Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[CH:4][C:3]=1[C:7]([OH:9])=O.S(Cl)([Cl:12])=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[O:6][N:5]=[CH:4][C:3]=1[C:7]([Cl:12])=[O:9]
Reactant: Cc1oncc1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1oncc1C(=O)Cl
Temperature: 80 °C

Procedure:
127.1 g (1.0 mol) of 5-methylisoxazole-4-carboxylic acid are initially introduced into 1 l of toluene, 129.8 g (1.1 mol) of thionyl chloride are added dropwise and the mixture is then heated at 80° C. for 6 h. The volume is concentrated under reduced pressure to approximately one half and the toluene solution is used directly for further reactions.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:5]=2[N:6]=1>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: O=[N+]([O-])c1ccc2nc(Cl)sc2c1
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1ccc2nc(Cl)sc2c1
Temperature: 40 °C
Reaction time: 5 h
Yield: 33.5 %

Procedure:
Suspend 2-Chloro-6-nitro-benzothiazole (21.43 g, 99.8 mmol) in glacial acetic acid (300 mL). Add elemental iron (12.9 g, 231 mmol) and stir at 40° C. for 5 h. Filter the reaction mixture through Celite®, concentrate in vacuo, and adsorb onto silica gel. Subject the residue to silica gel flash column chromatography in two portions [(120 g column, 0-10% CH3OH/CH2Cl2), (120 g column, 0-5% CH3O/CH2Cl2)] to yield the desired product (6.17 g, 33%). mass spectrum (m/e): 185.0 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:15]=[C:14]([CH3:16])[S:13][C:4]=2[NH:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1.[CH3:17][N:18]1[CH2:23][CH2:22]N[CH2:20][CH2:19]1.C(O)CC>O>[CH3:16][C:14]1[S:13][C:4]2[NH:5][C:6]3[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=3[N:8]=[C:2]([N:1]3[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]3)[C:3]=2[CH:15]=1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N
Reactant: CN1CCNCC1
Solvent: O
Solvent: CCCO
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)CC1
Temperature: 110 °C
Yield: 89 %

Procedure:
4-Amino-2-methyl-10H-thieno-[2,3-b][1,5]benzodiazepine (5 g, 0.02 mol), N-methylpiperazine (12.5 mL, 2.5 vol) and 1-propanol (15 mL, 3 vol) were charged into a three-necked round bottom flask equipped with a reflux condenser, overhead stirrer, and thermometer. The reaction mixture was heated slowly to 110° C. under a nitrogen atmosphere and then refluxed overnight. The reaction mixture was cooled to below 50° C. whereupon water (15 mL, 3 volumes) was added to precipitate out the solid, which was isolated by Buchner filtration. The resulting light yellow solid was washed twice with water (5 mL) and dried to afford olanzapine in 89% yield (5.22 g).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[CH:16]=[C:15]([CH3:17])[S:14][C:5]=2[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1.CO.O.[CH3:21][N:22]1[CH2:27][CH2:26]N[CH2:24][CH2:23]1>CS(C)=O>[CH3:17][C:15]1[S:14][C:5]2[NH:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[N:9]=[C:3]([N:2]3[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]3)[C:4]=2[CH:16]=1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N
Reactant: CN1CCNCC1
Agent: Cl
Solvent: CO
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)CC1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
4-amino-2-methyl-10H-thieno[2,3-b][1,5]benzodiazepine, hydrochloride (50 g) was stirred in a mixture of N-Methylpiperazine (113 g) and Dimethylsulfoxide (300 mL) at 120° C. for 20 h under nitrogen atmosphere. The reaction mass was cooled to 20° C., followed by addition of methanol (500 mL) and the reaction mass was stirred for 30 min. Water (150 mL) was added at 20° C. in 25 min, and the reaction mass was cooled to 5° C. The reaction mass was stirred for 30 min at 0-5° C. The product was filtered and was washed with chilled methanol (50 mL, 5° C.). Dried the product at 50° C. under reduced pressure to give technical 2-Methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine or Olanzapine.
Reaction SMILES: C[O:2][C:3](=[O:38])[C@H:4]([NH:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)=[CH:26][CH:25]=1)(=[O:23])=[O:22])[C@H:5]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)[C:6]1[S:7][CH:8]=[CH:9][N:10]=1.[OH-].[Li+].Cl>O.CO.C1COCC1>[CH3:37][O:36][C:33]1[CH:32]=[CH:31][C:30]([C:27]2[CH:26]=[CH:25][C:24]([S:21]([NH:20][C@H:4]([C@H:5]([O:11][CH2:12][C:13]3[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=3)[C:6]3[S:7][CH:8]=[CH:9][N:10]=3)[C:3]([OH:38])=[O:2])(=[O:23])=[O:22])=[CH:29][CH:28]=2)=[CH:35][CH:34]=1
Reactant: COC(=O)[C@H](NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1)[C@H](OCc1ccc(C)cc1)c1nccs1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(-c2ccc(S(=O)(=O)N[C@@H](C(=O)O)[C@H](OCc3ccc(C)cc3)c3nccs3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2R,3S)-2-(4′-Methoxy-biphenyl-4-sulfonylamino)-3-(4-methyl-benzyloxy)-3-thiazol-2-propionic acid. The (2R,3S)-2-(4′-methoxy-biphenyl-4-sulfonylamino)-3-(4-methyl-benzyloxy)-3-thiazol-2-yl-propionic acid methyl ester 1f (550 mg, 1.00 mmol) is dissolved in water/methanol/THF (5 mL/5mL/5mL) and then lithium hydroxide (1 g, excess) is added. The resulting mixture is stirred overnight at room temperature. The reaction is acidified with 1N HCl and then the product precipitates out of solution to form a white powder. The product is filtered and the desired product is obtained as a white powder.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1.[Cl:14][C:15]1[C:16]2[CH:23]=[CH:22][NH:21][C:17]=2[N:18]=[CH:19][N:20]=1>CC(C)=O>[Cl:14][C:15]1[C:16]2[CH:23]=[CH:22][N:21]([S:10]([C:7]3[CH:8]=[CH:9][C:4]([CH3:3])=[CH:5][CH:6]=3)(=[O:12])=[O:11])[C:17]=2[N:18]=[CH:19][N:20]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)ncnc32)cc1
Temperature: 20 °C
Reaction time: 6 h
Yield: 101.5 %

Procedure:
At about 0° C., sodium hydroxide (2 mol/L in water, 8 mL, 1.20 equiv.) was added to a solution of 4-methylbenzene-1-sulfonyl chloride (2.7 g, 13.9 mmol, 1.10 equiv.) and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (2 g, 12.8 mmol, 1.00 equiv.) in acetone (20 mL). The resulting solution was stirred at about 20° C. for about 6 hours. The solids were collected by filtration and washed with acetone/water to give the title product as a white solid (4.0 g; yield=97%). 1H NMR (300 MHz, CDCl3) δ: 8.78 (s, 1H), 8.11 (d, J=8.4 Hz, 2H), 7.80 (d, J=4.2 Hz, 1H), 7.34 (d, J=8.4 Hz, 2H), 7.73 (d, J=4.2 Hz, 1H), 2.42 (s, 3H). LC-MS: m/z=308/310 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)[N:5]2[CH:15]=[C:16]([CH:18]([CH3:20])[CH3:19])[N:17]=[C:4]2[CH:3]=1.[CH2:21]([N:23]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)[S:24]([CH3:27])(=[O:26])=[O:25])[CH3:22].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[CH2:21]([N:23]([C:28]1[CH:29]=[CH:30][CH:31]=[C:32]([C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=3)[N:5]3[CH:15]=[C:16]([CH:18]([CH3:20])[CH3:19])[N:17]=[C:4]3[CH:3]=2)[CH:33]=1)[S:24]([CH3:27])(=[O:25])=[O:26])[CH3:22]
Reactant: CCN(c1cccc(B(O)O)c1)S(C)(=O)=O
Reactant: Cc1cc(Nc2nc(Cl)cc3nc(C(C)C)cn23)n[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCN(c1cccc(-c2cc3nc(C(C)C)cn3c(Nc3cc(C)[nH]n3)n2)c1)S(C)(=O)=O

Procedure:
7-chloro-2-isopropyl-N-(5-methyl-1H-pyrazol-3-yl)imidazo[1,2-c]pyrimidin-5-amine (0.17 mmol, 0.05 g), 3-(N-ethylmethylsulfonamido)phenylboronic acid (0.35 mmol) and (Ph3)4Pd (O) (0.086 mmol, 0.1 g) were stirred in dioxane (3 mL) and sat. K2CO3 (1.5 mL) The reaction mixture was heated to 150° C. using a microwave reactor for 20 minutes. The mixture was then concentrated and purified by LC-MS to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.06 (t, J=7.07 Hz, 3H) 1.35 (d, J=6.82 Hz, 6H) 2.29 (s, 3H) 3.04 (s, 3H) 3.76 (q, J=7.07 Hz, 2H) 6.70 (s, 1H) 7.57 (s, 1H) 7.59-7.67 (m, 2H) 8.11 (d, J=7.58 Hz, 1H) 8.17 (s, 1H) 8.45 (s, 1H) 10.80 (s, 1H) 12.35 (s, 1H); ESI-MS: m/z calc'd for C22H27N7O2S 453.56; found 454.4 (M+H)+
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[CH:7]=1)(=[O:4])=[O:3]>[Ni].CO>[CH3:1][S:2]([CH2:5][C:6]1[CH:7]=[C:8]([NH2:12])[CH:9]=[CH:10][CH:11]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Cc1cccc([N+](=O)[O-])c1
Agent: [Ni]
Solvent: CO
Product: CS(=O)(=O)Cc1cccc(N)c1
Reaction time: 4 h
Yield: 89.9 %

Procedure:
1-Methanesulfonylmethyl-3-nitro-benzene (4.3 g; 20 mmol) was hydrogenated over Raney nickel (0.5 g) in methanol at 50° C. and 70 psi for 4 h. The catalyst was filtered out, washed with warm methanol, and the combined filtrates were evaporated to give 3.33 g (90%) of 3-methanesulfonylmethyl-phenylamine as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:22]2[C@H:9]3[CH2:10][CH2:11][C@@:12]4([CH3:21])[C@H:16]([C@@H:8]3[CH2:7][CH2:6][C:5]=2[CH:4]=1)[CH2:15][CH2:14][C:13]14[O:20][CH2:19][CH2:18][O:17]1.COC1C=CC2[C@H]3CC[C@@]4(C)[C@H]([C@@H]3CCC=2C=1)CCC4=O>>[CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:22]2[C:9]3=[CH:10][CH2:11][C@@:12]4([CH3:21])[C@H:16]([C@@H:8]3[CH2:7][CH2:6][C:5]=2[CH:4]=1)[CH2:15][CH2:14][C:13]14[O:17][CH2:18][CH2:19][O:20]1
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CCC21OCCO1
Agent: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: COc1ccc2c(c1)CC[C@@H]1C2=CC[C@@]2(C)[C@H]1CCC21OCCO1

Procedure:
The procedure described in Example 1 hereinbefore was repeated except that 2.3 grams of 3-methoxy-13β-methyl-17,17-(ethylenedioxy)gona-1,3,5(10)-triene was substituted for the 3-methoxy-13β-methylgona-1,3,5(10)-trien-17-one in that example.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH3:9])=[CH:4][N:3]=1.Br[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.CN(C=O)C.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=2)[C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: Cc1cnc(Cl)nc1N
Reactant: FC(F)(F)c1cc(Br)ccc1Cl
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: Cc1cnc(Cl)nc1Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 96.1 %

Procedure:
A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.30 g, 2.1 mmol), 4-bromo-1-chloro-2-trifluoromethyl-benzene (0.40 mL, 2.7 mmol), Pd2(dba)3 (0.10 g, 0.11 mmol), Xantphos (0.13 g, 0.22 mmol) and cesium carbonate (1.5 g, 4.6 mmol) in dioxane/DMF (6/1, 7 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160° C. for 15 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by flash chromatography on silica gel (hexanes to 50% EtOAc/hexanes) to afford the title compound (0.65 g, 96%) as a white solid. MS (ES+): m/z 322 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH2:10].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][S:18]([C:15]1[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=1)(=[O:20])=[O:19]
Reactant: COC(=O)c1ccccc1N
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: COC(=O)c1ccccc1NS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
To a mixture of 2-Amino-benzoic acid methyl ester (900 g, 6 mol) in pyridine (6 L) was added p-Toluenesulfonyl chloride (1500 g, 7.5 mol). The mixture was stirred overnight at room temperature. The mixture was poured into ice water, and the resultant precipitates were collected by filtration. The filtrates were dissolved in CH2Cl2, and the solution washed with diluted HCl, H2O, and dried over MgSO4. The residue thus obtained was crystallized from ethanol to give 2-(Toluene-4-sulfonylamino)-benzoic acid methyl ester (1454 g, 80%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([C:8]2[NH:13][C:12]3=[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:15]=[N:16][C:11]3=[CH:10][N:9]=2)[CH2:5][CH:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[NH:3]1.CC[O:31]C(C)=O.[ClH:35]>CO>[OH2:31].[ClH:35].[CH3:1][CH:2]1[CH2:7][CH:6]([C:8]2[NH:13][C:12]3=[C:14]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=[N:16][C:11]3=[CH:10][N:9]=2)[CH2:5][CH:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[NH:3]1
Reactant: CCOC(C)=O
Agent: CC1CC(c2ncc3ncc(-c4ccccc4)c-3[nH]2)CC(c2ccccc2)N1
Agent: Cl
Solvent: CO
Product: O

Procedure:
Using the method described in Example 30 by employing (1,2-diphenylvinyl)pyrrolidine (freshly prepared before use) (1.83 g, 7.35 mmol), 2-methyl-4,6-dichloro-5-nitropyrimidine (Example 76(b)) (1.50 g, 7.35 mmol), N,N-diisopropylethyl amine (Aldrich Chemical Company) (1.3 mL, 7.35 mmol), piperidine (1.2 mL, 11.8 mmol), NEt3 (Aldrich Chemical Company) (2.0 mL) and SnCl2 (Aldrich Chemical Company) (22 mL of a 2M solution in DMF). The residue was purified by flash chromatography on silica gel with 95:5 CHCl3:MeOH as elutant to give 110 mg (4%) of the free base as a pale yellow colored solid. H NMR (DMSO-d6; 400 MHz): δ 1.65 (br s, 6), 2.42 (s, 3), 3.72 (br s, 4), 7.19 (m, 1), 7.28 (m, 2), 7.39-7.44 (m, 7), 11.20 (s, 1). MS m/z: 369 (M+1). To a solution of 2-methyl-6,7-diphenyl-4-piperidylpyrrolo[3,2-d]pyrimidine (148 g, 0.40 mmol) in 1:1 EtOAc: MeOH (50 mL) was added 1M etheral HCl (Aldrich Chemical Company) (400 mL, 0.40 mmol). The solvent was removed under reduced pressure and then dried under vacuum to give 83 mg (51%) of the title compound as a beige colored solid. Mp: 169-171° C. 1H NMR (DMSO-d6; 400 MHz): δ 1.72 (br s, 6), 2.56 (s, 3), 4.06 (br s, 4), 7.29 (dd, 2, J=1.7, 6.0), 7.37-7.45 (m, 8), 12.26 (s, 1), 13.40 (s, 1). MS m/z: 369 (M+1). Anal. Calcd. for C24H24N4.HCl.H2O: C, 68.25; H, 6.40; N, 13.27; Cl, 8.29. Found C, 68.33; H, 6.41; N, 13.15; Cl, 8.50.
Reaction SMILES: C(O)(=O)[C@@H]([C@H](C(O)=O)O)O.[NH2:11][C@H:12]1[C@@H:16]2[O:17][C:18]([CH3:21])([CH3:20])[O:19][C@@H:15]2[C@@H:14]([O:22][CH2:23][CH2:24][OH:25])[CH2:13]1.C(=O)(O)[O-].[Na+].[Cl:31][C:32]1[C:37]([NH2:38])=[C:36](Cl)[N:35]=[C:34]([S:40][CH2:41][CH2:42][CH3:43])[N:33]=1.C(O)CC(C)C>C1(C)C=CC=CC=1.O>[NH2:38][C:37]1[C:36]([NH:11][C@H:12]2[C@@H:16]3[O:17][C:18]([CH3:20])([CH3:21])[O:19][C@@H:15]3[C@@H:14]([O:22][CH2:23][CH2:24][OH:25])[CH2:13]2)=[N:35][C:34]([S:40][CH2:41][CH2:42][CH3:43])=[N:33][C:32]=1[Cl:31]
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](OCCO)C[C@H]2N
Reactant: CCCSc1nc(Cl)c(N)c(Cl)n1
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCCSc1nc(Cl)c(N)c(N[C@@H]2C[C@H](OCCO)[C@H]3OC(C)(C)O[C@H]32)n1
Temperature: 105 °C
Reaction time: 0.33 h
Yield: 82 %

Procedure:
A flask was charged with 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethanol L-tartaric acid salt (17 g), sodium bicarbonate (21.2 g), 4,6-dichloro-2-(propylthio)pyrimidin-5-amine (10 g) and isoamyl alcohol (30 mL). The mixture was heated to about 100-110° C. and maintained at the same temperature for about 10-12 hours and completion of the reaction was monitored by TLC. After completion of reaction the mixture was cooled to room temperature then filtered and the bed was washed with isoamyl alcohol (10 mL). The filtrate was subjected to complete distillation under vacuum at about 65-70° C. to afford the crude. Then water (100 mL) and toluene (100 mL) were charged. The mixture was stirred for about 20 minutes and layers were separated. The organic layer was separated and washed with water (100 mL). The organic layer was separated and subjected to complete distillation under vacuum at 60-65° C. followed by cooling to room temperature and subsequent addition of n-heptane (150 mL). The mixture was stirred for about 4-5 hours followed by isolation of solid by filtration and washing with n-heptane (20 mL). The solid isolated was subjected to drying under vacuum at 50-55° C. to afford the title compound in about 82% yield having HPLC purity of about 99%.
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[C:4]([S:10][CH2:11][CH2:12][CH3:13])[N:3]=1.C(O)(=O)[C@@H]([C@H](C(O)=O)O)O.[NH2:24][C@H:25]1[C@@H:29]2[O:30][C:31]([CH3:34])([CH3:33])[O:32][C@@H:28]2[C@@H:27]([O:35][CH2:36][CH2:37][OH:38])[CH2:26]1.C(=O)(O)[O-].[Na+]>CCCCCC.O.C(OCC)(=O)C>[NH2:8][C:7]1[C:2]([NH:24][C@H:25]2[C@@H:29]3[O:30][C:31]([CH3:33])([CH3:34])[O:32][C@@H:28]3[C@@H:27]([O:35][CH2:36][CH2:37][OH:38])[CH2:26]2)=[N:3][C:4]([S:10][CH2:11][CH2:12][CH3:13])=[N:5][C:6]=1[Cl:9]
Reactant: CCCSc1nc(Cl)c(N)c(Cl)n1
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](OCCO)C[C@H]2N
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCSc1nc(Cl)c(N)c(N[C@@H]2C[C@H](OCCO)[C@H]3OC(C)(C)O[C@H]32)n1
Temperature: 100 °C
Reaction time: 7 h
Yield: 95 %

Procedure:
A flask was charged with 4,6-dichloro-2-(propylthio)pyrimidin-5-amine (25 g), 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethanol L-tartaric acid salt (42.5 g), water (75 mL) and sodium bicarbonate (53 g). The mixture was heated to about 100° C. and maintained at the same temperature for about 14 hours and completion of the reaction was monitored by TLC. After completion of reaction, the mixture was cooled to 60° C. followed by addition of ethyl acetate (25 mL), water (175 mL) and n-hexane (375 mL). The mixture was stirred for about 7 hours. The solid obtained was isolated by filtration and washed with water (50 mL). The wet compound and water (500 mL) were charged into round bottom flask and stirred for overnight. The solid was isolated by filtration and washed with water (50 mL) and was subjected to drying under vacuum at 60° C. for 9 hours to afford the title compound in about 95% yield having HPLC purity of about 98.5%.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N([Cl:21])C(=O)C1>>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][Cl:21])=[N:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccc(-c2ccccc2)cn1
Product: ClCc1ccc(-c2ccccc2)cn1

Procedure:
MS(ESI) 204, 206 (M+H)+, Cl pattern. Prepared from 5-phenyl-2-methylpyridine (example 104) and NCS in place of NBS.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3](=[O:20])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[S:13]([NH:16][CH2:17][CH2:18][OH:19])(=[O:15])=[O:14].[H-].[Na+].[Na].[C:25]1(C)C=CC(S(OC)(=O)=O)=CC=1>CN(C=O)C.CCOC(C)=O>[CH3:1][N:2]([CH3:21])[C:3](=[O:20])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[S:13]([N:16]([CH2:17][CH2:18][OH:19])[CH3:25])(=[O:15])=[O:14]
Reactant: CN(C)C(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)NCCO
Reactant: COS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)N(C)CCO
Reaction time: 20 h

Procedure:
A solution of N,N-Dimethyl-2-(N-(2-hydroxyethyl) aminosulfonyl]-6-nitrobenzamide (3.97 g, 12.5 mmol) in dry DMF (40 ml) was added slowly to a stirred suspension of 50% NaH (0.60 g, 12.5 mmol) in dry DMF (10 ml) under N2 at 20°-25°. After formation of the sodium salt was complete, a solution of methyl p-toluenesulfonate (2.40 g, 12.9 mmol) in DMF (4 ml) was added and the reaction mixture stirred at 20°-25° for 20 hours and then at 60° for 23 hours. The orange solution was mixed with EtOAc (400 ml) and the white solid which formed was filtered off. This precipitate was washed with EtOAc (100 ml). The combined EtOAc solutions were washed with a saturated aqueous NaCl solution, dried (Na2SO4), filtered and concentrated under reduced pressure. Pure product, mp 107°-08°, 2.5 g (60%) was obtained by flash chromatography over silica gel and elution with a 65% n-butylchloride-35% acetonitrile solvent mixture.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Cl:5][CH2:6][CH2:7][CH2:8][C:9](Cl)=[O:10].[C:12]1([CH3:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:5][CH2:6][CH2:7][CH2:8][C:9]([C:15]1[CH:16]=[CH:17][C:12]([CH3:18])=[CH:13][CH:14]=1)=[O:10]
Reactant: Cc1ccccc1
Reactant: O=C(Cl)CCCCl
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1ccc(C(=O)CCCCl)cc1
Temperature: 3 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
Suspend anhydrous AlCl3 (156 g, 1.15 mol) in toluene (1500 mL) and cool to 2-4° C. Add, by slow addition, a solution of 4-chlorobutyryl chloride (165.5 g, 1.15 mol) in toluene (300 mL). Stir for 15 minutes and pour into stirring ice-water (2.5 L). Stir for 30 hours, decant the toluene and extract the aqueous phase with toluene (700 mL). Combine the organic layers and wash three times with water (1 L, 1 L, 500 mL). Evaporate the solvent in vacuo to give the title compound as a pale yellow oil (292.3 g, 95%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>CN(C)C=O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: BrCc1ccc(Br)cc1
Solvent: CN(C)C=O
Product: Brc1ccc(CN2CCOCC2)cc1

Procedure:
4-Bromobenzyl bromide (2.0 g) and morpholine (1.39 ml) were stirred in dimethylformamide (25 ml) for 18 h. The mixture was partitioned between diethyl ether (50 ml) and water (80 ml). The aqueous phase was extracted further with ether (50 ml) and the combined organics were washed with water (80 ml), dried (magnesium sulphate) and evaporated. The residue was purified by column chromatography, eluting with a gradient of ethyl acetate/iso-hexane; 0/100 to 50/50, to give the product as a white crystalline solid (1.44 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][C@@H:12]([O:14][CH2:15][CH3:16])[C@H:11]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:19][CH:18]=2)[C@@H:10]([O:35][CH2:36][C:37]2[CH:46]=[CH:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH:38]=2)[CH2:9]1)=O)(C)(C)C.Cl>CO>[CH2:28]([O:27][CH2:26][CH2:25][CH2:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([C@H:11]2[C@H:12]([O:14][CH2:15][CH3:16])[CH2:13][NH:8][CH2:9][C@@H:10]2[O:35][CH2:36][C:37]2[CH:46]=[CH:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH:38]=2)=[CH:22][CH:21]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](OCc2ccc3ccccc3c2)[C@H]1c1ccc(OCCCOCc2ccccc2)cc1
Agent: Cl
Solvent: CO
Product: CCO[C@@H]1CNC[C@H](OCc2ccc3ccccc3c2)[C@H]1c1ccc(OCCCOCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
14.4 g (23.0 mmol) of (3R,4S,5S)-4-[4-(3-benzyloxy-propoxy)-phenyl]-5-ethoxy-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butylester were placed in 350 ml of abs. methanol at 0° C., then 24 ml (48 mmol) of hydrochloric acid in methanol (2.0 molar) were added dropwise at 5° C. max. and thereafter the mixture was warmed to room temperature. After 120 minutes the reaction mixture was poured into ice-cold sodium hydrogen carbonate solution and the product was extracted three times with dichloromethane, the organic phases were washed once with distilled water, then dried over magnesium sulphate, filtered and concentrated in a water-jet vacuum. The resulting crude product was chromatographed on silica gel with dichloromethane and methanol to yield (3R,4S,5S)-4-[4-(3-benzyloxy-propoxy)-phenyl]-5-ethoxy-3-(naphthalen-2-ylmethoxy)-piperidine as colorless oil; MS: 526(M+H+).