Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:12]=[C:13]([C:32]([O:34][CH3:35])=[O:33])[C:14]2[NH:15][C:16]3[CH:17]=[C:18]([C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:25])[CH:19]=[CH:20][C:21]=3[C:22]=2[N:23]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:26]1([C:24]([C:18]2[CH:19]=[CH:20][C:21]3[C:22]4[N:23]=[C:11]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[CH:12]=[C:13]([C:32]([O:34][CH3:35])=[O:33])[C:14]=4[NH:15][C:16]=3[CH:17]=2)=[O:25])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1cc(Br)nc2c1[nH]c1cc(C(=O)N3CCOCC3)ccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Product: COC(=O)c1cc(-c2ccccc2)nc2c1[nH]c1cc(C(=O)N3CCOCC3)ccc12
Temperature: 80 °C
Yield: 75.1 %

Procedure:
A mixture of phenylboronic acid (92 mg, 0.75 mmol), methyl 2-bromo-7-(morpholine-4-carbonyl)-5H-pyrido[3,2-b]indole-4-carboxylate (150 mg, 0.359 mmol), finely powdered potassium phosphate tribasic (183 mg, 0.861 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (56.8 mg, 0.119 mmol), and palladium(II) acetate (11 mg, 0.047 mmol) in a vial was flushed with nitrogen. Tetrahydrofuran (3 mL) was added and the reaction was heated at 80° C. overnight. It was partitioned between water and methylene chloride. The organic phase was separated, washed with brine, and dried over sodium sulfate. Removal of the solvents followed by radial silica gel chromatography (step gradient elution with methylene chloride containing 0 to 2% MeOH) afforded methyl 7-(morpholine-4-carbonyl)-2-phenyl-5H-pyrido[3,2-b]indole-4-carboxylate (112 mg) as a solid. MS (ESI) m/z 416.1 (M+H). 1H NMR (CDCl3) δ ppm 9.82 (1H, s), 8.40 (1H, d, J=7.93 Hz), 8.25 (1H, s), 8.12 (2H, d, J=7.63 Hz), 7.60 (1H, s), 7.48 (2H, t, J=7.63 Hz), 7.36-7.42 (1H, m), 7.32 (1H, d, J=7.93 Hz), 4.03 (3H, s), 3.38-3.95 (8H, m).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([CH2:10][C@@H:11]([NH:15][C:16]([CH2:18][CH2:19][C@@H:20]([NH2:24])[C:21](O)=[O:22])=[O:17])[C:12]([OH:14])=[O:13])=[CH:8][NH:9][C:4]2=[CH:3][CH:2]=1.[NH2:25][C@@H](C(N[C@@H](C(O)=O)CC1C2C(=CC=CC=2)NC=1)=O)CCC(=O)O>>[NH2:24][C@@H:20]([C:21](=[O:22])[NH2:25])[CH2:19][CH2:18][C:16]([NH:15][C@@H:11]([C:12]([OH:14])=[O:13])[CH2:10][C:7]1[C:5]2[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=2)[NH:9][CH:8]=1)=[O:17]
Reactant: N[C@H](CCC(=O)O)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: N[C@H](CCC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O)C(=O)O
Product: NC(=O)[C@H](N)CCC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
A method for the preparation of thymodepressin was disclosed in example 1 of U.S. Pat. Nos. 5,736,519, 6,103,699 and 6,410,515. However, the manufacture of thymodepressin on a large scale cannot be conducted using the experimental details of this method since a mixture of D-glutamyl-D-tryptophan and D-isoglutamyl-D-tryptophan is produced which must be separated and purified by ion exchange chromatography resulting in a very low yield (12.25%) of thymodepressin.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18](=[O:20])[N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: C1CCNCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Cn1c(-c2ccc(Cl)cc2)nc2cccnc21)N1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.4 %

Procedure:
Under nitrogen bubbling, a mixture of 2-(4-chlorophenyl)-3H-imidazo [4,5-b]pyridine-3-acetic acid (4.0 g, 0.014 mole) and 1,1'-carbonyldiimidazole (2.27 g, 0.014 mole), in 150 ml of tetrahydrofuran was stirred at room temperature for 3 hours. Then, under nitrogen atmosphere, piperidine (1.31 g, 0.015 mole) was added and the reaction mixture was allowed to stir at room temperature overnight. The tetrahydrofuran was evaporated to give a solid which was triturated with water and dried under high vacuum over the weekend at 50° C. The solid was recrystallized from isopropyl alcohol and refrigerated overnight. The crystalline material was collected by filtration, washed with cold isopropyl alcohol, and dried under high vacuum at 50° C. overnight to give 2.95 g (59%) of title compound, mp 176°-178° C.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:10]=[CH:9][C:7](=[O:8])[NH:6][C:4]1=[O:5].[CH3:11][Si:12]([CH3:19])([CH3:18])[CH2:13][CH2:14][O:15][CH2:16]Cl>CN(C=O)C.O>[CH3:11][Si:12]([CH3:19])([CH3:18])[CH2:13][CH2:14][O:15][CH2:16][N:3]1[CH:10]=[CH:9][C:7](=[O:8])[NH:6][C:4]1=[O:5]
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=c1cc[nH]c(=O)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 4 h
Yield: 14.8 %

Procedure:
A solution of 60% sodium hydride (2 g, 50 mmol) in mineral oil was washed with hexanes (2×20 mL) and cooled to 0° C. The solution was diluted with DMF (200 mL) and then uracil (5.6 g, 50 mmol) was added portionwise over 30 minutes. The mixture was treated with 2-(trimethylsilyl)ethoxymethyl chloride (8.8 mL, 50 mmol) and allowed to warm to 25° C. and stand 4 hours. The reaction mixture was diluted with water (500 mL) and extracted with diethyl ether (4×100 mL). The combined extract was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by chromatography on silica gel eluting with hexanes/ethyl acetate (2:1) to give 1-[2-(trimethylsilyl)ethoxymethyl]-2,4(1H,3H)-pyrimidinedione (1.8 g, 7.4 mmol), M.p. 120°-122° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH:7]1[C:12](=O)[CH2:11][CH2:10][C@@H:9]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[CH2:20][C@H:8]12.[OH-].[Na+].C(OCC)(=O)C>O1CCCC1>[NH:7]1[CH2:12][CH2:11][CH2:10][C@@H:9]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[CH2:20][C@H:8]12
Reactant: O=C1CC[C@@H]2c3ccccc3C[C@@H]2N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Lithium aluminum hydride (1 mol/L in tetrahydrofuran, 12 mL) is added to a solution of cis-1,3,4,4a,9,9a-hexahydro-indeno[2,1-b]pyridin-2-one (0.95 g) in tetrahydrofuran (15 mL) at room temperature. The resulting solution is heated to reflux temperature and stirred at this temperature for 2 h. After cooling to room temperature, the solution is poured into ice-cold water, 1 M aqueous NaOH solution and ethyl acetate are added, and the resulting mixture is filtered over Celite. The aqueous phase of the filtrate is separated and extracted with ethyl acetate and the extracts are combined with the organic phase of the filtrate. The organic phase is washed with brine and dried (MgSO4). The solvent is evaporated to give the title compound as a colorless solid. Yield: 0.83 g (94% of theory); LC (method 1): tR=1.29 min; Mass spectrum (ESI+): m/z=174 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1.CCN(CC)CC.Cl[C:34]([O:36][CH3:37])=[O:35].O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:25][C:21]1[CH:20]=[C:19]([C@H:5]([O:4][CH2:3][CH2:2][NH:1][C:34]([O:36][CH3:37])=[O:35])[C@@H:6]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:7]2)[CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCN)c2cccc(F)c2)C1
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)NCCO[C@@H](c1cccc(F)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 96.9 %

Procedure:
To a solution of (R)-tert-butyl 3-((R)-(2-aminoethoxy)(3-fluorophenyl)methyl)piperidine-1-carboxylate (10 g, 28.41 mmol) and DMAP (1.8 g, 14.21 mmol, 0.5 eq) in dry CH2Cl2 (150 mL), Et3N (8.62 g, 11.42 mL, 85.23 mmol) was added. The resulting mixture was cooled to 0-5° C. under ice-water bath, a solution of methyl chloroformate (10.95 mL, 142.05 mmol, 5 eq) in dry CH2Cl2 (60 mL) was added dropwise. After addition, the reaction mixture was stirred for 1-2 hr at 0-5° C. Water (80 mL) was added to quench the reaction. The aqueous layer was extracted with CH2Cl2 (3×50 mL), the combined organic layers were washed with 10% citric acid (2×80 mL) and brine, then dried over Na2SO4, filtered and concentrated to the crude product, which was purified by silica gel to afford (R)-tert-butyl 3-((R)-(3-fluorophenyl)(2-(methoxycarbonylamino)ethoxy)methyl)piperidine-1-carboxylate (11.3 g, 97%).
Reaction SMILES: Cl[C:2]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[OH:18][CH2:19][CH:20]1[CH2:22][CH2:21]1.[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:2]([O:18][CH2:19][CH:20]3[CH2:22][CH2:21]3)=[N:3][CH:4]=[C:5]([CH:9]=2)[C:6]([OH:8])=[O:7])=[CH:12][CH:13]=1
Reactant: OCC1CC1
Reactant: O=C(O)c1cnc(Cl)c(-c2ccc(Cl)cc2)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=C(O)c1cnc(OCC2CC2)c(-c2ccc(Cl)cc2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
6-Chloro-5-(4-chloro-phenyl)-nicotinic acid (22.3 g, 0.083 mol) was dissolved in dimethylsulfoxide (130 mL). To this solution was added (hydroxymethyl)cyclopropane (10.1 g, 0.125 mol) and potassium hydroxide powder (18.7 g, 0.333 mol). This mixture was reacted (in ten portions) for 20 min in a microwave at 100° C. The reaction mixture was poured into ice-water (500 mL) and citric acid (10%, 3000 mL) was added with stirring. Stirring was continued for 30 min during which time the product precipitated. The product was filtered off washed with water and dissolved in ethylacetate (1500 mL). The solution was concentrated in vacuo and the title compound crystallized from the concentrated solution as a white solid (21.5 g); MS (ISP) 302.2 (M−H)
Reaction SMILES: [CH3:1][C:2]([CH3:34])([O:4][C:5]([C@H:7]([NH:25][C@H:26]([C:31]([OH:33])=O)[CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[CH:16]=[C:15]3[CH:20]=[CH:21][CH:22]=[CH:23][C:14]3=[CH:13][C:12]=2[C:11]1=[O:24])=[O:6])[CH3:3].[N:35]1([CH2:41][CH2:42][NH2:43])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:3][C:2]([O:4][C:5](=[O:6])[C@H:7]([NH:25][C@H:26]([C:31]([NH:43][CH2:42][CH2:41][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)=[O:33])[CH2:27][CH:28]([CH3:29])[CH3:30])[CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[CH:16]=[C:15]3[CH:20]=[CH:21][CH:22]=[CH:23][C:14]3=[CH:13][C:12]=2[C:11]1=[O:24])([CH3:34])[CH3:1]
Reactant: CC(C)C[C@H](N[C@H](CCN1C(=O)c2cc3ccccc3cc2C1=O)C(=O)OC(C)(C)C)C(=O)O
Reactant: NCCN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)C[C@H](N[C@H](CCN1C(=O)c2cc3ccccc3cc2C1=O)C(=O)OC(C)(C)C)C(=O)NCCN1CCOCC1
Temperature: 20 °C
Reaction time: 18 h

Procedure:
200 mg of N-[(R)-1-[(1,1-dimethylethoxy)carbonyl]-3-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)propyl]-L-leucine, prepared as in Example L, was added to a stirred mixture of 0.044 mL 2-Morpholin-4-ylethylamine, 0.174 mL diisopropylethylamine, and 1 mL DMF at 0° C. 1.1 mL of 0.45M hydroxybenzotriazol-benzotriazoltetramethyluronium hexafluorophosphate in DMF was added. The mixture was warmed to 20° C. with stirring for 18 h, diluted with 30 mL ethyl acetate, washed two times with 20 mL of 10% sodium carbonate, washed with 20 mL brine, and dried with sodium sulfate. The solvents were removed by evaporation to give the title compound as an oil; 240 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:6]([OH:8])[CH:7]=1.[CH3:27][O:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36]Br)[CH:31]=1>>[CH3:27][O:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][O:8][C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[C:9]2[N:13]([CH2:14][CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)[CH:31]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: Oc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1CC1CCCCC1
Product: COC(=O)c1cccc(COc2cc(Cl)ccc2-c2nc3cc(F)c(F)cc3n2CC2CCCCC2)c1

Procedure:
The title compound was prepared in analogy to Example 19, from 5-chloro-2-(1-cyclohexylmethyl-5,6-difluoro-1H-benzoimidazol-2-yl)-phenol (Example 19, intermediate a) and (3-bromomethyl-benzoic acid methyl ester CAS Reg. No. 1129-28-8). Brown sticky solid (90%). MS (Turbo Spray): m/z=524.0 (M+H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([OH:12])(=[O:11])[C:8]([OH:10])=[O:9].[CH3:13][O:14][C:15]1[CH:52]=[CH:51][C:18]2[S:19][C:20]([C:37]3[CH:50]=[CH:49][C:40]([O:41][CH2:42][CH2:43][CH2:44][C:45](OC)=[O:46])=[CH:39][CH:38]=3)=[C:21]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)=[C:25]([O:35][CH3:36])[CH:24]=3)[C:17]=2[CH:16]=1.[SiH](CC)(CC)CC.C(O)(C(F)(F)F)=O>C1COCC1.C(Cl)Cl.C([O-])(=O)C([O-])=O>[C:7]([OH:12])(=[O:11])[C:8]([OH:10])=[O:9].[CH3:13][O:14][C:15]1[CH:52]=[CH:51][C:18]2[S:19][C:20]([C:37]3[CH:38]=[CH:39][C:40]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][OH:46])=[CH:49][CH:50]=3)=[C:21]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)=[C:25]([O:35][CH3:36])[CH:24]=3)[C:17]=2[CH:16]=1
Reactant: COC(=O)CCCOc1ccc(-c2sc3ccc(OC)cc3c2Cc2ccc(CN3CCCC3)c(OC)c2)cc1
Agent: CC[SiH](CC)CC
Agent: O=C(O)C(=O)O
Agent: O=C([O-])C(=O)[O-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2sc(-c3ccc(OCCCCO)cc3)c(Cc3ccc(CN4CCCC4)c(OC)c3)c2c1
Yield: 27 %

Procedure:
The title compound was prepared in 27% yield in three steps from LAH reduction of methyl 4-[4-[5-methoxy-3-[3-methoxy-4-(1-pyrrolidinylmethyl)benzoyl]benzo[b]thiophen-2-yl]phenoxy]butyrate (Part C of Example 38) in THF at 0-10° C. for 1 h, followed by dehydroxylation with Et3SiH/TFA in CH2Cl2 and oxalate formation as previously described.
Reaction SMILES: [O:1]1[CH:6]2[CH:2]1[CH2:3][N:4]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH2:5]2.[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[Na+]>C(#N)C.O>[OH:1][C@H:2]1[C@H:6]([O:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1
Reactant: Oc1ccccc1
Reactant: O=C(OCc1ccccc1)N1CC2OC2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: O=C(OCc1ccccc1)N1C[C@@H](O)[C@H](Oc2ccccc2)C1

Procedure:
21.9 g (0.1 mol) of 3,4-epoxy-1-carbobenzyloxy-pyrrolidine [S. Oida et al., Chem. Pharm. Bull., 18 (12), 2478 (1970)] are dissolved, together with 18.8 g (0.2 mol) of phenol and 100 ml of 2 N sodium hydroxide solution (0.2 mol) in 300 ml of acetonitrile. The reaction mixture is heated under reflux for 5 hours and after cooling is diluted with 600 ml of water and extracted by shaking with methylene chloride. The organic phase is washed with 2 N sodium hydroxide solution and then with water, dried over sodium sulphate and evaporated under a water pump vacuum and trans-3-hydroxy-4-phenoxy-1-carbobenzyloxy-pyrrolidine is obtained in the form of a pale yellow oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:9](=[O:18])[CH2:10][C:11]2[NH:12][C:13]([CH3:17])=[C:14]([CH3:16])[N:15]=2)[CH:6]=[CH:7][CH:8]=1.C[O-].[Na+].[C:22](OC)(=[O:25])[C:23]#[CH:24]>>[Cl:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[C:9]([C:10]1[CH:24]=[CH:23][C:22](=[O:25])[N:15]2[C:14]([CH3:16])=[C:13]([CH3:17])[NH:12][C:11]=12)=[O:18]
Reactant: C#CC(=O)OC
Reactant: Cc1nc(CC(=O)c2cccc(Cl)c2)[nH]c1C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: Cc1[nH]c2c(C(=O)c3cccc(Cl)c3)ccc(=O)n2c1C

Procedure:
The compound is prepared as described in example 20 with 200 mg (0.70 mmol) of 1-(3-Chlorophenyl)-2-(4,5-dimethyl-1H-imidazol-2-yl)ethanone hydrochloride (example XXV), 65 mg (1.20 mmol) of sodium methylate and 59 mg (0.70 mmol) methyl propiolate.
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:16](=[O:17])[C:12]3([CH2:15][CH2:14][CH2:13]3)[N:11]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[C:20]([F:27])[CH:19]=3)[C:10]2=[S:28])=[CH:5][C:4]=1[C:29]([F:32])([F:31])[F:30])#[N:2].[N:33]1([CH2:38][CH2:39][CH2:40][NH2:41])[CH2:37][CH2:36][CH2:35][CH2:34]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.[Cl-].[Na+].O.CCOC(C)=O>[C:1]([C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:16](=[O:17])[C:12]3([CH2:13][CH2:14][CH2:15]3)[N:11]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:41][CH2:40][CH2:39][CH2:38][N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)=[O:23])=[C:20]([F:27])[CH:19]=3)[C:10]2=[S:28])=[CH:5][C:4]=1[C:29]([F:32])([F:31])[F:30])#[N:2]
Reactant: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(C(=O)O)c(F)c3)C2=S)cc1C(F)(F)F
Reactant: NCCCN1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(C(=O)NCCCN4CCCC4)c(F)c3)C2=S)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluorobenzoic acid (Compound 224, 550 mg, 1.18 mmol), 3-(pyrrolidin-1-yl)propan-1-amine (303 mg, 2.37 mmol), HATU (673 mg, 1.77 mmol), and DIEA (0.6 mL, 3.54 mmol) in DMF (25 mL) was stirred at room temperature overnight. Brine and EtOAc were added and the aqueous layer was extracted with EtOAc (4×), the organics were combined, dried over sodium sulfate, and evaporated to dryness. The residue was purified by column chromatography on silica gel eluting with 0 to 20% MeOH/DCM to afford 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluoro-N-(3-(pyrrolidin-1-yl)propyl)benzamide as a pale orange solid. 1H NMR (300 MHz, DMSO-d6) δ 9.22 (d, 1H), 8.75 (d, 1H), 8.64 (t, 1H), 7.83 (t, 1H), 7.47 (dd, 1H), 7.38 (dd, 1H), 3.35 (m, 4H), 2.65-2.54 (m, 6H), 2.53-2.43 (m, 2H), 2.03-1.93 (m, 1H), 1.74 (m, 6H), 1.64-1.53 (m, 1H). LCMS [M+1]+ 575.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([CH3:11])=[N:8][C:7]=1[CH3:12])=[O:5])[CH3:2].[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:13][CH2:11][C:9]1[S:10][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:7]([CH3:12])[N:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1sc(C)nc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1sc(CBr)nc1C
Yield: 41.4 %

Procedure:
A mixture of 5-ethoxycarbonyl-2,4-dimethylthiazole (926 mg), N-bromosuccinimide (890 mg) and benzoyl peroxide (8 mg) in carbon tetrachloride (11 ml) was heated at reflux. After 11/2 h the reaction mixture was allowed to cool and filtered. The filtrate was evaporated and the residual oil diluted with petrol (b.p. 40°-60° C.)-ethyl acetate, 4:1, (5 ml) resulting in the precipitation of a solid. After 1 h the suspension was filtered and the filtrate evaporated to an orange oil. Petrol (2 ml) was added to the oil resulting in the formation of a solid which after cooling was collected to give crystals of 2-bromomethyl-5-ethoxycarbonyl-4-methylthiazole (546 mg), m.p. 48°-58° C., λmax (EtOH) 266 nm (ε 8,640).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[Br-].[F:59][C:60]1[CH:67]=[CH:66][C:63]([CH2:64][Zn+])=[CH:62][CH:61]=1>O1CCCC1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([CH2:64][C:63]2[CH:66]=[CH:67][C:60]([F:59])=[CH:61][CH:62]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Reactant: Fc1ccc(C[Zn+])cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1ccc(Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1
Temperature: 65 °C
Yield: 52.6 %

Procedure:
To a solution of 3,4-bis(benzyloxy)-6-chloropyridazine (Intermediate 1) (1 g, 3.06 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.117 g, 0.245 mmol) and palladium (II) acetate (0.027 g, 0.122 mmol) in tetrahydrofuran (6.12 ml) under nitrogen was added (4-fluorobenzyl)zinc(II) bromide (9.18 ml, 4.59 mmol) and the resulting red/brown mixture was heated at 65° C. for 24 hours. The reaction mixture was cooled, diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, saturated ammonium chloride solution and brine. The organics were dried (MgSO4), filtered and solvent removed in vacuo to give a brown oil. The oil was purified by silica chromatography (eluting with 0-100% ethyl acetate in petrol) to yield the title compound (663 mg, 1.61 mmol, 97% yield).
Reaction SMILES: C([BH3-])#N.[Na+].[CH:5]1([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:7][CH2:6]1.O.[OH-].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[CH:5]1([CH:8]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9]2)[CH2:7][CH2:6]1
Reactant: c1ccc2[nH]c(C3CC3)cc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: c1ccc2c(c1)CC(C1CC1)N2
Temperature: 15 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
1.0 g of sodium cyanoborohydride is gradually added to a solution of 1.25 g of 2-cyclopropylindole in 80 ml of acetic acid under argon cooled to a temperature of about 15° C. The reaction mixture is stirred at a temperature of about 15° C. for 2 hours, and is then treated with 100 ml of water. It is then cooled to a temperature of about 5° C. and alkalinized by gradual addition of 140 ml of a 30% sodium hydroxide solution. The reaction mixture is diluted with 200 ml of ethyl acetate and is then stirred at ambient temperature for 15 hours. After settling out, the organic phase is separated and the aqueous phase is extracted with 3×200 ml of ethyl acetate. The organic phases are combined, dried over anhydrous magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. The residue is taken up in a mixture of 60 ml of ethyl acetate, 40 ml of water and 10 ml of concentrated sodium hydroxide, and then the mixture is stirred at ambient temperature for 10 minutes. After settling out, the organic phase is separated and the aqueous phase is extracted with 2×50 ml of ethyl acetate. The organic phases are combined, dried over anhydrous magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. 1.2 g of (±)-2-cyclopropylindoline are thus obtained in the form of a brown oil which is used as it is.
Reaction SMILES: FC(F)(F)[C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13](CCl)=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:7]=2[CH:25]=1.[I-].[K+].C(N)C=C>O1CCCC1>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:8]1[C:7]2[CH:25]=[CH:3][CH:4]=[CH:5][C:6]=2[N:12]2[CH:13]=[N:14][N:15]=[C:11]2[CH2:10][N:9]=1
Reactant: FC(F)(F)c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CCl)n1-2
Agent: [I-]
Agent: [K+]
Solvent: C=CCN
Solvent: C1CCOC1
Product: Clc1ccccc1C1=NCc2nncn2-c2ccccc21

Procedure:
In the manner given in Example 31, 8-(trifluoromethyl)-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine, potassium iodide and allylamine in tetrahydrofuran are reacted to give 8-(trifluoromethyl)-1-(allylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine.