](=[O:40])[CH2:38][NH:37][C:35]([O:34][CH2:33][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:36])[C:3]1([C:6]([O:8][CH3:9])=[O:7])[CH2:5][CH2:4]1
Reactant: CNC1(C(=O)OC)CC1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)C1(N(C)C(=O)CNC(=O)OCc2ccccc2)CC1
Reaction time: 8 h
Yield: 96.4 %

Procedure:
To a solution of methyl 1-(methylamino)cyclopropanecarboxylate (1.53 g, 11.85 mmol) and HOBt (1.920 g, 14.21 mmol) in CH2Cl2 (30 mL) was added 4-methylmorpholine (5.2 mL, 47.40 mmol), N-{[(phenylmethyl)oxy]carbonyl}glycine (2.48 g, 11.85 mmol), and EDCI (2.73 g, 14.21 mmol). After stirring overnight, the solution was washed 6 N aq. HCl (100 mL) and water (100 mL). The aqueous layers were extracted with CH2Cl2 (1×100 mL), and the combined organic layers were washed with water (100 mL) and brine (100 mL), then dried over anhydrous MgSO4 and concentrated in vacuo to provide pure methyl 1-[methyl(N-{[(phenylmethyl)oxy]carbonyl}glycyl)amino]cyclopropanecarboxylate (3.66 g, 97%). LCMS: (M+H)+: 321.1.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7](I)[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:10][N:11]1[CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(O)CO.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(O)(C)C.C(Cl)Cl.CO.[NH4+].[OH-].[Cu]I>[CH3:10][N:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:7]2[CH:6]=[CH:5][C:3]([NH2:4])=[C:2]([F:1])[CH:8]=2)[CH2:13][CH2:12]1
Reactant: Nc1ccc(I)cc1F
Reactant: CN1CCCNCC1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Solvent: CO
Product: CN1CCCN(c2ccc(N)c(F)c2)CC1
Temperature: 85 °C

Procedure:
A mixture of 2-fluoro-4-iodoaniline (474 mg, 2.00 mmol), 1-methylhomopiperazine (0.372 mL, 3.00 mmol), ethylene glycol (0.222 mL, 4.00 mmol) and K3PO4 (848 mg, 4.00 mmol) in isopropanol (2 mL) was degassed with Ar before being charged with CuI (76 mg, 0.40 mmol). The mixture in a sealed tube was heated at 85° C. for three days. One fifth of the reaction mixture was applied to a silica gel prep TLC plate, which was then developed in CH2Cl2/MeOH/NH4OH (85/15/0.5). The area containing the desired product was scraped out, and the product was extracted out with CH2Cl2/MeOH (2/1) to give a solid (54 mg).
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[O:14])[N:8]=1)=[O:5].[CH:27](=O)[CH3:28].C([BH3-])#N.[Na+].FC(F)(F)C(O)=O>CO>[F:26][C:21]1[CH:22]=[C:23]([F:25])[CH:24]=[C:2]([F:1])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH:15]2[CH2:16][CH2:17][N:18]([CH2:27][CH3:28])[CH2:19][CH2:20]2)=[O:14])[N:8]=1)=[O:5]
Reactant: O=C(Nc1cccc(C(=O)C2CCNCC2)n1)c1c(F)cc(F)cc1F
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCN1CCC(C(=O)c2cccc(NC(=O)c3c(F)cc(F)cc3F)n2)CC1
Temperature: 90 °C
Yield: 30 %

Procedure:
Mix 2,4,6-trifluoro-N-[6-(piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamide (26 mg), acetaldehyde (42 mg), sodium cyanoborohydride (10 mg) and trifluoroacetic acid (16.4 mg) in methanol (2 mL) in a sealed tube and heat in an oil bath at 90° C. overnight. Dilute with methanol and load on a SCX column (10 g), wash with methanol, elute the product with 2M NH3-methanol, evaporate, purify on a silica gel column (4 g, solvent: dichloromethane-2M NH3 in methanol, gradient) to obtain the title compound (8.4 mg). Mass spectrum (electrospray) m/z=392 (M+1); 1H NMR (CDCl3): 8.51 (d, 1H), 8.42 (br, 1H), 7.92 (t, 1H), 7.82 (dd, 1H), 6.84 (m, 2H), 3.63 (m, 1H), 3.02 (m, 2H), 2.44 (m, 2H), 2.04 (m, 2H), 1.87 (m, 4H), 1.60 (m, 5H), 1.11 (t, J=6.8 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Cl.[CH3:11][O:12][C:13](=[O:17])[CH:14]([CH3:16])[NH2:15].S([O-])([O-])(=O)=O.[Mg+2].C(N(CC)CC)C>C(Cl)Cl>[CH3:11][O:12][C:13](=[O:17])[CH:14]([CH3:16])[N:15]=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: COC(=O)C(C)N
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(C)N=Cc1ccc(Cl)cc1
Reaction time: 20 h
Yield: 94.5 %

Procedure:
To a stirring mixture of 4-chlorobenzaldehyde (42.2 g, 0.3 mol), DL-alanine methyl ester hydrochloride (42.7 g, 0.306 mol), and 150 g of magnesium sulfate in 1 L of methylene chloride was added 30.3 g (0.3 mol) of triethylamine in 150 ml of methylene chloride in one portion and the resulting mixture was stirred for 20 hours. The reaction mixture was filtered, the filtrate concentrated in vacuo, and the residue (solid and oil) was dissolved in 500 ml of ether. The insoluble solid (triethylamine hydrochloride) was removed by filtration and the filtrate was concentrated in vacuo to afford 64.01 g (94.6%) of N-(4-chlorophenyl)methylene-DL-alanine methyl ester as a yellow oil.