Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:6]2[CH:7]=[C:8]([N+:11]([O-])=O)[CH:9]=[CH:10][C:5]=2[S:4][N:3]=1.[Cl-].[NH4+]>C(O)C.O.C(OCC)(=O)C.[Fe]>[Cl:1][C:2]1[C:6]2[CH:7]=[C:8]([NH2:11])[CH:9]=[CH:10][C:5]=2[S:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc2snc(Cl)c2c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc2snc(Cl)c2c1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 95 %

Procedure:
A solution of 3-chloro-5-nitrobenzo[d]isothiazole (4.53 g, 21.1 mmol), iron (7.2 g, 129 mmol) and ammonium chloride (2.4 g, 45 mmol) in ethanol/water (2:1, 270 mL) is allowed to stir at 80° C. for 1.5 h. The resulting dark reaction mixture was filtered through Celite while still hot and concentrated under reduced pressure to give a brown solid, which was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and brine. The resulting organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a brown solid which was triturated with hexanes to provide 3-chlorobenzo[d]isothiazol-5-amine (3.7 g) as a yellow solid. 1H NMR (300 MHz, CDCl3): 7.57 (dd, 1H), 6.99 (dd, 1H), 6.66 ppm (dd, 1H). MW=184 confirmed by LC-MS, tr=10.41 min (Method Y) MH+=185.
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[C:26]([F:28])[C:25]([O:29][CH3:30])=[CH:24][C:23]=2B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18]1>>[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[C:26]([F:28])[C:25]([O:29][CH3:30])=[CH:24][C:23]=2[C:2]2[C:3]3[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][CH2:19]1
Reactant: CCOC(=O)c1c(C)[nH]c2c(Cl)ncnc12
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)c(OCC2CC2)cc1F
Product: CCOC(=O)c1c(C)[nH]c2c(-c3cc(OC)c(F)cc3OCC3CC3)ncnc12

Procedure:
Starting from ethyl 4-chloro-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example A4) and 2-(2-Cyclopropylmethoxy-4-fluoro-5-methoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (example B.c2) the title compound is obtained as off-white solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[C:13]([O:18][CH3:19])=[N:14][CH:15]=[CH:16][CH:17]=3)[N:7]([CH2:20][CH2:21][CH2:22][CH2:23]O)[C:6]=2[C:5]([CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:4][CH:3]=1.CS(Cl)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.CN(C)C=O.O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:12]4[C:13]([O:18][CH3:19])=[N:14][CH:15]=[CH:16][CH:17]=4)[CH2:23][CH2:22][CH2:21][CH2:20][N:7]3[C:6]=2[C:5]([CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:4][CH:3]=1
Reactant: CCC(CC)c1ccc(Cl)c2nc(Nc3cccnc3OC)n(CCCCO)c12
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1cccnc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.5 %

Procedure:
To a solution of 4-{4-chloro-7-(1-ethylpropyl)-2-[(2-methoxypyridin-3-yl)amino]-1H-benzimidazol-1-yl}butan-1-ol (200 mg, 0.480 mmol) in pyridine (5 mL) was added methanesulfonyl chloride (275 mg, 2.40 mmol) at 0° C. The mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated in vacuo. The residue was dissolved in water and ethyl acetate. The mixture was extracted with ethyl acetate (×2). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude mesylate (MS Calcd.: 398; Found: 399 (M+H)) was subjected for the next step without further purification. The crude material in N,N-dimethylformamide (3.0 mL) was added potassium carbonate (663 mg, 4.80 mmol). The reaction mixture was stirred at 80° C. for 12 hr. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-20% ethyl acetate/n-hexane gradient mixture to give the title compound (137 mg, 0.343 mmol, 71.6% yield) as a white amorphous.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:9][Si:10]([CH3:15])([O:13][CH3:14])[O:11][CH3:12].N.[Cl-]>>[C:2]1([NH:1][CH2:9][Si:10]([O:13][CH3:14])([O:11][CH3:12])[CH3:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[Si](C)(CCl)OC
Reactant: Nc1ccccc1
Agent: N
Agent: [Cl-]
Product: CO[Si](C)(CNc1ccccc1)OC
Temperature: 30 °C
Yield: 94.4 %

Procedure:
In a 500 ml four-necked flask having a reflux condenser, KPG stirrer, thermometer and gas inlet tube, 298 g of dry aniline were heated to 130° C. and 124 g of (chloromethyl)methyldimethoxysilane were added over the course of 60 min with stirring. After the end of the addition, ammonia was passed through the mixture with stirring at constant temperature until no further reaction was observable (about 60 min). Thereafter, excess aniline was removed under reduced pressure, the suspension was cooled to 30° C. and then 150 ml of isohexane were added. Thereafter, the white precipitate formed was filtered using a pressure filter, and was rinsed with two 80 ml portions of isohexane. Filtrate and wash solutions were combined and were freed from the solvent under reduced pressure. The subsequent fractional distillation gave 160 g (yield 95%) of (N-phenylaminomethyl)dimethoxy(methyl)silane having a chloride content of <20 ppm. When 1% of ammonia was added before the distillation of the product and any precipitate which had separated out was filtered off, a product having a chloride content of <10 ppm was obtained in the same yield.
Reaction SMILES: O=[C:2]([CH2:8][C:9](=[O:11])[CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].S(O)(O)(=O)=O.[NH2:17]O.C(O)C.[OH-].[NH4+]>O.C1(C)C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:10][C:9]1[O:11][N:17]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:8]=1
Reactant: NO
Reactant: CCOC(=O)C(=O)CC(C)=O
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(C)on1
Temperature: 40 °C
Reaction time: 4 h
Yield: 118.3 %

Procedure:
A mixture of 0.16 mole ethyl 2,4-dioxovalerate and 0.08 mole hydroxylamine sulfate, 50 ml ethanol and 70 ml toluene was stirred at 40° C. for four hours. The mixture was cooled to 15°-20° C., 1.8 g of concentrated ammonium hydroxide added and stirring continued at room temperature for 60 hours. The mixture was poured into water/toluene, the aqueous layer extracted with toluene, the organic layers combined, washed with brine and dried (Na2SO4). Evaporation of solvent in vacuo gave a yellow liquid which was distilled to afford 14.68 g of product, b.p. 120°-124° C. at 30 torr which crystallized upon standing.
Reaction SMILES: [CH2:1]1[O:9][CH:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:10][CH2:11][CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[OH:13].O.CO.C([O:26][CH:27]([CH3:29])[CH3:28])(C)C.CO>>[N:10]([CH2:1][CH:2]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:9])([CH2:29][CH:27]([C:28]1[CH:5]=[CH:4][CH:3]=[CH:2][CH:1]=1)[OH:26])[CH2:11][CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[OH:13]
Reactant: c1ccc(C2CO2)cc1
Reactant: NCC(O)c1ccccc1
Reactant: CC(C)OC(C)C
Solvent: O
Solvent: CO
Product: OC(CN(CC(O)c1ccccc1)CC(O)c1ccccc1)c1ccccc1
Temperature: 125 °C
Yield: 6 %

Procedure:
A mixture of styrene oxide (2.40 g, 0.020 mol) and 2-amino-1-phenylethanol (4.11 g, 0.030 mol) was heated in an oil bath at 125° C. for 3 hours. The reaction mixture was cooled, dissolved in 15 mL of methanol, and the solution poured into 100 mL of water. The mixture was extracted with 2×75 mL portions of methylene chloride, the extracts combined, dried (magnesium sulfate) and concentrated to give a yellow oil that showed several products on tlc analysis. To purify, the oil was dissolved in methylene chloride (50 mL) and extracted with 2×50 mL portions of 1N HCl solution. A precipitate appeared in the methylene chloride layer which was collected and shown by mass spectral analysis to be the product. NMR analysis showed the solid to be the hydrochloride salt. The solid (0.48 g, 6% yield) was recrystallized from methanol-isopropyl ether; mp 206°-208° C. This compound is reported in Arch Pharm 293, 27-28 (1960) (CA 54:18417 g).
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=[O:8])=CC=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[CH2:28]([CH:35]1[C:44]2[C:39](=[CH:40][CH:41]=[C:42]([O:45][CH3:46])[CH:43]=2)[CH2:38][CH2:37][C:36]1=[N:47]O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>ClCCl>[CH2:28]([CH:35]1[C:44]2[CH:43]=[C:42]([O:45][CH3:46])[CH:41]=[CH:40][C:39]=2[CH2:38][CH2:37][C:36](=[O:8])[NH:47]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[CH2:28]([CH:35]1[C:44]2[CH:43]=[C:42]([O:45][CH3:46])[CH:41]=[CH:40][C:39]=2[CH2:38][CH2:37][NH:47][C:36]1=[O:8])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COc1ccc2c(c1)C(Cc1ccccc1)C(=NO)CC2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2c(c1)C(Cc1ccccc1)C(=O)NCC2
Product: COc1ccc2c(c1)C(Cc1ccccc1)NC(=O)CC2
Temperature: 25 °C
Yield: 67 %
Yield: 26 %

Procedure:
To a solution of 8.46 mmol of p-toluenesulfonylchloride, 8.4 mmol triethylamine and 0.16 mmol of dimethylaminopyridine in 5 ml of dichloromethane was added a solution of 945 mg of 1-benzyl-7-methoxy-3,4-dihydronaphthalen-2(1H)-one oxime in 5 ml dichloromethane. The solution was stirred at room temperature over night. The mixture was diluted with dichloromethane and washed with water and saturated NaHCO3 solution. The combined organic layers were dried over MgSO4 and filtered. Evaporation of the solvent gave 1.9 g of crude material that was purified by flash chromatography to yield 637 mg of the desired isomer 1-benzyl-8-methoxy-4,5-dihydro-1H-benzo[c]azepin-3(2H)-one (67%) and 248 mg of its regioisomer 1-benzyl-8-methoxy-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one (26%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:13]2[N:14]([CH3:30])[C:15](=[O:29])[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=3[CH2:27][OH:28])[C:21]([OH:23])=O)=[CH:17][C:12]=2[CH:11]=[N:10]1.[CH:31]1([NH2:34])[CH2:33][CH2:32]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[CH:31]1([NH:34][C:21](=[O:23])[C:20]2[CH:24]=[CH:25][C:26]([CH2:27][OH:28])=[C:18]([C:16]3[C:15](=[O:29])[N:14]([CH3:30])[C:13]4[N:9]([C:3]5[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=5[F:1])[N:10]=[CH:11][C:12]=4[CH:17]=3)[CH:19]=2)[CH2:33][CH2:32]1
Reactant: Cn1c(=O)c(-c2cc(C(=O)O)ccc2CO)cc2cnn(-c3c(F)cccc3F)c21
Reactant: NC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cn1c(=O)c(-c2cc(C(=O)NC3CC3)ccc2CO)cc2cnn(-c3c(F)cccc3F)c21
Temperature: 25 °C

Procedure:
3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-(hydroxymethyl)benzoic acid (310 mg, 754 μmol) was treated with cyclopropanamine (0.21 mL, 3014 μmol) and HATU (430 mg, 1130 μmol) in THF (5.00 mL) under nitrogen and allowed to stir at RT. After 2 h the reaction was quenched by the addition of 1N NaOH (10 mL). The reaction mixture was extracted with EtOAc (2×25 mL), dried over MgSO4, filtered and concentrated. The crude residue was purified on the ISCO 12 g column (70-100% EtOAc in hexanes) affording the title compound as an amorphous white solid. MS (ESI, pos.ion) m/z: 451.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:13]([CH2:14][O:15][CH3:16])[CH2:12][N:11](C(OC(C)(C)C)=O)[CH:10](OC)[CH:9]2[C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:4][CH:3]=1.[ClH:36].[CH3:37][OH:38]>C(Cl)Cl>[ClH:36].[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH:13]([CH2:14][O:15][CH3:16])[CH2:12][N:11]([O:38][CH3:37])[CH2:10][CH:9]2[C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:6][CH:7]=1
Reactant: CO
Reactant: COCC1CN(C(=O)OC(C)(C)C)C(OC)C(c2ccc3ccccc3c2)C1c1ccc(Br)cc1
Agent: Cl
Solvent: ClCCl
Product: COCC1CN(OC)CC(c2ccc3ccccc3c2)C1c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
A solution of 60 mg (0.11 mg) of tert-butyl (3RS,4RS,5SR)-4-(4-bromo-phenyl)-5-methoxymethyl-3-naphthalen-2-yl-methoxy-piperidine-1-carboxylate in 5 ml of methylene chloride was treated with 2 ml of 2 N hydrogen chloride in methanol and stirred at room temperature for 2 hours. For the working-up, the reaction solution was evaporated under reduced pressure. The residue was recrystallized from diethyl ether and gave 53 mg (98% of theory) of (3RS,4RS,5SR)-4-(4-bromo-phenyl)-5-methoxymethyl-3-naphthalen-2-yl-methoxy-piperidine hydrochloride as a colourless solid; MS: 442 (M+H)+.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[NH:15][CH2:16][CH:17]([N:19]([CH3:21])[CH3:20])[CH3:18].C(N(CC)CC)C>ClCCCl>[CH3:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([CH3:7])[C:9]=1[N:15]([CH2:16][CH:17]([N:19]([CH3:21])[CH3:20])[CH3:18])[C:2]([O:4][CH2:5][CH3:6])=[O:3]
Reactant: CCOC(=O)Cl
Reactant: Cc1cccc(C)c1NCC(C)N(C)C
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCOC(=O)N(CC(C)N(C)C)c1c(C)cccc1C
Reaction time: 6 h
Yield: 67.4 %

Procedure:
0.78 ml (0.88 g, 8 mmoles) of ethyl chloroformate are added to a mixture of 1.0 g (4.85 mmoles) of 1-(2,6-dimethylphenyl-amino)-2-dimethylamino-propane, prepared as described in Example 8, 0.60 ml (0.51 g, 5 mmoles) of triethylamine and 20 ml of 1,2-dichloroethane, and the reaction mixture is boiled for 6 hours. The mixture is washed thrice with 10 ml of water, each, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The oily residue is subjected to column chromatography on 20 g of silica gel, applying ethyl acetate as eluant. 0.91 g (67.4%) of 1-[N-(2,6-dimethylphenyl)-N-ethoxycarbonyl-amino]-2-dimethylamino-propane are obtained as a light yellow, oily substance. The hydrochloride of this base melts at 165°-167° C.
Reaction SMILES: [CH3:1][O-].[Na+].CI.[OH:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2>CN(C)C=O>[CH3:1][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2
Reactant: C[O-]
Reactant: Cc1ccc(-c2cc3ccccc3[nH]2)c(O)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(C)ccc1-c1cc2ccccc2[nH]1
Reaction time: 2 h
Yield: 70 %

Procedure:
At a temperature of 25° C. 54 g (1 mol) of sodium methylate and 170 g (1.2 mol) of methyl iodide were added to a solution of 223 g (1 mol) of 2-(2'-hydroxy-4'-methyl-phenyl)-indole, prepared as in Example 1, in 1200 ml of N,N-dimethylformamide. The solution was then stirred for 2 hours and the crude product was precipitated by adding water. After recrystallization from benzene, 166 g of 2-(2'-methoxy-4'-methyl-phenyl)-indole were obtained. M.P.: 125° C. Yield: 70%.
Reaction SMILES: NC1C=CC(C2C=CC(C(=O)CC(C)(C)C(OC)=O)=CC=2)=CC=1.BrC1SC=CN=1.[S:30]1[C:34]2C=CC=C[C:33]=2[N:32]=[C:31]1[NH:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[CH:51]=[CH:50][C:49]([C:52](=[O:60])[CH2:53][C:54]([CH3:59])([CH3:58])[C:55]([OH:57])=[O:56])=[CH:48][CH:47]=2)=[CH:42][CH:41]=1>>[CH3:58][C:54]([CH3:59])([CH2:53][C:52](=[O:60])[C:49]1[CH:48]=[CH:47][C:46]([C:43]2[CH:44]=[CH:45][C:40]([NH:39][C:31]3[S:30][CH:34]=[CH:33][N:32]=3)=[CH:41][CH:42]=2)=[CH:51][CH:50]=1)[C:55]([OH:57])=[O:56]
Reactant: CC(C)(CC(=O)c1ccc(-c2ccc(Nc3nc4ccccc4s3)cc2)cc1)C(=O)O
Agent: Brc1nccs1
Agent: COC(=O)C(C)(C)CC(=O)c1ccc(-c2ccc(N)cc2)cc1
Product: CC(C)(CC(=O)c1ccc(-c2ccc(Nc3nccs3)cc2)cc1)C(=O)O
Yield: 24 %

Procedure:
This compound was prepared from methyl 4-(4′-amino-1,1′-biphenyl-4-yl)-2,2-dimethyl-4-oxobutanoate (64 mg, 0.21 mmol) and 2-bromothiazole (41 mg, 0.25 mmol) in a similar manner to the method described for 4-[4′-(1,3-benzothiazol-2-ylamino)-1,1′-biphenyl-4-yl]-2,2-dimethyl-4-oxobutanoic acid, providing 18.6 mg (24%) of the desired product. LC-MS m/z 381.4 (MHz, ret. time 2.53 min.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[CH2:6]([O:8][C:9](=[O:26])[CH2:10][C:11]1[N:24]=[C:23](O)[C:14]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]=3[S:22][C:13]=2[N:12]=1)[CH3:7]>>[CH2:6]([O:8][C:9](=[O:26])[CH2:10][C:11]1[N:24]=[C:23]([Cl:3])[C:14]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]=3[S:22][C:13]=2[N:12]=1)[CH3:7]
Reactant: CCOC(=O)Cc1nc(O)c2c3c(sc2n1)CCCCC3
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)Cc1nc(Cl)c2c3c(sc2n1)CCCCC3
Yield: 34.3 %

Procedure:
The POCl3 (20 ml, 215 mmol)) was added to (4-hydroxy-6,7,8,9-tetrahydro-5H-10-thia-1,3-diaza-benz[a]azulen-2-yl)-acetic acid ethyl ester (5.5 g, 0.01795 mol) and the solution was refluxed for 2 h. The reaction was quenched into 200 g of ice and extracted with 3×100 ml ethyl acetate. The combined organic layers were dried over sodium sulphate and concentrated under vacuum. The crude was purified by chromatography on silica gel using 10% ethyl acetate in hexanes to give (4-chloro-6,7,8,9-tetrahydro-5H-10-thia-1,3-diaza-benz[a]azulen-2-yl)-acetic acid ethyl ester (2 g, 34%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3): δ 4.19 (q, 2H), 4.02 (s, 2H), 3.30-3.37 (m, 2H), 2.92-2.98 (m, 2H), 1.85-1.95 (m, 2H), 1.65-1.78 (m, 4H), 1.25 (t, 3H); LC-MS: [M+H]=325.0 & 327.1 m/z.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:14][C:15]1[N:24]=[C:23]([NH2:25])[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([NH2:26])[CH:21]=2)[N:16]=1.CCN([CH2:32][CH3:33])CC>>[NH2:14][C:15]1[N:24]=[C:23]([NH2:25])[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([NH:26][CH:12]3[C:13]4[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=4[CH:6]=[CH:7][C:8]4[CH:9]=[CH:10][CH:11]=[CH:32][C:33]3=4)[CH:21]=2)[N:16]=1
Reactant: Nc1ccc2nc(N)nc(N)c2c1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: CCN(CC)CC
Product: Nc1nc(N)c2cc(NC3c4ccccc4C=Cc4ccccc43)ccc2n1

Procedure:
5-[N-(2,4-Diaminoquinazolin-6-yl)amino]-5H-dibenzo[a,d]cycloheptene (Formula I: Ar=2,4-diaminoquinazolin-6-yl; W=NH; X=CH; Z=CH═CH; m=n=0) is prepared similarly to N-(2,4-diaminopyrido[2,3-d]pyrimidin-6-yl)amino]fluorene as disclosed above by using 5H-dibenzo[a,d]cycloheptan-5-one (412 mg, 2.0 mmol), 2,4,6-triaminoquinazoline (350 mg, 2.0 mmol), and BH3.Et3N (75 mg, 6.6 mmol). The product can be purified by chromatography.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH2:5][CH2:4]1.[Br:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([C:29]([C:31]1[CH:36]=[C:35](Cl)[N:34]=[CH:33][N:32]=1)=[O:30])[CH2:24][CH2:23]2.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([C:29]([C:31]1[N:32]=[CH:33][N:34]=[C:35]([N:3]3[CH2:4][CH2:5][CH:6]([N:9]4[C:17]5[C:12](=[N:13][CH:14]=[CH:15][CH:16]=5)[NH:11][C:10]4=[O:18])[CH2:7][CH2:8]3)[CH:36]=1)=[O:30])[CH2:24][CH2:23]2
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: O=C(c1cc(Cl)ncn1)N1CCc2cc(Br)ccc21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1)N1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 22 h

Procedure:
70 mg (0.24 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one dihydrochloride were added to 100 mg (0.30 mmol) (5-bromo-2,3-dihydroindol-1-yl)-(6-chloropyrimidin-4-yl)-methanone and 100 μL (0.58 mmol) DIPEA in 10 mL DMF. The reaction mixture was stirred for 22 h at RT and then evaporated down i. vac. The residue was combined with 20 mL water and stirred for 30 min at RT. The precipitated product was suction filtered. The purification was carried out using a silica gel column. The product fractions were combined and the solvent was eliminated using the rotary evaporator. The residue was stirred with water, suction filtered and dried at 40° C. in the CAD.
Reaction SMILES: [CH2:1]1[C:8]2[N:4]([C:5]([C:9]([C:11]3[N:12]4[C:16](=[C:17]([C:20]([O:22]CC)=[O:21])[C:18]=3[CH3:19])[CH:15]([C:25]([O:27]CC)=[O:26])[CH2:14][CH2:13]4)=[O:10])=[CH:6][CH:7]=2)[CH2:3][CH2:2]1.CO.[OH-].[K+]>O>[CH2:1]1[C:8]2[N:4]([C:5]([C:9]([C:11]3[N:12]4[C:16](=[C:17]([C:20]([OH:22])=[O:21])[C:18]=3[CH3:19])[CH:15]([C:25]([OH:27])=[O:26])[CH2:14][CH2:13]4)=[O:10])=[CH:6][CH:7]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(C)c(C(=O)c2ccc3n2CCC3)n2c1C(C(=O)OCC)CC2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c(C(=O)O)c2n(c1C(=O)c1ccc3n1CCC3)CCC2C(=O)O
Yield: 100.6 %

Procedure:
A mixture of the diester from Step B (1.62 g, 0.004 m), methanol (15 ml), water (5 ml), and potassium hydroxide (1.6 g, 0.026 m) was refluxed in an inert atmosphere for 5.5 hours, cooled, diluted with water (ca. 80 ml), filtered, the filtrate acidified with 2N hydrochloric acid, and the cooled, aged mixture filtered. After drying the well-washed (water) solid, 1.4 g of 5-(2,3-dihydro-1H-pyrrolizin-5-oyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-1,7-dicarboxylic acid is obtained as a white solid.
Reaction SMILES: O=[C:2]1[C:11]2[O:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]2[O:12][CH2:13][CH2:14][CH:3]12.Cl.[NH2:16][OH:17].C([O-])(=O)C.[Na+]>C(O)C>[OH:17][N:16]=[C:2]1[C:11]2[O:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]2[O:12][CH2:13][CH:14]=[C:3]12
Reactant: NO
Reactant: O=C1C2=C(C=C3OCCC13)CCCO2
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: ON=C1C2=CCOC2=CC2=C1OCCC2

Procedure:
27.4 g of 2,3,7,8-tetrahydro-4-oxofuro[2,3-g]benzopyran (see Preparation 1), 42 g of hydroxylamine hydrochloride and 41.9 g of sodium acetate in 288 ml of ethanol are heated at reflux for 1 hour. The solvent is evaporated off and the residue is taken up in dichloromethane and washed with water. After drying over magnesium sulphate, evaporation and then recrystallisation from ethanol, 21.85 g of the desired compound are obtained.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[CH:13][Cl:14])[CH2:10][C@H:9]1[C:15]([OH:17])=O)=[O:7])(C)(C)C.[C:18]([N:26]=C=O)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH:29]1([NH2:32])[CH2:31][CH2:30]1>>[C:18]([NH:26][C:6]([N:8]1[CH2:12][C:11](=[CH:13][Cl:14])[CH2:10][C@H:9]1[C:15]([NH:32][CH:29]1[CH2:31][CH2:30]1)=[O:17])=[O:7])(=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: NC1CC1
Reactant: CC(C)(C)OC(=O)N1CC(=CCl)C[C@H]1C(=O)O
Reactant: O=C=NC(=O)c1ccccc1
Product: O=C(NC(=O)N1CC(=CCl)C[C@H]1C(=O)NC1CC1)c1ccccc1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tertbutoxycarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxylic acid, benzoyl isocyanate, and cyclopropylamine the title compound was obtained in 76% purity by LC/MS. MS(ESI+): m/z=348.6.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:32])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=O)[NH:12][CH:11]3[C:24]3[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[CH:25]=3)[C:5]2=[CH:4][CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:42]2)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:32])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[S:42])[NH:12][CH:11]3[C:24]3[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[CH:25]=3)[C:5]2=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2ccc(F)c(F)c2)N1
Solvent: Cc1ccccc1
Product: O=C1Nc2cc(Cl)ccc2C12C(c1cccc(Cl)c1)CC(=S)NC2c1ccc(F)c(F)c1
Yield: 94.1 %

Procedure:
In a manner similar to the method described in example 30, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3,4-difluorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.3 g, 0.63 mmol) prepared in example 46b was reacted with 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide (0.32 g, 0.77 mmol) in toluene to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3,4-difluorophenyl)-6′-thioxospiro[3H-indole-3,3′-piperidine]-2(1H)-one (Yield 0.29 g, 94%).