Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:19]=[C:18]([CH2:20][CH:21]([CH3:23])[CH3:22])[S:17][C:16]=3[C:24]([NH2:26])=[O:25])=[CH:11][CH:10]=2)[CH:7]=[CH:6][N:5]=[CH:4]1.[CH2:27]([S:31](Cl)(=[O:33])=[O:32])[CH2:28][CH2:29][CH3:30]>C1COCC1>[CH2:27]([S:31]([NH:26][C:24]([C:16]1[S:17][C:18]([CH2:20][CH:21]([CH3:22])[CH3:23])=[CH:19][C:15]=1[C:12]1[CH:13]=[CH:14][C:9]([CH2:8][N:3]2[CH:7]=[CH:6][N:5]=[CH:4]2)=[CH:10][CH:11]=1)=[O:25])(=[O:33])=[O:32])[CH2:28][CH2:29][CH3:30]
Reactant: CCCCS(=O)(=O)Cl
Reactant: CC(C)Cc1cc(-c2ccc(Cn3ccnc3)cc2)c(C(N)=O)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCS(=O)(=O)NC(=O)c1sc(CC(C)C)cc1-c1ccc(Cn2ccnc2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 49.6 %

Procedure:
NaH (55%, 12 mg, 0.28 mmol) was added to a solution of 3-(4-imindazol-1-ylmethylphenyl)-5-iso-butylthiophene-2-carboxamide (46 mg, 0.136 mmol, see step (e) above) in THF (1 mL). The mixture was stirred at 50° C. for 0.5 hours. Butanesulfonyl chloride (29 μL, 0.223 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated and purified using silica gel chromatography (CH2Cl2:MeOH, 9:1) to give 31 mg of the title compound as a white powder (yield: 50%).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH:23][CH3:24])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:8]=1)=O.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][NH2:34]>>[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][C:17]([S:20]([NH:23][CH3:24])(=[O:22])=[O:21])=[CH:16][CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:34]1
Reactant: NNc1ccccc1F
Reactant: CNS(=O)(=O)c1ccc(-n2ccc(=O)c(C(=O)/C=C/N(C)C)n2)cc1
Product: CNS(=O)(=O)c1ccc(-n2ccc(=O)c(-c3ccnn3-c3ccccc3F)n2)cc1

Procedure:
The product was obtained starting from 4-[3-((E)-3-Dimethylamino-acryloyl)-4-oxo-4H-pyridazin-1-yl]-N-methyl-benzenesulfonamide (A-30) and 2-fluoro-phenylhydrazine according to the method described for example 91. MS: M=426.1 (M+H)+
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([OH:7])=[O:6])[CH2:2]1.[C:8](OC(=O)C)(=[O:10])[CH3:9]>>[C:8]([N:1]1[CH2:4][CH:3]([C:5]([OH:7])=[O:6])[CH2:2]1)(=[O:10])[CH3:9]
Reactant: O=C(O)C1CNC1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1CC(C(=O)O)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Azetidine carboxylic acid (2.25 g, 22.2 mmol) and acetic anhydride (80 ml) were heated gently until all of the acid had dissolved. The reaction was stirred at room temperature for 18 hours and then the acetic anhydride was removed under reduced pressure. Water was added and evaporated under reduced pressure. The residue was dissolved in hot ethyl acetate and filtered whilst hot and the filtrate was evaporated under reduced pressure to afford the title compound as a white solid, 1.54 g.
Reaction SMILES: [Sn](Cl)Cl.[Cl:4][C:5]1[CH:11]=[C:10]([N+:12]([O-])=O)[C:8]([NH2:9])=[C:7]([CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:6]=1>Cl>[Cl:4][C:5]1[CH:11]=[C:10]([NH2:12])[C:8]([NH2:9])=[C:7]([CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:6]=1
Reactant: Nc1c(CN2CCOCC2)cc(Cl)cc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Product: Nc1cc(Cl)cc(CN2CCOCC2)c1N
Reaction time: 1 h
Yield: 94.7 %

Procedure:
To a flask containing a solution of tin (II) chloride (1.1 g, 6 mmol) in concentrated HCl (1.5 mL) is added a solution of 4-chloro-2-(morpholin-4-ylmethyl)-6-nitroaniline (543 mg, 2 mmol) in concentrated HCl (1 mL). The reaction is stirred for 1 h. The thick slurry is filtered and the filter cake rinsed with HCl. The filter cake is dissolved in water (10 mL), is treated with 2M aqueous K2CO3 and is extracted with CH2Cl2. The organic layer is separated, dried (Na2SO4) and concentrated to afford the title compound (458 mg, 95%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:3]=1[C:4]([NH:6][CH:7]([CH2:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:29])[CH:16]=[CH:15]2)[C:8](O)=[O:9])=[O:5].CC[N:37](CC)CC.ClC(OCC)=O.N>C1COCC1>[NH2:37][C:8](=[O:9])[CH:7]([NH:6][C:4](=[O:5])[C:3]1[C:30]([Cl:34])=[CH:31][CH:32]=[CH:33][C:2]=1[Cl:1])[CH2:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([C:22]1[C:23]([Cl:29])=[CH:24][CH:25]=[CH:26][C:27]=1[Cl:28])[CH:16]=[CH:15]2
Reactant: CCN(CC)CC
Reactant: O=C(NC(Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)C(=O)O)c1c(Cl)cccc1Cl
Agent: CCOC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: NC(=O)C(Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)NC(=O)c1c(Cl)cccc1Cl
Reaction time: 0.33 h
Yield: 55 %

Procedure:
2-[(2,6-dichlorobenzoyl)amino]-3-[2-(2,6-dichlorophenyl)-6-quinolinyl]propanoic acid 38 (2.12 g) in dry THF (15 ml) is cooled to −20° C. NEt3 (0.54 ml) and ethyl chloroformate (0.37 ml) are added. The solution is stirred at this temperature for 20 minutes. The resulting solution is saturated with gaseous NH3 at −30° C. The mixture is allowed to reach room temperature. After one night, the residue is filtered and washed with THF, then dried under vacuum at 60° C. and purified over silica gel using CH2Cl2/CH3OH (95/5) as eluent to give N-(2-amino-1-{[2-(2,6-dichlorophenyl)-6-quinolinyl]methyl}-2-oxoethyl)-2,6-dichlorobenzamide 122.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)[S:13]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[CH3:24])(=[O:15])=[O:14])=[CH:8][CH:7]=1.[OH-].[Na+].Cl>O1CCCC1.O>[OH:32][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[CH2:25][N:12]([S:13]([C:16]1[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=1[CH3:24])(=[O:15])=[O:14])[C:9]1[CH:10]=[CH:11][C:6]([CH:5]=[CH:4][C:3]([OH:33])=[O:2])=[CH:7][CH:8]=1
Reactant: COC(=O)C=Cc1ccc(N(Cc2cccc(O)c2)S(=O)(=O)c2c(C)cc(C)cc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)c(S(=O)(=O)N(Cc2cccc(O)c2)c2ccc(C=CC(=O)O)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 3-{4-[(3-hydroxy-benzyl)-(2,4,6-trimethyl-benzenesulfonyl)-amino]-phenyl}-acrylic acid methyl ester (0.040 g, 0.08 mmol) in 0.5 mL tetrahydrofuran was added sodium hydroxide (0.010 g, 0.25 mmol) in 0.5 mL water. The reaction was stirred at room temperature for 24 hr. The reaction mixture was adjusted to a pH of 4 with 1N HCl and water was added. The aqueous solution was washed with methylene chloride and the organic layer was dried (magnesium sulfate) and concentrated. Preparative TLC afforded 3-{4-[(3-hydroxy-benzyl)-(2,4,6-trimethyl-benzenesulfonyl)-amino]-phenyl}-acrylic acid. 1H NMR (CDCl3) δ 7.58 (d, 1H, J=16 Hz), 7.29 (d, 2H, J=8.4 Hz), 7.04 (d, 2H, J=8.4 Hz), 7.05–7.00 (m, 1H), 6.86 (s, 2H), 6.70–6.60 (m, 3H), 6.28 (d, 1H, J=16 Hz), 4.77 (s, 2H), 2.45 (s, 6H), 2.25 (s, 3H).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.Cl[CH:13]([O:15][CH3:16])[CH3:14]>CN(C=O)C>[CH3:16][O:15][CH:13]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1)[CH3:14]
Reactant: COC(C)Cl
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(C)n1ccc2ccccc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 58 %

Procedure:
To a suspension of NaH (1.92 gm of a 60% dispersion in oil) in 75 mL of DMF was added indole (4.68 gm, 40 mmol) (Aldrich). The mixture was stirred for 15 minutes at 0° C., and 1-chloroethyl methylether (4 mL) was added dropwise. The resulting mixture was stirred at 0° C. for 1 hour and poured over ice/water, and extracted with toluene. The organic layer was dried over magnesium sulfate, and evaporated. The residue was purified by flash chromatography using EtOAc/hexanes to give 4 gm of 1-[1-methoxyethyl]indole. (Yield 58%).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:18])=[C:13]([CH:17]=1)[C:14](O)=[O:15])=[O:7].S(Cl)(Cl)=O.[NH2:28][C:29]1[CH:30]=[N:31][C:32]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([C:42]([N:44]3[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]3)=[O:43])=[CH:38][CH:37]=2)=[N:33][CH:34]=1>ClCCl.C1COCC1>[Cl:18][C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:19]=[CH:20][CH:21]=[C:3]([C:2]([F:1])([F:22])[F:23])[CH:4]=2)=[CH:17][C:13]=1[C:14]([NH:28][C:29]1[CH:34]=[N:33][C:32]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([C:42]([N:44]3[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]3)=[O:43])=[CH:38][CH:37]=2)=[N:31][CH:30]=1)=[O:15]
Reactant: O=C(Nc1ccc(Cl)c(C(=O)O)c1)c1cccc(C(F)(F)F)c1
Reactant: CN1CCN(C(=O)c2ccc(Nc3ncc(N)cn3)cc2)CC1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CN1CCN(C(=O)c2ccc(Nc3ncc(NC(=O)c4cc(NC(=O)c5cccc(C(F)(F)F)c5)ccc4Cl)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.4 %

Procedure:
A mixture of intermediate 1 (Example 2) (40 mg, 1.2 mmol) and thionyl chloride (875 μL, 12 mmol) in dichloromethane (20 mL) was heated under reflux for 6 h. The reaction mixture was evaporated to dryness. To the residue was added (4-(5-aminopyrimidin-2-ylamino)phenyl)(4-methylpiperazin-1-yl)methanone (20 mg, 0.064 mmol) and TEA (44 μL, 0.31 mmol) in THF (7 mL). The reaction mixture was stirred at room temperature for 1 h and evaporated. The residue was purified by HPLC to give title compound as a yellow solid (21 mg, 52%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1)([O-])=O.C([O-])=O.[NH4+]>CO.[Pd]>[O:12]=[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:10][C:7]1[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=1
Reactant: O=C(Cc1ccc([N+](=O)[O-])cc1)N1CCCC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Nc1ccc(CC(=O)N2CCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
To a solution of 0.8 g of 1-[(4-nitrophenyl)acetyl]pyrrolidine obtained in stage a) below in 20 mL of methanol are added, under argon, 1.72 g of ammonium formate and 36 mg of 10% palladium-on-charcoal. The reaction mixture is stirred at room temperature for 1 hour and then filtered through Celite and concentrated under reduced pressure. The residue is taken up in water and extracted with dichloromethane. The organic phase is then washed with water and with saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated under reduced pressure to give 0.49 g of 4-(2-oxo-2-pyrrolidin-1-ylethyl)aniline, the characteristics of which are as follows:
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[C:11]([O:15][C:16]([NH:18][C:19]1[CH:20]=[C:21]([CH2:25][CH2:26][C:27](OCC)=[O:28])[CH:22]=[CH:23][CH:24]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12].Cl>O1CCCC1>[C:11]([O:15][C:16]([NH:18][C:19]1[CH:20]=[C:21]([CH2:25][CH2:26][CH2:27][OH:28])[CH:22]=[CH:23][CH:24]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CCOC(=O)CCc1cccc(NC(=O)OC(C)(C)C)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc(CCCO)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 40.4 %

Procedure:
Diisobutylaluminium hydride (1.5 M in toluene, 57.0 ml, 85.5 mmol) was added dropwise to a stirred solution of ethyl 3-(3-tert-butoxycarbonylaminophenyl)propionate (9.35 g, 31.9 mmol) in tetrahydrofuran (100 ml) at 0° C. and the mixture was stirred at room temperature for 24 hours. 2N-hydrochloric acid was added to the mixture and the mixture was extracted with ethyl acetate. The extract was successively washed with water saturated aqueous NaHCO3 and brine, dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel (100 g) with hexane-ethyl acetate (2:1) to give 3-(3-tert-butoxycarbonylaminophenyl)propanol as a colorless oil (3.24 g, 40%).
Reaction SMILES: Cl[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])[CH:12]=2)[N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C@H:72]12[CH2:78][C@H:75]([NH:76][CH2:77]1)[CH2:74][N:73]2[C:79]([O:81][C:82]([CH3:85])([CH3:84])[CH3:83])=[O:80].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:82]([O:81][C:79]([N:73]1[CH2:74][C@@H:75]2[CH2:78][C@H:72]1[CH2:77][N:76]2[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])[CH:12]=2)[N:3]=1)=[O:80])([CH3:85])([CH3:83])[CH3:84]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: CC(Nc1cc(-n2nc(Cl)c3ccccc32)ccn1)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C[C@H](Nc1cc(-n2nc(N3C[C@@H]4C[C@H]3CN4C(=O)OC(C)(C)C)c3ccccc32)ccn1)c1ccccc1
Temperature: 90 °C
Reaction time: 20 h

Procedure:
To a solution of [4-(3-chloro-indazol-1-yl)-pyridin-2-yl]-(1-phenyl-ethyl)-amine (0.17 g, 0.48 mmol) in toluene (3 mL) under nitrogen were added palladium acetate (0.011 g, 0.05 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.03 g, 0.05 mmol), and t-butyl(1S,4S)-(−)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.14 g, 0.72 mmol), followed by sodium t-butoxide (0.13 g, 1.3 mmol). The resulting mixture was stirred at 90° C. for 20 h. After cooling to room temperature, the reaction was diluted with methylene chloride and washed with saturated sodium bicarbonate and brine; dried (MgSO4). Flash chromatography of the crude product mixture with 25:10:65, 40:10:50, 50:10:40, 60:10:30, and 70:10:20 EtOAc-CH2Cl2-Hexane gave the title compound. MS (ES+): 511.4 [M+H]+, 509.2 [M−H]−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH2:21].CS([C:25]1[N:30]=[CH:29][C:28]2=[CH:31][CH:32]=[C:33]([N:34]3[CH:38]=[CH:37][CH:36]=[N:35]3)[N:27]2[N:26]=1)=O.C(N(CC)C(C)C)(C)C.COCC(O)C>CS(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH:21][C:25]1[N:30]=[CH:29][C:28]2=[CH:31][CH:32]=[C:33]([N:34]3[CH:38]=[CH:37][CH:36]=[N:35]3)[N:27]2[N:26]=1
Reactant: CS(=O)c1ncc2ccc(-n3cccn3)n2n1
Reactant: COc1cc(N2CCC(N3CCOCC3)CC2)ccc1N
Solvent: CS(C)=O
Solvent: COCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CCC(N3CCOCC3)CC2)ccc1Nc1ncc2ccc(-n3cccn3)n2n1

Procedure:
To a RB flask under argon were introduced 7-Bromo-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (300 mg, 1 mmol), 1H-Pyrazole (88.5 mg, 1.30 mmol), Cesium carbonate (801 mg, 2.46 mmol), Copper(I) iodide (50 mg, 0.3 mmol) and DMF (5 mL). The mixture was degassed for few minutes and heated at 110° C. overnight under argon. Solvent was removed and the mixture was taken in EtOAc and was passed through a pad of celite. Solvent evaporation gave the crude product which was purified by flash chromatography (ISCO, hexane :EtOAc 3:1). 2-Methylsulfanyl-7-pyrazol-1-yl-pyrrolo[2,1-f][1,2,4]triazine was isolated as a yellow syrup (23, 8%). LCMS (E/I+) 232 (M+H). 2-Methoxy-4-(4-morpholin-4-yl-piperidin-1-yl)-phenylamine (47.1 mg, 0.162 mmol), 2-Methanesulfinyl-7-pyrazol-1-yl-pyrrolo[2,1-f][1,2,4]triazine (20 mg, 0.08 mmol), N,N-Diisopropylethylamine (30 uL, 0.2 mmol) and 1-Methoxy-2-propanol (200 uL,) were combined in a microwave vial. The reaction was microwaved at 200° C. for 2.5 hours, taken up in DMSO, purified by Gilson RP-HPLC. The product, [2-Methoxy-4-(4-morpholin-4-yl-piperidin-1-yl)-phenyl]-(7-pyrazol-1-yl-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-amine was isolated as a tan solid (8 mg, 21%). LCMS (E/I+) 475 (M+H). NMR 1H (DMSO-d6)-9.75 (br s, 1H), 8.94 (s, 1H), 8.58 (d, 1H, J=2.09 Hz), 7.94 (s, 1H), 7.83 (s, 1H), 7.67 (d, 1H, J=8.72 Hz), 6.94 (s, 2H), 6.70 (s, 1H), 6.60 (s, 1H), 6.52 (d, 1H, J=8.74 Hz), 4.04-3.13 (series of m, s along with the water peak, 14H), 2.71 (m, 2H), 2.15 (d, 2H, J=11.30 Hz), 1.72 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([C:10]#[C:11][CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:8][CH:9]=1)=[O:4]>CO.[Pd]>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(C#CCNC(=O)OC(C)(C)C)o1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(CCCNC(=O)OC(C)(C)C)o1
Reaction time: 18 h
Yield: 24.6 %

Procedure:
To a solution of 5-(3-tert-butoxycarbonylamino-prop-1-ynyl)-furan-2-carboxylic Acid methyl ester (1.69 g) in MeOH (50 mL) was added 10% palladium on carbon (850 mg) and the mixture was hydrogenated on a Parr shaker at 50 psi for 18 h. The catalyst was removed via filtration through Celite and the volatiles were concentrated in vacuo. Flash chromatography (hexanes:EtOAc 4:1) provided 5-(3-tert-butoxycarbonylaminopropyl)-furan-2-carboxylic Acid methyl ester (422 mg, MS 284 M+) followed by 5-(3-tert-butoxycarbonylamino-propyl)-tetrahydrofuran-2-carboxylic Acid methyl ester (903 mg).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[CH3:19][C:20]1[S:24][C:23]([S:25](Cl)(=[O:27])=[O:26])=[CH:22][CH:21]=1>>[F:8][C:7]1[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])=[C:5]([NH:18][S:25]([C:23]2[S:24][C:20]([CH3:19])=[CH:21][CH:22]=2)(=[O:27])=[O:26])[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: Cc1ccc(S(=O)(=O)Cl)s1
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Product: Cc1ccc(S(=O)(=O)Nc2ccc(F)c(F)c2Nc2ccc(I)cc2F)s1

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine was reacted with 5-methylthiophene-2-sulfonyl chloride to obtain the title compound. 1H NMR (300 MHz, CDCl3): δ 7.34 (dd, J=0.9 & 10.2 Hz, 1H), 7.30 (ddd, J=2.1, 4.8 & 9.0 Hz, 1H), 7.25 (d, J=3.9 Hz, 1H), 7.07 (m, 2H), 6.65 (dd, J=1.2 & 3.9 Hz, 1H), 5.89 (dt, J=2.4, 8.7 & 17.4 Hz, 1H), 5.54 (br s, D2O exchangeable, 1H), 2.46 (s, 3H).
Reaction SMILES: [ClH:1].[C:2]([N:5]1[CH2:12]C[CH2:10][C@H:6]1[C:7]([OH:9])=[O:8])(=[O:4])[CH3:3]>>[Cl:1][CH2:3][C:2]([N:5]([CH3:12])[C@H:6]([C:7]([OH:9])=[O:8])[CH3:10])=[O:4]
Reactant: CC(=O)N1CCC[C@H]1C(=O)O
Reactant: Cl
Product: C[C@@H](C(=O)O)N(C)C(=O)CCl

Procedure:
1 ml of a 30 mM solution of N-choloracetyl-N-methyl-L-alanine in 0.1M tris-HC1, pH 7.0 was introduced into a reaction container thermostatted to 30° C. and mixed with 1.99 ml 0.1M tris --HCl pH 7.0. The reaction was started by adding 0.01 ml N-acyl-L-proline acylase from Comamonas TESTOSTERONI DSM 5416 corresponding to 0.23 units and 0.2 μg protein. 1 unit is defined as the amount of enzyme which converts 1 μmole of N-acetyl-L-proline per minute at 30° C. and pH 7.0. Specimens were taken at various points in time to detect the course of the reaction, compounded with 2N HCl 1:2 and subsequently analyzed by HPLC using an RP 8-column (250×4 mm). After elution with 7% (v/v) acetonitrile in 0.01M heptane sulfonic acid (adjusted to pH 2.2 with 85% H3PO4) at a flow rate of 2.2 ml/min. and a column temperature of 40° C., the decrease of N-chloroacetyl-N-methyl-L-alanine was determined by measuring the UV absorption at 210 nm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[NH:15][C:16]([C@@H:18]1[CH2:22][C@H:21]([NH:23][C:24]([C:26]2[S:27][C:28]([Cl:31])=[CH:29][CH:30]=2)=[O:25])[C:20](=O)[CH2:19]1)=[O:17].[CH3:33][NH2:34]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[NH:15][C:16]([CH:18]1[CH2:22][C@H:21]([NH:23][C:24]([C:26]2[S:27][C:28]([Cl:31])=[CH:29][CH:30]=2)=[O:25])[CH:20]([NH:34][CH3:33])[CH2:19]1)=[O:17]
Reactant: CN
Reactant: O=C(N[C@H]1C[C@@H](C(=O)Nc2ccc(-n3ccccc3=O)cc2F)CC1=O)c1ccc(Cl)s1
Solvent: C1CCOC1
Product: CNC1CC(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C[C@@H]1NC(=O)c1ccc(Cl)s1

Procedure:
In analogy to example 24B 5-chloro-thiophene-2-carboxylic acid {(1S,4R)-4-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-2-oxo-cyclopentyl}-amide was reacted with methylamine (using a saturated solution in THF) to give 5-chloro-thiophene-2-carboxylic acid {(S)-4-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-2-methylamino-cyclopentyl}-amide. Crystalline white solid. MS 489.3 ([M+H]+).
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([O-:13])=O)[C:6]([O:8]CC)=[O:7])C.[Cl:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][CH:19]([CH3:25])[NH:20]2.P(=O)(O)(O)O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[OH-].[Na+]>O.C(O)C>[Cl:14][C:15]1[C:16]2=[C:21]3[N:20]([CH:19]([CH3:25])[CH2:18][CH2:17]2)[CH:4]=[C:5]([C:6]([OH:8])=[O:7])[C:11](=[O:13])[C:22]3=[CH:23][CH:24]=1
Reactant: CC1CCc2c(Cl)cccc2N1
Reactant: CCOC=C(C(=O)[O-])C(=O)OCC
Agent: O=P(O)(O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC1CCc2c(Cl)ccc3c(=O)c(C(=O)O)cn1c23
Yield: 68.5 %

Procedure:
25 g of ethyl ethoxymethylenemalonate was added to 21 g of 5-chloro-2-methyl-1,2,3,4-tetrahydroquinoline and the mixture was heated on an oil bath at 110° to 120° C. during which time distillation of ethanol was observed. After heating the mixture at the same temperature as above for 30 minutes 160 g of polyphosphoric acid prepared from 80 g of phosphoric acid and 80 g of phosphorus pentoxide was added thereto followed by heating on an oil bath at 130° to 140° C. for 1 hour. After completion of the reaction the reaction mixture was poured into 600 ml of water and the resulting mixture was rendered neutral with a 10% aqueous sodium hydroxide solution to precipitate crystals, which were collected by filtration and mixed with 200 ml of a 10% aqueous sodium hydroxide solution and the mixture was heat-refluxed for 1 hour during which time the crystals were dissolved to form a uniform solution. The solution was treated with activated carbon while hot and filtered. The filtrate was allowed to cool and pH was adjusted with concentrated hydrochloric acid to a pH of 2 to precipitate crystals. Recrystallization of the crude crystals thus-obtained from dimethylformamide gave 22 g of 8-chloro-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo-[ij]quinolizine-2-carboxylic acid as colorless rhombic crystals having a melting point of 290° to 291° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.C([BH3-])#N.[Na+].O.[OH-].[Na+]>C(O)(=O)C>[F:13][C:2]([F:1])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][NH:7]2
Reactant: FC(F)(F)c1cccc2[nH]ccc12
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: FC(F)(F)c1cccc2c1CCN2
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 76 %

Procedure:
4.4 mmol of 4-trifluoromethyl-1H-indole were dissolved in 8 ml acetic acid. 8.8 mmol of sodium cyanoborohydride were added at once and the reaction mixture stirred at room temperature for 3.5 hours. 20 ml of water were added. The reaction mixture is treated with aqueous sodium hydroxide 40% until basic. Extraction with ethyl acetate yields the crude title compound as a yellowish waxy solid. Yield=76%. MS (m/e): 188.4 ([M+H]+, 97%).