Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)([OH:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11].[Br:20]N1C(C)(C)C(=O)N(Br)C1=O>ClC(Cl)(Cl)Cl>[Br:20][CH:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])[C:3]([C:13]1[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=1)([OH:12])[CH2:2][Cl:1]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: OC(CCl)(Cc1ccccc1Cl)c1ccc(F)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: OC(CCl)(c1ccc(F)cc1)C(Br)c1ccccc1Cl

Procedure:
4.0 g (13.4 mmol) of 1-chloro-3-(2-chlorophenyl)-2-(4-fluorophenyl)-2-propanol are photobrominated with 2.3 g (8.0 mmol) of 1,3-dibromo-5,5-dimethylhydantoin in 80 ml of tetrachloromethane at 35° C. while stirring vigorously and irradiating with mixed light from an Osram HWL 235 V/500 W lamp. The hydantoin is filtered off with suction, the filtrate is extracted with dilute sodium carbonate solution and water, and conventional working up provides 5.1 g of crude product as an oil which is employed for the next stage. The erythro:threo isomer ratio found from the signals for the --CHBr--groups in the 1H-NMR spectrum, which appear at 6.4 ppm for the erythro compounds and at 6.2 ppm for the threo compound (each measured in CDCl3), is 4:1. The erythro isomer is also characterized by a doublet of doublets at 4.1 ppm.
Reaction SMILES: O=[C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].Cl.[F:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23]N)=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:18]=[C:19]2[C:20](=[CH:21][CH:22]=1)[NH:23][C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[C:3]2[CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: NNc1ccc(F)cc1
Reactant: O=C(O)CCCC(=O)c1ccccc1
Agent: Cl
Product: O=C(O)CCc1c(-c2ccccc2)[nH]c2ccc(F)cc12

Procedure:
Prepared from δ-oxobenzenepentanoic acid and (4-fluorophenyl)hydrazine hydrochloride according to the method of Description 7. 1H NMR (360 MHz, CDCl3) (Contains 40% δ-oxobenzenepentanoic acid) δ8.04 (1H, s), 7.56-7.39 (5H, m), 7.30-7.25 (2H, m), 6.98-6.93 (1H, m), 3.23-3.18 (2H, m), and 2.71-2.67 (2H, m).
Reaction SMILES: ClCS(Br)(=O)=O.O1CC=CC1.C(OO)(C)(C)C.[Cl:18][CH2:19][S:20]([CH:23]1[CH:27](Br)[CH2:26][O:25][CH2:24]1)(=[O:22])=[O:21]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[Cl:18][CH2:19][S:20]([C:23]1[CH2:24][O:25][CH2:26][CH:27]=1)(=[O:22])=[O:21]
Reactant: O=S(=O)(CCl)C1COCC1Br
Agent: C1=CCOC1
Agent: CC(C)(C)OO
Agent: O=S(=O)(Br)CCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=S(=O)(CCl)C1=CCOC1
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
19.3 g (0.1 mole) of chloromethanesulfonic acid bromide are added in the course of 10 minutes to a solution of 14 g (0.2 mole) of 2,5-dihydrofuran and 0.5 ml of tert.-butyl hydroperoxide in 30 ml of chloroform at -40° C. After 15 minutes, 16.5 ml of triethylamine, dissolved in 20 ml of chloroform, are added dropwise at the same temperature, so as to dehydrobrominate the 3-chloromethylsulfonyl-4-bromotetrahydrofuran which has been formed. The mixture is stirred for half an hour at 20° C., washed with water, dried and concentrated. The residue is repeatedly digested with ether and the ether extract is distilled; it boils at 115°-120° C./0.2 mm Hg. 4.8 g of 3-chloromethylsulfonyl-2,5-dihydrofuran are obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]3=[N:22][CH:23]=[CH:24][CH:25]=[C:20]3[NH:19][C:18]2=[O:26])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH2:28][CH2:29][CH3:30].[Cl-].[Cl-].[Ca+2]>CN(C=O)C.CO>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([N:17]2[C:21]3=[N:22][CH:23]=[CH:24][CH:25]=[C:20]3[N:19]([CH2:28][CH2:29][CH3:30])[C:18]2=[O:26])=[CH:15][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCCI
Reactant: O=c1[nH]c2cccnc2n1-c1ccc(OCc2ccccc2)cc1
Agent: [Ca+2]
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Solvent: CO
Product: CCCn1c(=O)n(-c2ccc(OCc3ccccc3)cc2)c2ncccc21

Procedure:
NaH (1.260 g) was added to a solution of 3-[4-(benzyloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (5 g) and 1-iodopropane (3.07 mL) in DMF (50 mL) at room temperature. The mixture was stirred at room temperature under a dry atmosphere (CaCl2 tube) for 1 h. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0%-50% EtOAc in hexane) to give 3-[4-(benzyloxy)phenyl]-1-propyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1.5 g) as dark yellow oil.
Reaction SMILES: [I-].ClC1C=CC=C[N+]=1C.CCN(C(C)C)C(C)C.[NH2:19][C:20]1[S:21][C:22]([C:25]([NH:27][C:28]2[S:29][CH:30]=[C:31]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)[N:32]=2)=[O:26])=[CH:23][N:24]=1.[Br:40][C:41]1[S:42][C:43]([C:46](O)=[O:47])=[CH:44][N:45]=1>CN(C=O)C>[Br:40][C:41]1[S:42][C:43]([C:46]([NH:19][C:20]2[S:21][C:22]([C:25](=[O:26])[NH:27][C:28]3[S:29][CH:30]=[C:31]([C:33]4[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=4)[N:32]=3)=[CH:23][N:24]=2)=[O:47])=[CH:44][N:45]=1
Reactant: O=C(O)c1cnc(Br)s1
Reactant: Cc1ccc(-c2csc(NC(=O)c3cnc(N)s3)n2)cc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2csc(NC(=O)c3cnc(NC(=O)c4cnc(Br)s4)s3)n2)cc1
Temperature: 25 °C
Yield: 31.3 %

Procedure:
2-Chloro-1-methylpyridinium iodide (0.048 g, 0.18 mmol), DIEA (0.045 mL, 0.25 mmol) and 2-amino-N-(4-p-tolylthiazol-2-yl)thiazole-5-carboxamide (0.04 g, 0.126 mmol) were added to a solution of 2-bromothiazole-5-carboxylic acid (26 mg, 0.126 mmol) in DMF (1 mL). The resulting solution was stirred at RT until completion of the reaction. Then a solid was precipitated with AcOEt and the solid was separated by centrifugation, yielding 2-bromo-N-(5-(4-p-tolylthiazol-2-ylcarbamoyl)thiazol-2-yl)thiazole-5-carboxamide (20 mg, 30%) as a solid that was used in the following step without further purification.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:8]([NH:9][CH2:10][CH3:11])=[CH:7][N:6]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:5]=1.C1OC1C.[Cl:22][CH2:23][CH2:24][C:25](Cl)=[O:26]>C(Cl)Cl>[Cl:22][CH2:23][CH2:24][C:25]([N:9]([C:8]1[C:4]([Cl:3])=[N:5][N:6]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=1)[CH2:10][CH3:11])=[O:26]
Reactant: CCNc1cn(-c2cccnc2)nc1Cl
Reactant: O=C(Cl)CCCl
Agent: CC1CO1
Agent: Cl
Solvent: ClCCl
Product: CCN(C(=O)CCCl)c1cn(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.3 %

Procedure:
To a stirred solution of 3-chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine dihydrochloride (1.00 g, 3.38 mmol) in CH2Cl2 (7 mL) was added propylene oxide (1.00 mL, 13.5 mmol) followed by 3-chloropropanoyl chloride (0.360 mL, 3.72 mmol). This was stirred at room temperature for 16 hours, and then the reaction mixture was then diluted with CH2Cl2 and washed with water. The phases were separated, the organic were dried, concentrated and purified by silica gel chromatography eluting with 0%-50% acetone/hexanes to afford a white solid (0.850 g, 80%): mp 85-86° C.; 1H NMR (400 MHz, CDCl3) δ 8.96 (d, J=2.6 Hz, 1H), 8.64 (dd, J=4.7, 1.4 Hz, 1H), 8.05 (ddd, J=8.3, 2.7, 1.4 Hz, 1H), 7.98 (s, 1H), 7.47 (ddd, J=8.4, 4.8, 0.6 Hz, 1H), 3.80 (t, J=6.7 Hz, 2H), 3.74 (q, J=7.1 Hz, 2H), 2.64 (t, J=6.7 Hz, 2H), 1.18 (t, J=7.2 Hz, 3H); ESIMS m/z 313 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:37]C(=O)OCC2C3C=CC=CC=3C3C2=CC=CC=3)[C:14]([N:16]([C@@H:28]([CH3:36])[CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:27]=2[N:26]=[CH:25][CH:24]=[CH:23]3)=[O:15])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].N1CCCCC1>>[NH2:37][C@@H:13]([CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:7][CH:8]=1)[C:14]([N:16]([C@@H:28]([CH3:36])[CH:29]([O:30][CH2:31][CH3:32])[O:33][CH2:34][CH3:35])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:27]=1[N:26]=[CH:25][CH:24]=[CH:23]2)=[O:15]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCNCC1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Yield: 76.8 %

Procedure:
According to the procedure described in the synthesis method of Compound IV-1, (9H-fluoren-9-yl)methyl(S)-3-(4-tert-butoxyphenyl)-1-(((S)-1,1-diethoxypropan-2-yl)(quinolin-8-ylmethyl)amino)-1-oxopropan-2-ylcarbamate (Compound III-7) (2.41 g, 3.31 mmol) was treated with piperidine and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=9:1, chloroform:methanol=100:0 and 8:2) to obtain the title compound (1.29 g, 77%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH3:18])([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:19]=1.Br[C:21]1[CH:22]=[C:23]([C:26]#[N:27])[O:24][CH:25]=1>>[CH3:18][C:7]1([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[C:6]2[CH:19]=[C:2]([C:21]3[CH:22]=[C:23]([C:26]#[N:27])[O:24][CH:25]=3)[CH:3]=[CH:4][C:5]=2[NH:11][C:10](=[O:12])[CH2:9][O:8]1
Reactant: N#Cc1cc(Br)co1
Reactant: CC1(c2cccs2)OCC(=O)Nc2ccc(Br)cc21
Product: CC1(c2cccs2)OCC(=O)Nc2ccc(-c3coc(C#N)c3)cc21

Procedure:
Prepared from 7-bromo-5-methyl-5-thien-2-yl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 4-bromofuran-2-carbonitrile generally according to the coupling procedure described in examples 82 and 1. 1H-NMR (DMSO-d6) δ 10.09 (s, 1H), 8.60 (s, 1H), 8.16 (s, 1H), 7.61 (m, 2H), 7.54 (dd, J=4.9, 1.0 Hz, 1H), 7.22 (d, J=8.3 Hz, 1H), 6.97 (dd, J=5.4, 3.9 Hz, 1H), 6.84 (dd, J=3.4, 1.0 Hz, 1H), 4.16 (d, J=15.6 Hz, 1H), 4.00 (d, J=15.6 Hz, 1H), 2.07 (s, 3H); MS (ES) m/z 351 (M+H)+.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[CH2:9]([O:16][C@@H:17]([CH3:20])[CH:18]=[O:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl-].[NH4+]>CS(C)=O.C(COC)OC>[CH2:9]([O:16][C@@H:17]([CH3:20])[CH:18]1[O:19][CH2:2]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C[C@@H](C=O)OCc1ccccc1
Reactant: C[S+](C)(C)=O
Agent: [Cl-]
Agent: [H-]
Agent: [I-]
Solvent: COCCOC
Solvent: CS(C)=O
Product: C[C@H](OCc1ccccc1)C1CO1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58.4 %

Procedure:
Trimethylsulfoxonium iodide (1.22 g) was added to a stirred suspension of sodium hydride (60% in mineral oil, 234 mg) in dimethylsulfoxide (12 ml) and dimethoxyethane (10 ml) at −3° C. to −4° C. under nitrogen atmosphere. After 10 minutes, a solution of (S)-2-(benzyloxy)propionaldehyde (obtained in Preparation 8) (800 mg) in dimethoxyethane (2 ml) was added dropwise to the mixture for a period of 5 minutes at the same temperature, and the resulting mixture was stirred for 30 minutes at room temperature. The mixture was poured into a cold saturated ammonium chloride solution (50 ml) and extracted with ethyl acetate (100 ml). The organic layer was washed with brine (50 ml), dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel (20 g) chromatography eluted with hexane/ethyl acetate (30:1) to give (3S)-3-benzyloxy-1,2-epoxybutane (507 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@:10]2([CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:34])[C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=4[CH3:33])=[CH:19][CH:18]=3)[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:35](N1CCOCC1)=O>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@:10]2([CH2:16][CH2:15][N:14]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH:35]=[CH:33][C:26]5[C:25](=[CH:30][CH:29]=[C:28]([O:31][CH3:32])[CH:27]=5)[C:24]4=[O:34])=[CH:21][CH:22]=3)[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=CN1CCOCC1
Reactant: COc1ccc(C(=O)Nc2ccc(N3CC[C@]4(CCN(C(=O)OC(C)(C)C)C4)C3)cc2)c(C)c1
Product: COc1ccc2c(=O)n(-c3ccc(N4CC[C@]5(CCN(C(=O)OC(C)(C)C)C5)C4)cc3)ccc2c1

Procedure:
According to Method Q, (S)-7-[4-(4-methoxy-2-methyl-benzoylamino)-phenyl]-2,7-diaza-spiro[4.4]nonane-2-carboxylic acid tert-butyl ester was reacted with N-formylmorpholine. In this way the product was obtained with molecular weight 475.59 (C28H33N3O4); MS (ESI): 476 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH:4]([NH:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[CH2:5][C:6](=[O:18])[CH:7]([CH:15]([CH3:17])[CH3:16])C(OC(C)(C)C)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:30])[C@@H:4]([NH:19][C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21])[CH2:5][C:6](=[O:18])[CH2:7][CH:15]([CH3:17])[CH3:16]
Reactant: COC(=O)C(CC(=O)C(C(=O)OC(C)(C)C)C(C)C)NC(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](CC(=O)CC(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 90.1 %

Procedure:
A solution of 5-Benzyloxycarbonylamino-2-isopropyl-3-oxo-hexanedioic acid 1-tert-butyl ester 6-methyl ester (1.06 g, 2.51 mmol) and p-toluenesulfonic acid monohydrate (35.8 mg, 0.19 mmol) in toluene (20 mL) is heated to reflux under N2 for 6.5 hr. The mixture is cooled to room temperature, and concentrated in vacuum. The residue is purified over 35 g silica gel, eluting with EtOAc:Heptane (1:4) to afford (S)-2-Benzyloxycarbonylamino-6-methyl-4-oxo-heptanoic acid methyl ester (727 mg, 90%). 1H NMR (CDCl3): δ 7.4 (m, 5H), 5.78 (d, J=9.1 Hz, 1H), 5.13 (s, 2H), 4.6 (m, 1H), 3.74 (s, 3H), 3.2 (dd, J=18.3, 4.4 Hz, 1H), 2.95 (dd, J=18.2, 4.0 Hz, 1H), 2.3 (m, 2H), 2.1 (m, 1H), 0.92 (d, J=6.7 Hz, 6H); LC/MS: 77% 322 (MH+).
Reaction SMILES: [OH-].[Li+].[CH3:3][S:4]([NH:7][C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[C:13]([C:26]([O-:28])=[O:27])[N:14]2[C:17]([O:19]CCC(C)(C)C)=[O:18])=[CH:10][CH:9]=1)(=[O:6])=[O:5].CO.O>C1COCC1>[CH3:10][C:11]([O:19][C:17]([N:14]1[C:15]2[C:11](=[CH:10][CH:9]=[C:8]([NH:7][S:4]([CH3:3])(=[O:5])=[O:6])[CH:16]=2)[CH:12]=[C:13]1[C:26]([OH:28])=[O:27])=[O:18])([CH3:15])[CH3:12]
Reactant: CC(C)(C)CCOC(=O)n1c(C(=O)[O-])cc2ccc(NS(C)(=O)=O)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)n1c(C(=O)O)cc2ccc(NS(C)(=O)=O)cc21
Temperature: 50 °C
Yield: 79.2 %

Procedure:
Lithium hydroxide (0.068 g, 2.85 mmol) was added to a solution of 1-(1,1-dimethylethyl)2-ethyl 6-[(methylsulfonyl)amino]-1H-indole-1,2-dicarboxylate (0.109 g, 0.285 mmol) in THF:methanol:water/3:1:1 (3 mL). The mixture was heated at 50° C. for 2 hrs. The solvent was evaporated and the residue was dissolved in water, acidified with 1N aqueous HCl and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated to give the title compound (0.040 g, 55%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.92 (br. s., 1H), 11.41-11.79 (m, 1H), 9.32-9.73 (m, 1H), 7.48-7.57 (m, 1H), 7.31 (s, 1H), 6.94-7.00 (m, 1H), 6.88-6.94 (m, 1H), 2.88 (s, 3H). ES MS: m/z 253 (M−1).
Reaction SMILES: [CH2:1]([C:5]1[S:20][C:8]2[N:9]=[C:10]3[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][N:11]3[C:12](=[O:13])[C:7]=2[CH:6]=1)[CH2:2][CH2:3][CH3:4].[N-:21]=[N+:22]=[N-:23].[Na+].[Cl-].[NH4+]>CN(C)C=O>[CH2:1]([C:5]1[S:20][C:8]2[N:9]=[C:10]3[CH:17]=[CH:16][C:15]([C:18]4[NH:23][N:22]=[N:21][N:19]=4)=[CH:14][N:11]3[C:12](=[O:13])[C:7]=2[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc2c(=O)n3cc(C#N)ccc3nc2s1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1cc2c(=O)n3cc(-c4nnn[nH]4)ccc3nc2s1
Yield: 56.4 %

Procedure:
From 7 g (0.025 mol) of 2-butyl-4-oxo-4H-pyrido[1,2-a]thieno-[2,3-d]pyrimidine-7-carbonitrile (Example 30), 8.45 g (0.13 mol) of sodium azide and 6.85 g (0.13 mol) of ammonium chloride in 250 ml of dimethylformamide heated at 125°-128° C. under a nitrogen atmosphere, following the procedure of Example 34, there is obtained 4.6 g of 2-butyl-7-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidin-4-one; mp 281° C. (dec) after recrystallization from dimethylformamide-methanol.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][N:13]([CH3:15])[CH3:14])=[C:8]([Cl:16])[CH:7]=2)[CH2:2]1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[O:29][C:28]([C:30](OCC)=[O:31])=[N:27][N:26]=2)=[CH:21][CH:20]=1>>[Cl:16][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=1[CH2:12][N:13]([CH3:14])[CH3:15])[O:5][CH:3]1[CH2:4][N:1]([C:30]([C:28]2[O:29][C:25]([C:22]3[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=3)=[N:26][N:27]=2)=[O:31])[CH2:2]1
Reactant: CCOC(=O)c1nnc(-c2ccc(OC)cc2)o1
Reactant: CN(C)Cc1ccc(OC2CNC2)cc1Cl
Product: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(CN(C)C)c(Cl)c4)C3)o2)cc1
Yield: 81.8 %

Procedure:
Using a similar protocol as described in Example 16 employing 47A (70 mg, 0.29 mmol) and ethyl 5-(4-methoxyphenyl)-1,3,4-oxadiazole-2-carboxylate (75 mg, 0.30 mmol) as starting materials afforded 105 mg (82%) of 47 as a solid. 1H NMR (500 MHz, CDCl3): δ 2.20 (s, 6H), 3.48 (s, 2H), 3.90 (s, 3H), 4.32 (dd, 1H), 4.65 (dd, 1H), 4.74 (dd, 1H), 5.06 (m, 1H), 5.13 (dd, 1H), 6.68 (dd, 1H), 6.80 (d, 1H), 7.02 (d, 2H), 7.35 (d, 1H), 8.10 (d, 2H), MS (APCI+) m/z 443 [M+H]+, LC purity: 91%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:28]([C:30]1[N:31]=[C:32]([CH3:42])[N:33]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[CH:34]=1)#[CH:29]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]([C:29]#[C:28][C:30]2[N:31]=[C:32]([CH3:42])[N:33]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[CH:34]=2)[CH:5]=[CH:4][N:3]=1
Reactant: C#Cc1cn(-c2ccc(F)cc2)c(C)n1
Reactant: Clc1cc(I)ccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Chloro-4-iodopyridine (1.39 g, 5.8 mmol) was dissolved in 50 mL dry THF. This mixture was evacuated and backfilled with argon several times to remove oxygen from the solution. Triphenylphosphine (39 mg, 0.15 mmol) and bis(triphenylphosphine)palladium(II) chloride (170 mg, 0.24 mmol) were added and the reaction mixture was stirred at room temperature for 1 h. Copper(I) iodide (28 mg, 0.15 mmol) and 4-ethynyl-1-(4-fluoro-phenyl)-2-methyl-1H-imidazole (970 mg, 4.84 mmol) were added. The reaction mixture was stirred at room temperature for 3 days. The solvent was evaporated. The residue was taken up in 100 mL water and extracted three times with ethyl acetate (100 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate/triethyl amine 1:0:0->10:10:1 gradient) and recrystallized from heptane and ethyl acetate. The desired product was obtained as a white solid (545 mg, 36%), MS: m/e=312.1 (M+H+).
Reaction SMILES: C(N)C1C=CC=CC=1.C(O)(=O)C.O1CC1COC1C2C3C(=CC=CC=3)NC=2C=CC=1.[CH3:31][O:32][C:33]1[C:38]([O:39][CH2:40][CH2:41][N:42]([CH2:50][CH:51]([OH:67])[CH2:52][O:53][C:54]2[C:59]3[C:60]4[C:65]([NH:66][C:58]=3[CH:57]=[CH:56][CH:55]=2)=[CH:64][CH:63]=[CH:62][CH:61]=4)CC2C=CC=CC=2)=[CH:37][CH:36]=[CH:35][CH:34]=1>C(OC(=O)C)C.[Pd]>[CH3:31][O:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:38]=1[O:39][CH2:40][CH2:41][NH:42][CH2:50][CH:51]([OH:67])[CH2:52][O:53][C:54]1[CH:55]=[CH:56][CH:57]=[C:58]2[NH:66][C:65]3[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=3[C:59]=12
Reactant: COc1ccccc1OCCN(Cc1ccccc1)CC(O)COc1cccc2[nH]c3ccccc3c12
Agent: [Pd]
Agent: c1ccc2c(c1)[nH]c1cccc(OCC3CO3)c12
Solvent: NCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccccc1OCCNCC(O)COc1cccc2[nH]c3ccccc3c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 450 ml ethylacetate, 70 g (0.27 moles) of anhydrous N-2-[2-(methoxy)-phenoxy]-ethyl]-benzylamine, 3.65 g (0.06 moles) of acetic acid and 25 g (0.105 moles) of 4-(oxiranylmethoxy)-9H-carbazole are added and the reaction mixture is heated to reflux for 24 hrs ( TLC control for checking conversion to N-benzyl carvedilol). To the above reaction mixture, a second lot of 3.65 g (0.06 moles) of acetic acid and 25 g (0.105 moles) of 4-(oxiranylmethoxy)-9H-carbazole are added and the reaction mixture is further heated to reflux for 24 hrs (TLC control for checking conversion to N-benzyl carvedilol). The reaction mixture is cooled to ambient temperature and subjected to hydrogenation reaction. To this solution of N-benzyl carvedilol in ethylacetate, (7 g) of wet Pd/C catalyst (5% Pd content and 50% moisture content) is added. The reaction mixture is hydrogenated at 3.5-4.5 Kg/cm2 at temperature of 60-70° C. for a period of about 8 hours. The reaction mixture is filtered and the filtrate is washed with 12-15% v/v aqueous ammonia (1 volume w. r .t. to the carbazole). The product enriched organic layer is separated and concentrated to remove ethylacetate. To the resultant syrupy mass n-butanol (100 ml) is added and the solution is stirred for about 10 hours, the crystals separated by filtration, washed successively with n-butanol (50 ml) and toluene (50 ml) to obtain carvedilol (45 g). The product is recrystallized from 3 volumes of ethyl acetate to obtain carvedilol (41 g).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]([O:17][CH3:18])=[O:16]>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][C:14]1[O:10][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][CH:13]=1
Reactant: Cc1ccccc1CCl
Reactant: COC(=O)c1ccco1
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(Cc2ccccc2C)o1
Yield: 49.2 %

Procedure:
A mixture of 2-methylbenzyl chloride [prepared as described by Voronkov and Popova, Latv. P.S.R. Zinat. Akad. Vestis Kim. Sev. 1970(5), 595; 62 g.], methyl 2-furoate (114 g.) and anhydrous ferric chloride (1.4 g.) in dry carbon tetrachloride (120 ml.) was heated on a steam bath under relfux for 18 hours. The solution was then evapoated to dryness. The residue was dissolved in chloroform, washed with 2N hydrochloric acid and water, dried over magnesium sulphate and distilled to give methyl 5-(2-methylbenzyl)-2-furoate (50 g.) in the form of a yellow coloured oil, b.p. 140°-170° C./0.1-0.5 mm.Hg.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[C:17]1[CH2:26][CH:25]([C:27]([NH2:29])=O)[CH2:24][CH2:23][N:18]12.N1C=CC=CC=1>O1CCOCC1>[CH:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[C:17]1[CH2:26][CH:25]([C:27]#[N:29])[CH2:24][CH2:23][N:18]12
Reactant: NC(=O)C1CCn2c(cc3ccccc32)C1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: N#CC1CCn2c(cc3ccccc32)C1
Yield: 53.9 %

Procedure:
25.7 g (126 mmol) of trifluoroacetic anhydride were added dropwise to a stirred suspension of 26.5 g (123 mmol) of 6,7,8,9-tetrahydropyrido[1,2-a]indole-8-carboxamide and 23.4 g (300 mmol) of pyridine in 500 ml of dry dioxane at 10° C. After completion of the addition, the solvent was removed under reduced pressure and the residue was crystallized from methanol to give 13 g of 6,7,8,9-tetrahydropyrido[1,2-a]indole-8(RS)-carbonitrile, as a light tan solid of melting point 106°-109° C.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[N:3]1[CH2:12][C:13]([OH:15])=O.[Cl:16][C:17]1[C:18]([C:23]2[N:27]=[CH:26][NH:25][N:24]=2)=[C:19]([NH2:22])[S:20][CH:21]=1>>[Cl:16][C:17]1[C:18]([C:23]2[N:27]=[CH:26][NH:25][N:24]=2)=[C:19]([NH:22][C:13](=[O:15])[CH2:12][N:3]2[C:4]3[C:9](=[N:8][CH:7]=[CH:6][CH:5]=3)[CH:10]=[CH:11][C:2]2=[O:1])[S:20][CH:21]=1
Reactant: O=C(O)Cn1c(=O)ccc2ncccc21
Reactant: Nc1scc(Cl)c1-c1nc[nH]n1
Product: O=C(Cn1c(=O)ccc2ncccc21)Nc1scc(Cl)c1-c1nc[nH]n1

Procedure:
The title compound was prepared from 2-(2-oxo-1,5-naphthyridin-1(2H)-yl)acetic acid (0.13 g, 0.62 mmol) and 4-chloro-3-(1H-1,2,4-triazol-3-yl)thiophen-2-amine (0.22 g, 1.12 mmol) according to protocol A and purified by prep HPLC. Retention time (min)=1.010, method [4], MS (ESI) 389.0 (M+H).