Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[O:18]([C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.N1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCCO)C.O>[O:18]([C:25]1[CH:26]=[CH:27][C:28]([NH:29][C:2]2[C:11]3[C:6](=[CH:7][C:8]4[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=4[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])=[CH:30][CH:31]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: N#Cc1cnc2cc3ccccc3cc2c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: CCOCCO
Product: N#Cc1cnc2cc3ccccc3cc2c1Nc1ccc(Oc2ccccc2)cc1
Yield: 73.4 %

Procedure:
A reaction mixture of 141.8 mg (0.59 mmol) of 4-chlorobenzo[g]quinoline-3-carbonitrile, 111.1 mg (0.60 mmol) of 4-phenoxyaniline and 57.8 mg (0.50 mmol) of pyridine hydrochloride in 8 ml of 2-ethoxyethanol is heated at 110–120° C. for 1 hour. After cooling, the mixture is diluted with water and made basic by addition of 125.0 mg (1.18 mmol) of sodium carbonate. The precipitate is collected by filtration and washed with water. Drying in vacuo yields the crude product. The crude product is purified by chromatography, eluting with a methylene chloride/methanol gradient from 100:0 to 86:14, to provide 167.8 mg (73.4%) of the pure product as a yellow solid, mp 250–251° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:5][N:6]=1.ClC1C=CC=C(C(OO)=[O:22])C=1.C(O)C>ClCCl.C(Cl)(Cl)Cl>[NH2:1][C:2]1[S:3][C:4]([S:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[O:22])=[CH:5][N:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Nc1ncc(Sc2cccnc2)s1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: Nc1ncc(S(=O)c2cccnc2)s1
Yield: 37.2 %

Procedure:
To a mixture of 2-amino-5-(3-pyridylthio)thiazole (3.0 g) in a mixture of dichloromethane (100 ml) and chloroform (100 ml) was added dropwise the solution of 3-chloroperbenzoic acid (3.4 g) in dichloromethane (50 ml) at 5° C. with stirring. The mixture was stirred at 5° C. for hours. The reaction mixture was washed with aqueous sodium bicarbonate and the aqueous layer was extracted with a mixture of tetrahydrofuran and ethyl acetate (1:1), washed with aqueous saturated sodium chloride and dried over magnesium sulfate. The solvent was concentrated under reduced pressure and the residue was recrystallized from ethanol no give 2-amino-5-(3-pyridylsulfinyl)thiazole (1.2 g, yield: 37.2%). mp: 178°-179° C. IR (Nujol): 3300, 3150, 1630, 1580, 1520, 1485, 1325, 1220 cm-1NMR (DMSO-d6, 200 MHZ, ppm): 7.58-7.70 (1H, m), 7.80 (1H, s), 8.00 (2H, s), 7.98-8.05 (1H, m), 8.72 (2H, br s) Mass: M+1 226, M 225, m/e 209, 177, 147
Reaction SMILES: C([S:4][CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1)(=O)C.C[O-].[Na+].F[C:20]1[CH:21]=[C:22]([CH3:29])[CH:23]=[CH:24][C:25]=1[N+:26]([O-:28])=[O:27].[Cl-].[NH4+]>CO>[N+:26]([C:25]1[CH:24]=[CH:23][C:22]([CH3:29])=[CH:21][C:20]=1[S:4][CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1)([O-:28])=[O:27]
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: COC(=O)c1ccc(CSC(C)=O)cc1
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)c1ccc(CSc2cc(C)ccc2[N+](=O)[O-])cc1
Reaction time: 4 h
Yield: 63.2 %

Procedure:
To a solution of methyl 4-acetylthiomethylbenzoate (794 mg) in MeOH (5.0 ml), sodium methoxide (191 mg) and 3-fluoro-4-nitrotoluene (500 mg) were added suceedingly in a stream of argon at 0° C. The mixture was warmed slowly to become at room temperature. The mixture was stirred for 4 hours. To the reaction mixture, a saturated aqueous ammonium chloride was added. The mixture was extracted with ethyl acetate, washed, dried over and concentrated under the reduced pressure. The residue was recrystrallized from ethanol to give the title compound (646 mg) having the following physical data.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[N:10]1[C:19]2[C:14](=[CH:15][C:16]([CH2:20][C:21](O)=O)=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1.Cl>C([O-])([O-])=O.[Na+].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:21]([CH2:20][C:16]3[CH:15]=[C:14]4[C:19](=[CH:18][CH:17]=3)[N:10]=[CH:11][CH:12]=[CH:13]4)=[N:9][N:8]=2)[N:7]=1
Reactant: O=C(O)Cc1ccc2ncccc2c1
Reactant: NNc1ccc(Cl)nn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Clc1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Temperature: 110 °C

Procedure:
A mixture of 1-(6-chloropyridazin-3-yl)hydrazine (1.67 g, 12 mmol), 2-(quinolin-6-yl)acetic acid (1.65 g, 8.8 mmol), and HCl (2000 μl, 24 mmol) was heated in an oil bath at 110° C. for 20 min before it was heated in a microwave (Personal Chemistry) at 180° C.& 15 min. The mixture was quenched with a solution of NaOH (1.2 g, 5 mL) slowly until the suspension is neutral in pH. The mixture was filtered and washed with H2O (2×5 mL). A brown solid was obtained (2.2 g). The solid was treated with aqueous Na2CO3 (3 g, 20 mL, pH ˜11) and heated at 50° C. for 30 min. The blue mixture was cooled to room temperature, and filtered. The black solid was washed with H2O and lyophilized to give the product.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1.[O-:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Na+].O.C1(C)C=CC=CC=1>CS(C)=O.[Cl-].[Na+].O>[O:11]([C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: [O-]c1ccccc1
Reactant: COC(=O)c1csc(Br)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1csc(Oc2ccccc2)n1
Temperature: 80 °C

Procedure:
A mixture of commercially available methyl 2-bromothiazole-4-carboxylate (1.000 g; 4.50 mmol) and sodium phenoxide (627 mg; 5.40 mmol) in anh. DMSO (20 ml) was heated to 80° C., under nitrogen, for 17 h. A second addition of sodium phenoxide (314 mg; 2.70 mmol) was performed, and the resulting mixture was further heated at 80° C. for 1 h. After cooling to rt, water (50 ml), brine (10 ml), and toluene (20 ml) were added. The separated aq. layer was further extracted with toluene (2×20 ml). The mixed organic layers were washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=50/1) afforded methyl 2-phenoxythiazole-4-carboxylate as a yellow oil. LC-MS (conditions A): tR=0.73 min.; [M+H]+: 236.06 g/mol.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH:21]([CH2:24][OH:25])[O:22][CH3:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[S:33](Cl)([CH3:36])(=[O:35])=[O:34]>ClCCl>[CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH:21]([CH2:24][O:25][S:33]([CH3:36])(=[O:35])=[O:34])[O:22][CH3:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(CO)COCCCCCCCCCCCCC1CCCCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(COCCCCCCCCCCCCC1CCCCC1)COS(C)(=O)=O
Reaction time: 1 h

Procedure:
To a mixture of 1.70 g (4.78 millimole) of 1-O-(12-cyclohexyl)dodecyl-2-O-methylglycerol, 580 mg (5.74 millimole) of triethylamine and 10 ml of dichloromethane, 657 mg (5.74 millimole) of mesyl chloride was added dropwise under ice cooling. After stirring for 1 hour under ice cooling, the reaction mixture was washed with water, saturated solution of sodium hydrogencarbonate, and water, successively, and dried (MgSO4), followed by evaporation of the solvent. The residue was subjected to silica gel (60 g) column chromatography, and eluted with hexane-ethyl acetate (5:1), to give the above-captioned compound as colorless solid. Yield: 1.93 g (97%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:9][Si:10]([CH3:14])([CH3:13])[C:11]#[CH:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C.C1CCCCC1.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>[CH3:9][Si:10]([C:11]#[C:12][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1)([CH3:14])[CH3:13]
Reactant: C#C[Si](C)(C)C
Reactant: Nc1ccc(Br)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)C#Cc1ccc(N)nc1

Procedure:
The title compound is synthesized according to general procedure GP2 starting from 5.0 g (28.9 mmol) 5-bromo-pyridin-2-ylamine and 5.7 mL (40.5 mmol) 1-trimethylsilyl-ethyne using 168 mg (0.88 mmol) CuI, 758 mg (2.9 mmol) triphenylphosphine, 533 mg (0.76 mmol) PdCl2(PPh3)2 and 40 mL (288 mmol) triethylamine in 40 mL dry THF. For the work-up the reaction mixture is diluted with ethyl acetate and small amounts of cyclohexane, the organic phase is extracted with water and brine. The product is purified by chromatography on silica gel using hexane/ethyl acetate (10/1 v/v). Yield: 5.0 g (91%).
Reaction SMILES: [F:1][C:2]1[C:3]([N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]2)=[C:4]([CH3:12])[C:5](F)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[F-].[K+].[CH:26]1([NH2:29])[CH2:28][CH2:27]1>CS(C)=O>[CH:26]1([NH:29][C:5]2[C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]([F:1])=[C:3]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]3)[C:4]=2[CH3:12])[CH2:28][CH2:27]1
Reactant: CCOC(=O)N1CCN(c2c(F)cc([N+](=O)[O-])c(F)c2C)CC1
Reactant: NC1CC1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)N1CCN(c2c(F)cc([N+](=O)[O-])c(NC3CC3)c2C)CC1
Temperature: 60 °C
Yield: 93.7 %

Procedure:
To 3,6-difluoro-2-(4-ethoxycarbonyl-1-piperazinyl)-5-nitrotoluene(7.1 g) are added anhydrous dimethylsulfoxide (23 ml), potassium fluoride (2.0 g) and cyclopropylamine (1.5 g), and the mixture is heated at 60° C. for 6 hours. The reaction mixture is poured into ice water, and extracted with dichloromethane. The solvent is distilled off and the residue is recrystallized from ethanol to give N-cyclopropyl-2-methyl-3-(4-ethoxycarbonyl-1-piperazinyl)-4-fluoro-6-nitroaniline (7.4 g), as orange red prisms, m.p. 97°-98° C.
Reaction SMILES: N#N.[N+:3]([C:6]1[CH:10]=[N:9][NH:8][N:7]=1)([O-:5])=[O:4].CCN(C(C)C)C(C)C.[CH3:20][C:21]1([C:26]2[CH:27]=[C:28]([CH:35]=[CH:36][CH:37]=2)[CH2:29]OS(C)(=O)=O)[O:25][CH2:24][CH2:23][O:22]1>CN(C=O)C.CC(=O)OCC.O>[CH3:20][C:21]1([C:26]2[CH:27]=[C:28]([CH:35]=[CH:36][CH:37]=2)[CH2:29][N:8]2[N:7]=[C:6]([N+:3]([O-:5])=[O:4])[CH:10]=[N:9]2)[O:22][CH2:23][CH2:24][O:25]1
Reactant: O=[N+]([O-])c1cn[nH]n1
Reactant: CC1(c2cccc(COS(C)(=O)=O)c2)OCCO1
Agent: N#N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC1(c2cccc(Cn3ncc([N+](=O)[O-])n3)c2)OCCO1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 4-nitro-2H-[1,2,3]triazole (50 mg, 0.43 mmol) in DMF (1.0 mL) was treated with DIPEA (0.15 mL, 0.87 mmol). After 30 min, a solution of methanesulfonic acid 3-(2-methyl-[1,3]dioxolan-2-yl)-benzyl ester (106 mg, 0.52 mmol) in DMF (1.0 mL) was added and the reaction mixture was stirred for 3 days at 50° C. Water (10 mL), followed by EA (10 mL) were added. The aq. layer was extracted with EA (10 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (2:1 hept-EA) gave the title compound as a colorless oil: TLC:rf (1:2 hept-EA)=0.42. LC-MS-conditions 02: tR=0.99 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:22])=[C:4]([CH:19]=[CH:20][CH:21]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([OH:16])[CH:14]=2)[N:9]=[CH:8][N:7]=1.[N+](C1C=CC(S(O[C@@H:36]2[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37]2)(=O)=O)=CC=1)([O-])=O>>[Cl:1][C:2]1[C:3]([F:22])=[C:4]([CH:19]=[CH:20][CH:21]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([O:16][C@H:40]3[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:39]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](OS(=O)(=O)c2ccc([N+](=O)[O-])cc2)C1
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1CCN(C(=O)OC(C)(C)C)C1
Yield: 95 %

Procedure:
4-(3-chloro-2-fluoroanilino)-6-hydroxy-7-methoxyquinazoline was reacted with tert-butyl (3R)-3-[(4-nitrophenyl)sulfonyloxy]pyrrolidine-1-carboxylate to give 4-(3-chloro-2-fluoroanilino)-6-[(3S)-1-(tert-butoxycarbonyl)pyrrolidin-3-yloxy]-7-methoxyquinazoline as a dry foam (2.9 g, 95%); 1H NMR Spectrum: (DMSO d6) 1.40 (s, 9H); 2.07-2.29 (m, 21-1); 3.32-3.50 (m, 3H); 3.64-3.70 (dd, 1H); 3.92 (s, 3H); 5.08-5.18 (m, 1H); 7.21 (s, 1H); 7.23-7.30 (m, 1H); 7.43-7.55 (m, 2H); 7.79 (s, 1H); 8.36 (s, 1H); 9.6 (s, 1H); Mass Spectrum: (M+H)+ 489.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+].CC(C)([O-])C.[K+]>O.CN1CCCC1=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: Nc1ccccn1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc(Nc2ccccn2)cc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 19.7 %

Procedure:
0.3 g of 4-fluoronitrobenzene, 0.4 g of 2-aminopyridine, and 0.353 g of K2CO3 were added to a solution of 2.5 ml of N-methylpyrrolidinone. The reaction medium was heated at 60° C. for 1 hour and 0.286 g of potassium tert-butoxide was then added. Heating was then continued for 6 hours and, after cooling to room temperature, the reaction medium was then poured into a water and ice mixture. The yellow precipitate formed was filtered off, reslurried in water and then dried over P2O5. 0.09 g of N-(4-nitrophenyl)pyrid-2-amine (5) was obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)[S:6][CH:7]=1.[CH2:24]([NH:27][CH2:28][CH2:29][CH3:30])[CH2:25][CH3:26]>O1CCCC1>[CH2:24]([N:27]([CH2:2][C:3]1[N:4]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)[S:6][CH:7]=1)[CH2:28][CH2:29][CH3:30])[CH2:25][CH3:26]
Reactant: CCCNCCC
Reactant: CN1Cc2c(-c3nc(CCl)cs3)ncn2-c2ccccc2C1=O
Solvent: C1CCOC1
Product: CCCN(CCC)Cc1csc(-c2ncn3c2CN(C)C(=O)c2ccccc2-3)n1
Yield: 56.4 %

Procedure:
A solution of 1.0 g (0.0029 mol) of 3-(4-chloromethyl-thiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]-benzodiazepin-6-one in 60 ml of tetrahydrofuran was treated with 7.9 ml (0.058 mol) of dipropylamine. After stirring at reflux for 16 hrs. the solution obtained was completely freed from the solvents. The residue was chromatographed over silica gel with ethyl acetate and the eluent and recrystallized from hot isopropyl ether. There was obtained 0.67 g (56%) of 3-(4-dipropylaminomethyl-thiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as white crystals; m.p. 111°-112°.
Reaction SMILES: [OH:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:19].[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]1[C:29](Cl)=[O:30].CC#N>C(Cl)Cl.CN(C)C1C=CN=CC=1>[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]1[C:29]([O:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:19])=[O:30]
Reactant: O=C1Nc2ccccc2C(c2ccccc2)=NC1O
Reactant: O=C(Cl)c1cc2ccccc2[nH]1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: ClCCl
Product: O=C(OC1N=C(c2ccccc2)c2ccccc2NC1=O)c1cc2ccccc2[nH]1
Reaction time: 16 h
Yield: 63.5 %

Procedure:
1,3-Dihydro-3-(RS)-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one (100 mg, 0.398 mmol) was dissolved in CH2Cl2 (10 ml), treated with indole-2-carbonyl chloride (78.6 mg, 0.438 mmol) and 4-dimethylaminopyridine (DMAP, 53.5 mg, 0.438 mmol) and stirred 16 hrs. at 25° C. A second portion of indole-2-carbonylchloride (78.6 mg, 0.438 mmol and DMAP (53.5 mg, 0.438 mmol) was added and the reaction stirred an additional 24 hrs. Chromatography of the reaction mixture on silica gel (1% MeOH in CH2Cl2) gave the title compound (100 mg) as a white solid from MeCN: (m.p. 271°-273°).
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([I:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11]Br.[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][N:20]2[CH2:11][C:5]3[C:4](=[C:9]([I:10])[CH:8]=[CH:7][CH:6]=3)[C:3]2=[O:13])=[CH:17][CH:16]=1
Reactant: COC(=O)c1c(I)cccc1CBr
Reactant: NCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1c2c(I)cccc2CN1Cc1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 39.1 %

Procedure:
A mixture of 2-bromomethyl-6-iodo-benzoic acid methyl ester (0.200 g, 0.56 mmol), 4-chloro-benzylamine (0.7 mmol), and K2CO3 (0.166 g, 1.2 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-(4-chloro-benzyl)-7-iodo-2,3-dihydro-isoindol-1-one (0.084 g, 39%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.16 (s, 2H), 4.75 (s, 2H), 7.16-7.40 (m, 6H), 7.92 (d, 1H). GC-MS: m/z 367 (M)+.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[S:11][C:12]4[CH:18]=[C:17]([CH:19]=O)[CH:16]=[CH:15][C:13]=4[N:14]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO.C1COCC1>[CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[S:11][C:12]4[CH:18]=[C:17]([CH2:19][N:21]5[CH2:25][CH2:24][CH2:23][CH2:22]5)[CH:16]=[CH:15][C:13]=4[N:14]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: O=Cc1ccc2nc(N3CCN(C4CC4)CC3)sc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: c1cc2nc(N3CCN(C4CC4)CC3)sc2cc1CN1CCCC1
Temperature: 63 °C
Reaction time: 8 h
Yield: 54.6 %

Procedure:
To a solution of 2-(4-cyclopropylpiperazin-1-yl)benzothiazole-6-carboxaldehyde (500 mg, 1.7 mmol) in MeOH (14 mL) and THF (28 mL) was added pyrrolidine (242 mg, 3.4 mmol), acetic acid (22 mg, 0.4 mmol) and NaCNBH3 (158 mg, 2.7 mmol). The mixture was stirred at 63° C. overnight. Then the mixture was concentrated under reduced pressure and dichloromethane (15 mL) was added. The mixture was washed with brine and the organic phase was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 318 mg (27%) of 2-(4-cyclopropylpiperazin-1-yl)-6-(pyrrolidin-1-ylmethyl)-benzothiazole as a trifluoroacetate salt.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[Cl:11][CH2:12][CH2:13][CH2:14]O>S(=O)(=O)(O)O>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH2:14][CH2:13][CH2:12][Cl:11])=[O:6]
Reactant: OCCCCl
Reactant: O=C(O)c1cccc(O)c1
Agent: O=S(=O)(O)O
Product: O=C(OCCCCl)c1cccc(O)c1
Yield: 93.9 %

Procedure:
A solution of 3-hydroxybenzoic acid (16.0 g, 0.115 mol) in 3-chloropropanol (76 g, 0.81 mol) and 0.5 mL of concentrated sulfuric acid was refluxed overnight. The excess alcohol was removed by vacuum distillation. The brown viscous residue was dissolved in ethyl acetate (60 mL) and washed with water (2×15 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The brown viscous residue was purified by column chromatography (ethyl acetate/hexane, 30:70) to give the product as a white solid (23.3 g, 0.108 mol, 93.7%): 1H NMR (CDCl3) δ 2.19-2.28 (m, 2H), 3.69 (t, 2H, J=6.3 Hz), 4.48 (t, 2H, J=6Hz), 5.92 (s, 1H), 7.05-7.64 (m, 4H); MS exact mass: calcd. 214,0396, found 214.0400.
Reaction SMILES: O.O.[Sn](Cl)Cl.[N:6]1([C:12]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][C:13]=2[C:14]([O:16][CH2:17][CH:18]=[CH2:19])=[O:15])[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.C(O)C>CCOC(C)=O>[NH2:24][C:21]1[CH:22]=[CH:23][C:12]([N:6]2[CH2:7][CH2:8][O:9][CH2:10][CH2:11]2)=[C:13]([CH:20]=1)[C:14]([O:16][CH2:17][CH:18]=[CH2:19])=[O:15]
Reactant: C=CCOC(=O)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: C=CCOC(=O)c1cc(N)ccc1N1CCOCC1
Yield: 53.7 %

Procedure:
Tin(II) chloride dihydrate (17.37 g, 77 mmol) was added to a solution of allyl 2-morpholin-4-yl-5-nitrobenzoate (11.24 g, 38.5 mmol) in EtOAc (250 mL) and the mixture was stirred and heated under reflux for 4 h. Ethanol (150 mL) was added, followed by another portion of Tin(II) chloride dihydrate (17.4 g) and the mixture was heated for another 2 h. The mixture was cooled and filtered then the filtrate was washed repeatedly with aqueous ammonium hydroxide and re-filtered. The organic layer was dried and concentrated by evaporation to give the title compound (Intermediate 76, 5.42 g, 54%) as a solid; 1H NMR δ 6.90 (1H, d), 6.80 (1H, s), 6.70 (1H, d), 6.10-5.95 (1H, m), 5.40 (1H, d), 5.30 (1H, d), 5.00 (2H, s), 4.80 (2H, s), 3.70-3.60 (4H, m), 3.20-3.10 (4H, m); MS m/e MH+ 263.
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[C:4]([O:10][CH3:11])(=[O:9])[CH2:5][C:6]([CH3:8])=[O:7].N1C=CC=CC=1.[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:20]=1[C:21](Cl)=[O:22].S(=O)(=O)(O)O.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-]>C(#N)C.C1(C)C=CC=CC=1.O>[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:20]=1[C:21]([CH2:8][C:6](=[O:7])[CH2:5][C:4]([O:10][CH3:11])=[O:9])=[O:22]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: COC(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COC(=O)CC(=O)CC(=O)c1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.1 %

Procedure:
A slurry of anhydrous magnesium chloride (571 g, 6.0 moles) and methyl acetoacetate (697 g, 6.0 moles) in 3 l of acetonitrile was stirred in an ice-salt bath as 972 ml of pyridine (12 moles) was added at such a rate that the temperature did not exceed 5° C. (addition time 2 hrs.). The cooling bath was removed and toluene (500 ml) was added at once followed by the addition of a solution of 1255 g of 2,6-dichlorobenzoyl chloride (6.0 moles) in 1.5 l of toluene over one hour (final temperature 25° C.). The reaction was heated at reflux for 5 hours, and then allowed to cool over 14 hours to room temperature. The reaction was cooled in an ice bath to 0° C., and 400 ml of concentrated sulfuric acid (7.3 moles) was then added to the reaction mixture at a rate to maintain a temperature below 15° C., followed by 1.5 l of water. The mixture was stirred for 30 min. The organic layer was isolated and washed with 3 l of water. The acidic aqueous washes were back-extracted with 1 l of toluene. The product was extracted from the combined organic layers with an aqueous potassium carbonate solution (3.6 moles in 3 l water) and with a second potassiam carbonate solution (0.4 moles in 1 l water). The combined basic aqueous layers were washed with toluene (1 l) and acidified with concentrated hydrochloric acid. The resulting solid was isolated by filtration, washed with water (2×2 l), and dried under vacuum at 50° C. to give 1008 g (58%) of a granular orange solid.