Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[NH:10][CH:11]=[CH:12][N:13]=2)[CH:5]=[CH:4][C:3]=1[N+:14]([O-])=O.CO>[Fe].O>[NH2:14][C:3]1[CH:4]=[CH:5][C:6]([S:8][C:9]2[NH:13][CH:12]=[CH:11][N:10]=2)=[CH:7][C:2]=1[NH2:1]
Reactant: Nc1cc(Sc2ncc[nH]2)ccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CO
Solvent: O
Product: Nc1ccc(Sc2ncc[nH]2)cc1N
Reaction time: 2 h

Procedure:
A mixture of 2.6 g. of 2-amino-4-(imidazol-2-ylthio)-1-nitrobenzene, 2.6 g. of iron powder and 1.3 g. ferrous sulfate in 200 ml. methanol and 50 ml. water is refluxed for 2 hours. An additional 2.6 g. of iron is added and refluxing continued for 2 hours. The mixture is filtered and the filtrate stripped to yield 1,2-diamino-4-(imidazol-2-ylthio)benzene.
Reaction SMILES: [CH2:1]([C:4]1[C:13]([OH:14])=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC(C)=O.C(OCC)C>[CH2:1]([C:4]1[C:13]([O:14][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)[CH:2]=[CH2:3]
Reactant: BrCc1ccccc1
Reactant: C=CCc1ccc2cccnc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: C=CCc1ccc2cccnc2c1OCc1ccccc1
Temperature: 25 °C
Yield: 72 %

Procedure:
To a stirring solution of 7-allylquinolin-8-ol (14.56 mmol, 1 eq.) in acetone (50 mL) in a round bottom flask equipped with a reflux condenser was added potassium carbonate (151.94 mmol, 10.44 eq.) followed by benzyl bromide (17.47 mmol, 1.2 eq.) and the resulting solution was stirred and heated to reflux for 20 h. Additional potassium carbonate (151.94 mmol, 10.44 eq.) was added followed by additional benzyl bromide (29.12 mmol, 2 eq.) and the resulting mixture was heated at reflux and stirred 2 h. The reaction mixture was then cooled to room temperature and diluted with 50 mL of diethyl ether. The resulting suspension was filtered and the filtrate concentrated to a yellow oil that was purified by column chromatography using 10% acetone/dichloromethane to give the product as a pale yellow oil (10.48 mmol, 72%). MS (ESI) m/z 276.2; HRMS: calcd for C19H17NO+H+, 276.13829; found (ESI-FTMS, [M+H]1+), 276.13828.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9]2[CH:24]=[CH:23][C:12]([CH2:13][N:14]3[CH2:19][CH2:18][CH:17]([C:20]([OH:22])=[O:21])[CH2:16][CH2:15]3)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[F:25][CH:26]([F:43])[O:27][C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:25][CH:26]([F:43])[O:27][C:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:3]=[N:4][C:5]([NH:8][C:9]3[CH:24]=[CH:23][C:12]([CH2:13][N:14]4[CH2:19][CH2:18][CH:17]([C:20]([OH:22])=[O:21])[CH2:16][CH2:15]4)=[CH:11][CH:10]=3)=[N:6][CH:7]=2)=[CH:30][CH:29]=1
Reactant: CC1(C)OB(c2ccc(OC(F)F)cc2)OC1(C)C
Reactant: O=C(O)C1CCN(Cc2ccc(Nc3ncc(Br)cn3)cc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(O)C1CCN(Cc2ccc(Nc3ncc(-c4ccc(OC(F)F)cc4)cn3)cc2)CC1
Temperature: 150 °C

Procedure:
To a solution of 1-(4-(5-bromopyrimidin-2-ylamino)benzyl)piperidine-4-carboxylic acid 17 (0.05 mmol) in 1,4-dioxane (1.0 mL) is added 2-(4-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 7 (0.05 mmol), 3M Na2CO3 (0.15 mmol) and Pd(PPh3)4 (0.0025 mmol). The reaction is evacuated and backfilled with nitrogen twice then heated at 150° C. for 10 min. Purification by preparative HPLC (ACN gradient 10-70%) affords 1-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)benzyl)piperidine-4-carboxylic acid A4. 1H NMR (400 MHz, d4-MeOH) δ 8.64 (s, 2H), 7.78 (d, J=8.8 Hz, 2H), 7.56 (d, J=8.8 Hz, 2H), 7.32 (d, J=8.8 Hz, 2H), 7.16 (d, J=8.8 Hz, 2H), 6.78 (t, J=74.0 Hz, 1H), 4.11 (s, 2H), 3.31 (m, 2H), 2.92 (m, 2H), 2.36 (m, 1H), 2.02 (m, 2H), 1.81 (m, 2H). MS (m/z) (M+1)+: 455.2.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[N:10][C:11]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:13]=2[C:14]#[N:15])=[CH:6][C:5]([S:20](Cl)(=[O:22])=[O:21])=[C:4]([O:24][CH3:25])[CH:3]=1.N1C=CC=CC=1.[CH3:32][NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.Cl>ClCCl>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[N:10][C:11]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:13]=2[C:14]#[N:15])=[CH:6][C:5]([S:20]([N:33]([CH3:32])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)(=[O:22])=[O:21])=[C:4]([O:24][CH3:25])[CH:3]=1
Reactant: CNc1ccccc1
Reactant: COc1cc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)cc1S(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)cc1S(=O)(=O)N(C)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.4 %

Procedure:
To 4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-methoxy-benzenesulfonyl chloride (100 mg, 0.24 mmol) in dichloromethane (3 mL), was added pyridine (0.04 mL, 0.48 mmol), followed by addition of N-methylaniline (0.05 mL, 0.48 mmol). The mixture was stirred at r.t. for 16 hrs, then poured into 1 N HCl solution (10 mL). The product was extracted with ethyl acetate and the organic layer was washed with 1N HCl and water, then was dried over MgSO4. Concentration gave 4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-methoxy-N-methyl-N-phenyl-benzenesulfonamide 15-1, (108 mg). MS: 482.0 (M+H)+; tR=8.76 min (method 2).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@H:11]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[Cl:23])[CH2:10]2)[N:3]=1.[CH3:24][O-:25].[Na+].CO>COCCOC>[Cl:23][C:17]1[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=1[CH2:15][NH:14][CH:11]1[CH2:12][CH2:13][N:9]([C:4]2[N:3]=[C:2]([O:25][CH3:24])[C:7]([F:8])=[CH:6][N:5]=2)[CH2:10]1
Reactant: Fc1cnc(N2CC[C@H](NCc3ccc(Cl)cc3Cl)C2)nc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: COCCOC
Product: COc1nc(N2CCC(NCc3ccc(Cl)cc3Cl)C2)ncc1F
Temperature: 70 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
Dissolve (S)-[1-(4-chloro-5-fluoropyrimidin-2-yl)-pyrrolidin-3-yl]-(2,4-dichlorobenzyl)-amine (318 mg, 0.84 mmol) in dry 1,2-dimethoxyethane (20 mL) and add dropwise sodium methoxide in methanol (25% w/v, 1.9 mL, 8.46 mmol). Stir at 70° C. overnight. Add aqueous 2 N hydrochloric acid to a pH of about 6-7 and extract with 30:70 isopropanol:chloroform. Combine the organic layers, wash with saturated aqueous sodium chloride, dry (magnesium sulphate), filter, and concentrate to give a residue. Chromatograph the residue on silica gel to give the title compound (130 mg, 41%). Dissolve the title compound in methanol and add 1 M hydrogen chloride in diethyl ether (350 μL, 0.35 mmol), triturate, and concentrate to give the hydrochloride salt of the title compound. 1H NMR (400 MHz, MeOH-d4) δ 7.96 (1H, s), 7.65-7.76 (2H, m), 7.51 (1H, dd, J=8.2, 1.6 Hz), 4.45-4.56 (2H, m), 4.17 (2H, d, J=6.4 Hz), 3.99-4.10 (2H, m), 3.85-3.95 (4H, m), 2.61 (1H, d, J=6.4 Hz), 2.39 (1H, d, J=6.1 Hz); MS (ES): m/z=371 [M+].
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][C@@H:11]2[C:33](=[O:34])[N:13]3[C:14]([C:30]([O-:32])=[O:31])=[C:15]([CH2:18][S:19][C:20]4[N:24]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[N:23]=[N:22][N:21]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[K+].[C:36](=[O:49])([O:41][CH:42]([CH:46]([CH3:48])[CH3:47])[CH:43]([CH3:45])[CH3:44])[O:37][CH:38](I)[CH3:39].C(OCC)(=O)C.[Cl-].[Na+]>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][C@@H:11]2[C:33](=[O:34])[N:13]3[C:14]([C:30]([O:32][CH:38]([O:37][C:36]([O:41][CH:42]([CH:43]([CH3:44])[CH3:45])[CH:46]([CH3:48])[CH3:47])=[O:49])[CH3:39])=[O:31])=[C:15]([CH2:18][S:19][C:20]4[N:24]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[N:23]=[N:22][N:21]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CN(C)CCn1nnnc1SCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)Cc3csc(N)n3)[C@H]2SC1
Reactant: CC(I)OC(=O)OC(C(C)C)C(C)C
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(OC(=O)OC(C(C)C)C(C)C)OC(=O)C1=C(CSc2nnnn2CCN(C)C)CS[C@@H]2[C@H](NC(=O)Cc3csc(N)n3)C(=O)N12
Temperature: 0 °C

Procedure:
A mixture of 1.78 g of 1-chloroethyl 2,4-dimethyl-3-pentyl carbonate and 5 g of sodium iodide is stirred in 30 ml of acetonitrile at 70° C. for 4 hours and concentrated. The residue is extracted with ether and concentrated to give crude 1-iodoethyl 2,4-dimethyl-3-pentyl carbonate. In 30 ml of dimethylformamide is dissolved 3.6 g of potassium 7β-[2-(2-aminothiazol-4-yl)acetamido]-3-[[[1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl]thio]methyl]ceph-3-em-4-carboxylate, and with ice-cooling and stirring, the above 1-iodoethyl 2,4-dimethyl-3-pentyl carbonate is added thereto at one stroke, followed by stirring for 5 minutes. The reaction mixture is poured into a mixture of 150 ml of ethyl acetate and 150 ml of ice-cooled 20% aqueous sodium chloride. The organic layer is separated, washed with two 150-ml portions of saturated aqueous sodium chloride and extracted with 40 ml of 1N hydrochloric acid. The extract is subjected to column chromatography using Diaion MCI® GEL CHP-20P (Mitsubishi Chemical Industries Limited, Japan), elution being carried out with acetonitrile-0.01N hydrochloric acid. The fractions containing the desired product are combined and lyophilized to give 940 mg of the title compound as a white powder.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][C:9]([Br:16])=[CH:10][CH:11]=3)[CH:6]([C:17]#[N:18])[C:5]=2[CH:4]=1.BrC1C=CC2C3C(=CC(Br)=CC=3)CC=2[C:21]=1[CH:34]=[O:35]>>[CH2:34]([O:35][C:17]([CH:6]1[C:5]2[CH:4]=[C:3]([Br:2])[CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][C:9]([Br:16])=[CH:10][CH:11]=2)=[NH:18])[CH3:21]
Reactant: O=Cc1c(Br)ccc2c1Cc1cc(Br)ccc1-2
Reactant: N#CC1c2cc(Br)ccc2-c2ccc(Br)cc21
Agent: Cl
Product: CCOC(=N)C1c2cc(Br)ccc2-c2ccc(Br)cc21

Procedure:
Dry hydrogen chloride is passed into a solution of 2,7-dibromo-9H-fluorene-9-carbonitrile [obtainable e.g. from the corresponding 2,7-dibromo-9H-fluorene carboxaldehyde (J. Org. Chem., 1944, 9, 155) by oximation and dehydration] by a process analogous to that described in Example 1(a). After working up by a procedure similar to that described in Example 1(a) the product can be used crude or purified before use in Example 2(b) below.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.CN(C)C=O.C(Cl)(C([Cl:20])=O)=O>ClCCl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([Cl:20])=[O:10])=[N:6][CH:7]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cnc(Cl)cn1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cnc(Cl)cn1
Yield: 94 %

Procedure:
5-chloropyrazine-2-carboxylic acid (1.00 gram, 6.31 mmol) in dichloromethane (30 ml) was treated with catalytic amount of dimethylformamide, followed by (COCl)2 (0.85 ml, 9.46 mmol). The resulting mixture was stirred over night. The reaction was concentrated in vacuo, and dried under vacuum to give desired 5-chloropyrazine-2-carbonyl chloride as solid (1.05 g, 100%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)=[O:7].[NH:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:33])[CH2:31][CH3:32])[CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1>>[N+:14]([C:10]1[CH:9]=[C:8]([C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:24]=[C:25]([NH:29][C:30](=[O:33])[CH2:31][CH3:32])[CH:26]=[CH:27][CH:28]=3)[CH2:19][CH2:18]2)[CH:13]=[CH:12][CH:11]=1)([O-:16])=[O:15]
Reactant: CCC(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C(CCCCCl)c1cccc([N+](=O)[O-])c1
Product: CCC(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc([N+](=O)[O-])c3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B using 5-chloro-1-(3-nitrophenyl)-1-pentanone and N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 438.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.C1COCC1.[CH3:16][C:17]([CH3:20])([O-:19])[CH3:18].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O>[C:17]([O:19][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1)([CH3:20])([CH3:18])[CH3:16]
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)Oc1ccc(C(=O)O)cn1
Yield: 58.1 %

Procedure:
To a mixture of 3.0 g of 6-chloronicotinic acid and 111 ml of THF was added 6.4 g of potassium tert-butoxide, followed by heating under reflux for 1 day. The reaction solution was poured into water, neutralized with citric acid, and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 2.16 g of 6-tert-butoxynicotinic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:32]([F:35])([F:34])[F:33])[O:13][N:12]=[C:11]([C:14]3[S:18][C:17]([C:19]([NH:21][C@@H:22]4[CH2:26][CH2:25][NH:24][C:23]4=[O:27])=[O:20])=[C:16]4[CH2:28][CH2:29][CH2:30][CH2:31][C:15]=34)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)=O.CO>>[Cl:8][C:6]1[CH:5]=[C:4]([C@@:9]2([C:32]([F:34])([F:33])[F:35])[O:13][N:12]=[C:11]([C:14]3[S:18][C:17]([C:19]([NH:21][C@@H:22]4[CH2:26][CH2:25][NH:24][C:23]4=[O:27])=[O:20])=[C:16]4[CH2:28][CH2:29][CH2:30][CH2:31][C:15]=34)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: O=C(N[C@@H]1CCNC1=O)c1sc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2c1CCCC2
Agent: O=C=O
Solvent: CO
Product: O=C(N[C@@H]1CCNC1=O)c1sc(C2=NO[C@@](c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2c1CCCC2

Procedure:
Separate 3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N—((R)-2-oxopyrrolidin-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide (6.2 g 11.29 mmol) by SFC (Column: Chiralcel OD 250×30 mm I.D., 5 um. Mobile phase: Supercritical CO2/MeOH=60/40, Flow rate: 200 ml/min) to afford two diastereoisomers 3-((R)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N—((R)-2-ox pyrrolidin-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide (2.7 g, 4.92 mmol) and 3-((S)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N—((R)-2-oxopyrrolidin-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide (2.6 g, 4.74 mmol) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[Br:19][CH:20]([CH2:24][CH2:25][Br:26])[C:21](Cl)=[O:22]>O1CCCC1.Cl>[Br:19][CH:20]([CH2:24][CH2:25][Br:26])[C:21]([NH:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[CH:4][N:3]=1)=[O:22]
Reactant: O=C(Cl)C(Br)CCBr
Reactant: Nc1cc(C(F)(F)F)ccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cc(C(F)(F)F)ccn1)C(Br)CCBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
A solution of 2-amino-4-trifluoromethylpyridine (5.00 g) and triethylamine (3.43 g) in dry tetrahydrofuran (50 ml) was added dropwise, over ten minutes, to a stirred solution of 2,4-dibromobutanoyl chloride (9.51 g) in dry tetrahydrofuran (50 ml), whilst maintaining the temperature below 5° C. The mixture was allowed to stir overnight at room temperature, diluted with hydrochloric acid (1M) and extracted with ethyl acetate. The extracts were washed with brine, dried over magnesium sulphate and evaporated under reduced pressure. The residue was chromatographed on silica, using hexane-ethyl acetate (5:1) as eluant, to give the title compound (10.09 g, yellow gum) sufficiently pure for use in Step 2 below. Rechromatographed material had NMR (CDCl3): δ 2.57(1H,m); 2.74(1H,m); 3.62(2H,m); 4.71(1H,dd); 7.33(1H,dd); 8.49(3H,d+s); 8.84(1H,bs). MS: M+ 388.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[F:13])[NH:9][CH:8]=[CH:7]2.Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C1COCC1>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][N:9]1[C:10]2[C:6](=[CH:5][C:4]([Br:3])=[C:12]([F:13])[CH:11]=2)[CH:7]=[CH:8]1)[CH3:20]
Reactant: CCOC(=O)CBr
Reactant: Fc1cc2[nH]ccc2cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)Cn1ccc2cc(Br)c(F)cc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
NaH (81 mg, 3.21 mmol) was added to a 0° C. solution of 5-bromo-6-fluoro-1H-indole (0.343 g, 1.60 mmol) in THF (16 mL). The reaction mixture was stirred at 0° C. for 15 min, then ethyl bromoacetate (0.535 mL, 4.81 mmol) was added. The reaction was stirred at rt for 1 h, then partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated. The crude product was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][O:8][C@H:9]2[C@@H:14]([OH:15])[C@@H:13]([CH2:16][OH:17])[O:12][CH:11]=[CH:10]2)=[CH:5][CH:4]=1.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[H-].[Na+]>CN(C=O)C.O>[CH2:20]([O:15][C@H:14]1[C@@H:13]([CH2:16][O:17][CH2:7][C:6]2[CH:18]=[CH:19][CH:3]=[CH:4][CH:5]=2)[O:12][CH:11]=[CH:10][C@H:9]1[O:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:19][CH:18]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccc(CO[C@@H]2C=CO[C@H](CO)[C@@H]2O)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CO[C@@H]2C=CO[C@H](COCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
A solution of 3-O-(4-methoxybenzyl)-D-galactal (2.28 g, 8.56 mmol) and benzyl bromide (3.75 mL, 3.68 mol equiv; freshly passed through basic alumina) in DMF (30 mL) under N2 at 0° C. was treated with NaH (1.37 g, 4.0 mol equiv) in two portions. The reaction was stirred 0.5 h at 0° C. and 1 h at rt. The reaction was carefully poured into 50 g of crushed ice, diluted to 100 mL with water, then extracted with EtOAc-hexanes (1:1, 100 mL×3). Organic extracts were washed with water (100 mL×2), dried (Na2SO4) and concentrated. Flash chromatography with 15% EtOAc-hexanes gave 3.58 g (94%) of the title compound as a clear liquid.
Reaction SMILES: CN.[CH2:3]([N:5](CC)CC)C.[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:25]3[CH:26]=[C:27]4[O:32][CH2:31][O:30][C:28]4=[CH:29][C:24]=3[CH2:23][CH:22]([CH3:33])[N:21]([C:34](=[O:37])[CH2:35]Cl)[N:20]=2)=[CH:15][CH:14]=1)([O-])=O>C(O)C>[NH2:10][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:25]3[CH:26]=[C:27]4[O:32][CH2:31][O:30][C:28]4=[CH:29][C:24]=3[CH2:23][CH:22]([CH3:33])[N:21]([C:34](=[O:37])[CH2:35][NH:5][CH3:3])[N:20]=2)=[CH:15][CH:14]=1
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C(=O)CCl)OCO3
Reactant: CCN(CC)CC
Agent: CN
Solvent: CCO
Product: CNCC(=O)N1N=C(c2ccc(N)cc2)c2cc3c(cc2CC1C)OCO3
Yield: 53.5 %

Procedure:
1.03 g (15.3 mmol) of methylamine hydrocdhloride and 2.64 ml (18.3 mmol) of triethylamine were added to a suspension containing 1.23 g (3.06 mmol) of 1-(4-nitrophenyl)-3-chloroacetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine in 140 ml of ethanol and the reaction mixture was refluxed for 10 hours, then evaporated under reduced pressure. The residue was dissolved in 30 ml of chloroform, washed with 20 ml of 4% NaOH solution, then 2×20 ml of water, dried and evaporated under reduced pressure. The residue was reduced according to the process of Example 16 and the product obtained was purified by column chromatography (adsorbent: Kieselgel 60, eluent: methanol--benzene 4:1). The crude product obtained was triturated with 5 ml of ethyl acetate at 25° C. to obtain 0.60 g (53.6%) of the aimed product, m.p. 198°-200° C. (weak decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]([CH:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)[CH2:8][C:9]([NH2:11])=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH2:27]/[CH:28]=[C:29]1/[C:30]2[CH:43]=[C:42]([C:44]([OH:47])([CH3:46])[CH3:45])[CH:41]=[CH:40][C:31]=2[O:32][CH2:33][C:34]2[N:39]=[CH:38][CH:37]=[CH:36][C:35]/1=2>C(#N)C.O>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]([CH:12]2[CH2:16][CH2:15][N:14]([CH2:26][CH2:27][CH:28]=[C:29]3[C:35]4[CH:36]=[CH:37][CH:38]=[N:39][C:34]=4[CH2:33][O:32][C:31]4[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]3=4)[CH2:13]2)[CH2:8][C:9]([NH2:11])=[O:10])=[CH:4][CH:3]=1
Reactant: NC(=O)CN(Cc1ccc(Cl)cc1)C1CCNC1
Reactant: CC(C)(O)c1ccc2c(c1)/C(=C/CCBr)c1cccnc1CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCC(N(CC(N)=O)Cc3ccc(Cl)cc3)C1)c1cccnc1CO2
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of 2-[(4-chloro-benzyl)-pyrrolidin-3-yl-amino]acetamide (0.21 g, 0.8 mmol) in acetonitrile:water (4:1) was added potassium carbonate (0.6 mmol) and (E)-2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.15 g, 0.4 mmol) and the resulting mixture was stirred at 50° C. for 24 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate, and dried over sodium sulfate. The crude product was purified by HPLC. 1H-NMR (CDCl3) δ: 1.35 (6H, s), 1.55-1.75 (1H, m), 1.80-2.00 (1H, m), 2.20-2.85 (8H, m), 2.90-3.10 (2H, d), 3.30-3.50 (1H, m), 3.60 (1H, d), 4.80-5.30 (2H, br, s), 6.10 (1H, t), 6.70 (1H, dd), 7.00-7.45 (7H, m), 7.70 (1H, dd), 8.50 (1H, dd). ESI-MS m/z: 562 (M+1), UV retention time: 1.31 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][O:14][C:15]3[N:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=3)=[C:11]([CH3:24])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[CH:25]([NH2:28])([CH3:27])[CH3:26]>>[CH:25]([NH:28][C:21]([C:18]1[CH:17]=[N:16][C:15]([O:14][CH2:13][C:12]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:9]=[N:10][C:11]=2[CH3:24])=[CH:20][N:19]=1)=[O:23])([CH3:27])[CH3:26]
Reactant: CC(C)N
Reactant: Cc1nnn(-c2ccc(F)cc2)c1COc1cnc(C(=O)O)cn1
Product: Cc1nnn(-c2ccc(F)cc2)c1COc1cnc(C(=O)NC(C)C)cn1
Yield: 96 %

Procedure:
As described for example 80c, 5-[3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-pyrazine-2-carboxylic acid (83 mg, 0.25 mmol), was converted, using isopropylamine instead of 4-aminotetrahydropyran, to the title compound (90 mg, 96%) which was obtained as an off white solid. MS: m/e=371.1 [M+H]+.
Reaction SMILES: [I-].Br[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N+:8]([CH2:12][CH3:13])=[C:7]([CH3:14])[C:6]2([CH3:16])[CH3:15].[CH2:17]([O:19][P:20]([O:24]CC)[O:21][CH2:22][CH3:23])[CH3:18]>[Ni](Cl)Cl.CO>[CH2:17]([O:19][P:20]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH3:13])[C:7](=[CH2:14])[C:6]2([CH3:16])[CH3:15])(=[O:24])[O:21][CH2:22][CH3:23])[CH3:18]
Reactant: CCOP(OCC)OCC
Reactant: CC[N+]1=C(C)C(C)(C)c2cc(Br)ccc21
Agent: Cl[Ni]Cl
Agent: [I-]
Solvent: CO
Product: C=C1N(CC)c2ccc(P(=O)(OCC)OCC)cc2C1(C)C
Temperature: 175 °C
Reaction time: 0.5 h
Yield: 61.8 %

Procedure:
To a 250 mL flask were added 3 (9.6 g, 20 mmol) and nickel chloride (0.52 g, 4.0 mmol). The flask was fitted with a dropping funnel and a condenser and was then lowered into an oil bath. The mixture was heated to 175° C. At approx. 165° C. triethylphosphite (15 mL, 86 mmol) was added dropwise. The mixture fizzed and became dark before turning to a dark straw color. After heating at 175° C. for 30 min a second portion of nickel chloride (0.52 g, 4.0 mmol) was added. The mixture fizzed vigorously, gave off much vapor and became dark grey-green in color. Heating was continued for 30 min and then the reaction was cooled to rt. The mixture was treated with methanol (100 mL) and filtered through a bed of celite. The methanol was evaporated in vacuo to leave an oil that was fractionally distilled on a KUGELROHR® vacuum distillation apparatus to afford 5 as a colorless liquid (4.0 g, 62%). The oil was stored under argon.