Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:6]1[CH:15]=[CH:14][C:9]2[NH:10][C:11]([SH:13])=[N:12][C:8]=2[CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2].[OH-].[Na+].Cl.[CH3:19][O:20][C:21]1[C:22]([CH2:29]Cl)=[N:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>O.C(O)C>[C:1]([C:6]1[CH:15]=[CH:14][C:9]2[NH:10][C:11]([S:13][CH2:29][C:22]3[C:21]([O:20][CH3:19])=[C:26]([O:27][CH3:28])[CH:25]=[CH:24][N:23]=3)=[N:12][C:8]=2[CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: COc1ccnc(CCl)c1OC
Reactant: CCOC(=O)c1ccc2[nH]c(S)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1ccc2[nH]c(SCc3nccc(OC)c3OC)nc2c1
Reaction time: 6 h
Yield: 71 %

Procedure:
5-Carbethoxy-2-mercapto-1H-benzimidazole (2.0 g, 9 mmol) and NaOH (0.36 g, 9 mmol) in H2O (1 ml) were dissolved in ethanol (30 ml). 3,4-dimethoxy-2-chloromethylpyridine hydrochloride (≈6.6 mmol) as a crude material were added and the mixture was heated to boiling. NaOH (0.26 g, 6.6 mmol) in H2O (1 ml) was added and the reflux was continued for 6 hours. The solvent was evaporated off and the residue was diluted with methylene chloride and water. The organic phase was dried over Na2SO4 and the solvent removed under reduced pressure. Crystallizing from CH3CN gave the desired product (1.75 g, 71%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][OH:8].C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl-].[Li+].[CH3:22][O:23][CH2:24]OC>>[CH3:22][O:23][CH2:24][O:8][CH2:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: COCOC
Reactant: OCCc1cccs1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [Li+]
Product: COCOCCc1cccs1
Reaction time: 0.08 h
Yield: 96 %

Procedure:
150 g of 2-thiopheneethanol was dissolved in 2,250 mL of dimethoxymethane, and 22.3 g of p-toluenesulfonic acid and 20.3 g of lithium chloride were added thereto. The resulting mixture was refluxed for 5 hours and concentrated by evaporation under reduced pressure. To the residue, 1,000 mL of water and 1,500 mL of n-hexane were added, and the resulting mixture was stirred for 5 minutes. Aqueous layer was discarded, and the organic layer was washed twice with 700 mL portions of water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 193 g (yield of 96%) of the title compound as a colorless oil.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[C:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)#[N:20]>>[C:19]([C:21]1[CH:26]=[CH:25][C:24]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)=[CH:23][CH:22]=1)#[N:20]
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Reactant: N#Cc1ccc(B(O)O)cc1
Product: Cc1c2n(c3c(-c4ccc(C#N)cc4)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, light grey solid (73 mg, 89%), MS (ISP) m/z=327.5 [(M+H)+], mp 323° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 4-cyanophenylboronic acid (47.8 mg, 0.325 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[CH:30]([C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][C:41]([C:44]([OH:46])=[O:45])=[CH:40][CH:39]=2)=[CH:34][CH:33]=1)=O>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][CH2:30][C:32]3[CH:37]=[CH:36][C:35]([C:38]4[CH:43]=[CH:42][C:41]([C:44]([OH:46])=[O:45])=[CH:40][CH:39]=4)=[CH:34][CH:33]=3)[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1ccc(-c2ccc(C(=O)O)cc2)cc1
Product: O=C(O)c1ccc(-c2ccc(CNc3cccc(-c4c(C(=O)c5ccccc5)cnc5c(C(F)(F)F)cccc45)c3)cc2)cc1

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone and 4′-formyl-biphenyl-4-carboxylic acid according to the procedure of Example 66. MS (ES) m/z 600.9.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH2:8]([O:15][C:16]([N:18]1[CH2:24][CH2:23][CH:22]([OH:25])[CH:21]([NH2:26])[CH2:20][CH:19]1CC1C=CC=CC=1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:8]([O:15][C:16]([N:18]1[CH2:24][CH2:23][CH:22]([OH:25])[CH:21]([NH:26][C:1](=[O:3])[CH3:2])[CH2:20][CH2:19]1)=[O:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: NC1CC(Cc2ccccc2)N(C(=O)OCc2ccccc2)CCC1O
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)NC1CCN(C(=O)OCc2ccccc2)CCC1O
Reaction time: 1 h

Procedure:
3 mL acetic anhydride was added to 8.4 g benzyl 4-amino-5-hydroxy-azepane-1-carboxylic acid benzyl ester in 115 ml dichloromethane at 0° C. After 1 h at RT, saturated sodium bicarbonate was added. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed with brine, dried over sodium sulphate, filtered and concentrated. The residue was purified by chromatographie on silica gel (ethyl acetate/hexane 2:1) to yield 4.5 g of the desired product. (M+H)+: 307
Reaction SMILES: Br[C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]([OH:10])=O.C1COCC1.B.C1COCC1.[Cl:22][C:23]1[C:28]([F:29])=[CH:27][CH:26]=[C:25]([O:30][CH3:31])[C:24]=1[C@H:32]([C:34]1[C:42]2[C:37](=[N:38][CH:39]=[C:40](B3OC(C)(C)C(C)(C)O3)[CH:41]=2)[NH:36][CH:35]=1)[CH3:33].C([O-])([O-])=O.[K+].[K+].O>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O1CCOCC1>[Cl:22][C:23]1[C:28]([F:29])=[CH:27][CH:26]=[C:25]([O:30][CH3:31])[C:24]=1[C@H:32]([C:34]1[C:42]2[C:37](=[N:38][CH:39]=[C:40]([C:2]3[CH:6]=[N:5][N:4]([CH3:7])[C:3]=3[CH2:8][OH:10])[CH:41]=2)[NH:36][CH:35]=1)[CH3:33]
Reactant: Cn1ncc(Br)c1C(=O)O
Reactant: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: B
Solvent: O
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(-c3cnn(C)c3CO)cc12
Temperature: 60 °C

Procedure:
To a solution of 4-bromo-2-methyl-2H-pyrazole-3-carboxylic acid (20.0 mg, 0.0976 mmol) in THF (3 mL, 40 mmol) was added 1.0 M of BH3.THF in THF (0.49 mL, 0.49 mmol), and the resulting solution was heated to 60° C. overnight. The material was extracted with EtOAc, and washed with sat. NaHCO3 (3×) to remove carboxylic acid starting material. The organic layer was concentrated in vacuo. 3-[(S)-1-(2-Chloro-3-fluoro-6-methoxyphenyl)-ethyl]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (15.0 mg, 0.0348 mmol), (1,1′bis-(diphenylphosphino)-ferrocene) palladium dichloride (3.57 mg, 0.00488 mmol), K2CO3 (20.2 mg, 0.146 mmol) and 4:1 dioxane:H2O (1 mL, 10 mmol) were added, and the mixture was heated to 95° C. for 30 min. The solution was used directly for HPLC purification, and the fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.80 (d, J=7.1 Hz, 3H), 3.67 (br. s., 3H), 3.96 (s, 3H), 4.55 (s, 2H), 5.08-5.17 (m, 1H), 6.90 (dd, J=9.1, 4.3 Hz, 1H), 7.08 (t, J=8.8 Hz, 1H), 7.34 (d, J=1.3 Hz, 1H), 7.46 (s, 1H), 7.53 (s, 1H), 8.15-8.22 (m, 1H). MS (ES+): m/z=415.13/417.13 (100/50) [MH+]. HPLC: tR=1.37 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: BrC1C=C(C(Cl)=O)C=CC=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[C:28]([F:33])[CH:27]=1.[Br:34][C:35]1[CH:36]=[C:37]([C:41]([N:43]=[C:44]=[S:45])=[O:42])[CH:38]=[CH:39][CH:40]=1>C1(C)C=CC=CC=1.C(O)C>[Br:34][C:35]1[CH:36]=[C:37]([C:41]([N:43]=[C:44]=[S:45])=[O:42])[CH:38]=[CH:39][CH:40]=1.[Br:34][C:35]1[CH:36]=[C:37]([CH:38]=[CH:39][CH:40]=1)[C:41]([NH:43][C:44]([NH:30][C:29]1[CH:31]=[CH:32][C:26]([O:25][C:16]2[C:15]3[C:20](=[CH:21][C:22]([O:23][CH3:24])=[C:13]([O:12][CH3:11])[CH:14]=3)[N:19]=[CH:18][CH:17]=2)=[CH:27][C:28]=1[F:33])=[S:45])=[O:42]
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: O=C(Cl)c1cccc(Br)c1
Agent: O=C(N=C=S)c1cccc(Br)c1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(Br)c4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
3-Bromo-1-benzenecarbonyl isothiocyanate was prepared using commercially available 3-bromo-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3-bromo-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (85 mg, yield 96%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:8]([C:13](=O)[C:14]2[CH:19]=[CH:18][N:17]=[C:16]([Br:20])[CH:15]=2)=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.O.[NH2:23][NH2:24]>CO>[Br:20][C:16]1[CH:15]=[C:14]([C:13]2[C:8]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:10]([O:11][CH3:12])[CH:9]=3)[CH:6]=[N:24][N:23]=2)[CH:19]=[CH:18][N:17]=1
Reactant: NN
Reactant: COc1cc(C=O)c(C(=O)c2ccnc(Br)c2)cc1OC
Solvent: O
Solvent: CO
Product: COc1cc2cnnc(-c3ccnc(Br)c3)c2cc1OC

Procedure:
To a solution of 3,4-dimethoxy-6-(2-bromoisonicotinoyl)benzaldehyde (4.5 g) in methanol (70 ml) is added dropwise hydrazine monohydrate (0.8 ml). The reaction mixture is cooled with ice, and the precipitates are collected by filtration, and recrystallized from methanol to give 2-bromo-4-(6,7-dimethoxyphthalazin-1-yl)pyridine (4.01 g) as yellow crystals.
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].[I:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1>C1COCC1>[I:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](=[O:12])[CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)C(=O)c1ccc(I)cc1
Reaction time: 0.17 h

Procedure:
A 2.0 M solution of Isopropylmagnesium chloride (10 ml, 20 mmol) was added dropwise (30 min), under nitrogen, to a stirred solution of freshly distilled 4-iodobenzoyl chloride (5.32 g, 20 mmol) and Fe(acac)3 (0.35 g, 1 mmol) in 150 ml of dry THF at room temperature. After addition, the stirring was continued for 10 min at the same temperature. The reaction was quenched by pouring the mixture into dilute hydrochloric acid and extracted with several portions of ether. The combined ether extracts were washed with aq. NaHCO3, water, and dried over Na2SO4. Removal of the organic solvents under vacuum gave the product as colorless oil. And the crude product was used for the next step without further purification.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][C:11]=2[C:12]#[N:13])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].CCO.CC1C=C2N=C3C(=NC(NC3=O)=O)N(C[C@H](O)[C@H](O)[C@H](O)CO)C2=CC=1C>O.[Pd]>[NH2:18][C:15]1[CH:16]=[CH:17][C:10]([N:7]2[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]2)=[C:11]([CH:14]=1)[C:12]#[N:13]
Reactant: CC(C)N1CCN(c2ccc([N+](=O)[O-])cc2C#N)CC1
Agent: [Pd]
Agent: Cc1cc2nc3c(=O)[nH]c(=O)nc-3n(C[C@H](O)[C@H](O)[C@H](O)CO)c2cc1C
Solvent: CCO
Solvent: O
Product: CC(C)N1CCN(c2ccc(N)cc2C#N)CC1
Reaction time: 2 h
Yield: 95 %

Procedure:
A round-bottom flask was charged with 2-(4-isopropylpiperazin-1-yl)-5-nitrobenzonitrile (1.76 g, 6.42 mmol), EtOH (65 mL), and 10% Pd/C (50% in water, Degussa type E101; 355 mg, 20 wt % by weight of the starting nitro compound). The flask was sealed with a rubber septum, degassed, and back-filled with H2 (×3) from a balloon filled with H2. The reaction was stirred for 2 h using a H2 filled balloon. The reaction mixture was filtered through a pad of celite, and the pad of celite was rinsed with MeOH. The filtrate was evaporated to dryness, and the product dried in vacuo to provide 5-amino-2-(4-isopropylpiperazin-1-yl)benzonitrile (1.49 g, 95% yield) as a yellow solid that was used without further purification.
Reaction SMILES: [OH:1][CH2:2][C:3]([C@@H:5]([C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4].[OH:13][CH2:14][C:15]([CH:17]([CH:19]([CH:21]([CH2:23][OH:24])[OH:22])[OH:20])[OH:18])=[O:16]>>[O:1]=[CH:2][CH:3]([CH:5]([CH:7]([CH:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[OH:13][CH2:14][C:15]([C@@H:17]([C@H:19]([C@H:21]([CH2:23][OH:24])[OH:22])[OH:20])[OH:18])=[O:16]
Reactant: O=C(CO)C(O)C(O)C(O)CO
Agent: O=C(CO)[C@H](O)[C@@H](O)[C@@H](O)CO
Product: O=CC(O)C(O)C(O)C(O)CO

Procedure:
L-Fructose, which has not been found in nature, was synthesized for the first time by Fischer. See E. Fischer, Ber., 23 (1890) 370-394. DL-Glucose phenylosazone was prepared from α-acrose and hydrolyzed to the glycosulose, which was reduced to DL-fructose. L-Fructose was isolated from the mixture. L-Fructose was later synthesized by Wolfrom and Thompson from L-arabinonic acid in five steps. See M. L. Wolfrom and A. Thompson, Methods of Carbohydr. Chem., 1 (1962) 118-120.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:18]1(=O)[O:23][C:21](=[O:22])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.O>C(Cl)(Cl)Cl>[C:18]1(=[O:23])[N:8]([CH2:7][C:6]2[CH:9]=[CH:10][C:3]([Br:2])=[CH:4][CH:5]=2)[C:21](=[O:22])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12
Reactant: NCc1ccc(Br)cc1
Reactant: O=C1OC(=O)c2ccccc21
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
To a suspension of 10 g (44.94 mmol) of 4-bromobenzylamine hydrochloride in 200 ml of chloroform was added 12.5 ml (89.62 mmol) of triethylamine, followed by the addition of 8.99 g (60.67 mmol) of phthalic anhydride. The mixture was stirred at room temperature for 10 minutes to give a homogeneous solution, which was then heated at 75° C. for three hours. The reaction mixture was then evaporated to remove the chloroform and the residue was suspended in 400 ml of toluene followed by adding 700 mg of p-toluenesulfonic acid monohydrate. The resulting mixture was briefly refluxed at 140° C., and additional 3 ml of triethylamine was added to form a homogeneous solution. The solution was refluxed at 140° C. for 2 hours; and the water formed was collected through a Dean-Stark trap apparatus. The solution was then cooled to room temperature, washed with 3% sodium hydroxide (2×200 ml), water (1×200 ml), brine (1×200 ml), and dried over sodium sulfate. Removal of the solvent under reduced pressure gave 12.07 g (85% yield) of 4-phthalimidomethyl bromobenzene as a white solid. Rf: 0.6 (silica gel, ethyl acetate:hexane=1:2). 1H NMR (CDCl3): δ ppm 4.79 (2H, s), 7.31, 7.44 (2H each, AA'BB'), 7.73, 7.84 (2H each, m).
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=[O:23])[N:9]3[CH2:22][CH2:21][CH2:20][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](=[N:18][OH:19])[NH2:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:24][CH2:25][C:26](OC(=O)CCl)=O>CN(C)C=O>[Br:1][C:2]1[C:7]2[C:8](=[O:23])[N:9]3[CH2:22][CH2:21][CH2:20][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:17]=[C:26]([CH2:25][Cl:24])[O:19][N:18]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: NC(=NO)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Br)cccc1-2
Reactant: O=C(CCl)OC(=O)CCl
Solvent: CN(C)C=O
Product: O=C1c2c(Br)cccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCCN12
Yield: 76.7 %

Procedure:
11.5 g (30.6 mmol) of (S)-8-bromo-9-oxo-11,12, 13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxamidoxime were treated with 6.02 g (35.2 mmol) of chloroacetic anhydride in 60 ml of N,N-dimethylformamide at room temperature for 1 hour and at 105° for 3 hours. After evaporating the solvent the residue was dissolved in methylene chloride and the solution was washed with saturated sodium bicarbonate solution. By drying the organic phase over magnesium sulfate, evaporation of the solvent and chromatography of the residue on silica gel while eluting with ethyl acetate there were obtained 10.2 g (76%) of (S)-8-bromo-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one of m.p. 242°-244°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[NH:5][C:6]1[S:7][C:8]2[C:14](I)=[CH:13][CH:12]=[C:11]([O:16][CH3:17])[C:9]=2[N:10]=1)[CH3:2].C([Sn](CCCC)(CCCC)[C:24]1[O:25][CH2:26][CH2:27][O:28][CH:29]=1)CCC.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH2:1]([O:3][C:4](=[O:18])[NH:5][C:6]1[S:7][C:8]2[C:14]([C:24]3[O:25][CH2:26][CH2:27][O:28][CH:29]=3)=[CH:13][CH:12]=[C:11]([O:16][CH3:17])[C:9]=2[N:10]=1)[CH3:2]
Reactant: CCOC(=O)Nc1nc2c(OC)ccc(I)c2s1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=COCCO1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: C1COCCO1
Product: CCOC(=O)Nc1nc2c(OC)ccc(C3=COCCO3)c2s1
Temperature: 100 °C
Yield: 90.1 %

Procedure:
To a stirred solution of 5.0 g (13.2 mmol) (7-iodo-4-methoxy-benzothiazol-2-yl)-carbamic acid ethyl ester in 60 ml dioxane were added 6.94 g (18.5 mmol) tributyl-(5,6-dihydro-[1,4]dioxin-2-yl)-stannane, 456 mg (0.79 mmol) bis(dibenzylideneacetone)palladium and 491 mg (2.12 mmol) trifurylphosphine. The mixture was heated at 100° C. for 3 h, then cooled to room temperature and concentrated in vacuo. Flash chromatography (5/95 acetone/dichloromethane) afforded 4.00 g (90%) [7-(5,6-dihydro-[1,4]dioxin-2-yl)-4-methoxy-benzothiazol-2-yl]-carbamic acid ethyl ester as a light yellow foam. ES-MS m/e (%): 337 (M+H+, 100).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl:5][C:6]1[CH:7]=[C:8]([CH:33]=[CH:34][CH:35]=1)[CH2:9][N:10]1[C:14]2=[C:15]([N:21]3[CH2:30][CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22]3)[N:16]=[C:17]([C:19]#[N:20])[CH:18]=[C:13]2[C:12]([CH3:31])=[C:11]1[CH3:32].[Cl-].[NH4+].N([O-])=O.[Na+]>CN(C)C=O>[Cl:5][C:6]1[CH:7]=[C:8]([CH:33]=[CH:34][CH:35]=1)[CH2:9][N:10]1[C:14]2=[C:15]([N:21]3[CH2:30][CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22]3)[N:16]=[C:17]([C:19]3[NH:20][N:3]=[N:2][N:1]=3)[CH:18]=[C:13]2[C:12]([CH3:31])=[C:11]1[CH3:32]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1c(C)n(Cc2cccc(Cl)c2)c2c(N3CCc4ccccc4C3)nc(C#N)cc12
Agent: O=N[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cc1c(C)n(Cc2cccc(Cl)c2)c2c(N3CCc4ccccc4C3)nc(-c3nnn[nH]3)cc12
Yield: 33.4 %

Procedure:
Sodium azide (137 mg, 2.1 mmol) was added at 0° C. to a solution of 1-(3-chlorobenzyl)-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carbonitrile (300 mg, 0.7 mmol) prepared in Example 689 and ammonium chloride (74.9 mg, 1.4 mmol) in anhydrous N,N-dimethylformamide (10 ml). The reaction mixture was refluxed overnight. 6% sodium nitrite solution was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/3, v/v) to give 110 mg of the titled compound as a white solid. (Yield: 33%).
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1.Cl[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>CN1CCCC1=O>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[NH:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1
Reactant: Nn1ccc2ccccc21
Reactant: Clc1ccccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: c1ccc(Nn2ccc3ccccc32)nc1
Reaction time: 1 h

Procedure:
Potassium tert-butoxide (3.4 g) was added to a room temperature solution of N-aminoindole (2.0 g) in 1-methyl-2-pyrrolidinone (40 ml). After stirring for one hour, 2-chloropyridine (1.6 ml) was added and the resulting solution was stirred for forty-eight hours. The reaction mixture was then quenched with water, diluted with ethyl acetate (250 ml) and washed with brine (3×250 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give an oil. Purification of the residue by flash chromatography (silica, 0-5% ethyl acetate/dichloromethane) gave the title compound as a solid (2.0 g), m.p. 109°-110° C.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)=[C:15]3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:38](=[O:37])[CH2:39][OH:40])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:33])[NH:14][C:15]=23)[CH2:31][CH2:32]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ccnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Agent: Cl
Product: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ccnc2c1C(=O)N[C@H]1CC[C@H](NC(=O)CO)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-4-fluorophenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f5) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([NH2:10])=[N:6][O:7][C:8]=1[CH3:9].[S:11]1[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[C:13]([S:20](Cl)(=[O:22])=[O:21])=[CH:12]1>C1COCC1>[Cl:3][C:4]1[C:5]([NH:10][S:20]([C:13]2[C:14]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[S:11][CH:12]=2)(=[O:22])=[O:21])=[N:6][O:7][C:8]=1[CH3:9]
Reactant: O=S(=O)(Cl)c1csc2ncccc12
Reactant: Cc1onc(N)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1onc(NS(=O)(=O)c2csc3ncccc23)c1Cl
Yield: 45.5 %

Procedure:
The title compound was prepared by the method of Example 1(C) using NaH (0.12 g, 4.9 mmoles), THF (6 ml), 4-chloro-5-methyl-3-aminoisoxazole (0.26 g, 2.0 mmoles) and thieno[2,3-b]pyridine-3-sulfonyl chloride (0.50 g, 2.1 mmoles), giving 0.30 g (47%) of the title compound as an orange-brown oil.
Reaction SMILES: O=[C:2]([CH3:17])[CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[N+:14]([O-])=O>C(O)(=O)C>[CH3:11][O:10][C:8]([C:7]1[CH:6]=[C:5]2[C:4]([CH:3]=[C:2]([CH3:17])[NH:14]2)=[CH:13][CH:12]=1)=[O:9]
Reactant: COC(=O)c1ccc(CC(C)=O)c([N+](=O)[O-])c1
Solvent: CC(=O)O
Product: COC(=O)c1ccc2cc(C)[nH]c2c1
Yield: 28.9 %

Procedure:
A mixed solution of methyl 4-(2-oxopropyl)-3-nitrobenzoate (3.86 g), reduced iron (9.0 g) and acetic acid (40 ml) is stirred at 90° C. for 24 hours. The solid is removed through filtration, and the filtrate is concentrated under reduced pressure. The resulting residue is purified through silica gel column chromatography (eluent: hexane/ethyl acetate=3/1) to obtain 6-methoxycarbonyl-2-methylindole (0.890 g).