Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([CH3:43])([CH3:42])[O:6][CH2:7][CH2:8][C@:9]([OH:41])([C@H:17](/[CH:21]=[CH:22]/[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]1([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[O:33][CH2:32][CH2:31][O:30]1)[C:18]([O-])=[O:19])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:45][C@@H:46]([CH2:52][C:53]1[CH:58]=[CH:57][C:56]([O:59][CH:60]([CH2:62][CH3:63])C)=[CH:55][CH:54]=1)[C:47]([O:49][CH2:50][CH3:51])=[O:48].[CH:64](N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[C:1]([Si:5]([CH3:43])([CH3:42])[O:6][CH2:7][CH2:8][C@:9]([OH:41])([C@@H:17]([C:18](=[O:19])[NH:45][C@H:46]([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:52][C:53]1[CH:54]=[CH:55][C:56]([O:59][CH2:60][C:62]#[C:63][CH3:64])=[CH:57][CH:58]=1)/[CH:21]=[CH:22]/[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]1([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[O:33][CH2:32][CH2:31][O:30]1)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCCCCCCC1(CCCCCC/C=C/[C@H](C(=O)[O-])[C@@](O)(CCO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C)OCCO1
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(OC(C)CC)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC2(CCCCCCC)OCCO2)[C@@](O)(CCO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C)C(=O)OCC)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
No. 5328627, 1-tert-butyl (2S,3S)-2-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-3-[(E)-8-(2-heptyl-[1,3]dioxolan-2-yl)-oct-1-enyl]-2-hydroxy-succinate (2.81 g, 4.47 mmol) was dissolved in N,N-dimethylformamide (70 mL) and the mixture was then cooled to 0° C. in an ice bath. No. 5328632 (ethyl (S)-2-amino-3-(4-but-2-yloxy-phenyl)-propionate hydrochloride; 1.46 g, 4.90 mmol), N,N-diisopropylethylamine (3.1 mL, 17.80 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.87 g, 4.92 mmol) were added in this order, and the mixture was then stirred at 0° C. for 1.5 hours. After quenching with a mixture of a cooled solution (14 mL) of 0.5 M potassium hydrogen sulfate and water (84 mL), the mixture was extracted with 20% ethyl acetate/n-hexane (54 mL). The aqueous layer was further extracted three times with 20% ethyl acetate/n-hexane (27 mL). The organic layers were combined, and then washed with a mixture of a saturated aqueous solution (2.8 mL) of sodium chloride and water (14 mL), and with a saturated aqueous solution (14 mL) of sodium chloride in this order. The organic layers were combined, and then dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 3.95 g (4.53 mmol, quant.) of tert-butyl (E)-(2S,3S)-2-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-ethoxycarbonyl-ethylcarbamoyl]-11-(2-heptyl-[1,3]dioxolan-2-yl)-2-hydroxy-undec-4-enoate.
Reaction SMILES: [CH2:1]([S:4]([C:7]1[C:8]([S:13]([NH2:16])(=[O:15])=[O:14])=[N:9][CH:10]=[CH:11][CH:12]=1)(=[O:6])=[O:5])[CH2:2][CH3:3].[CH3:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21]([NH:27][C:28](=O)[O:29]C2C=CC=CC=2)[N:20]=1.N12CCCN=C1CCCCC2.Cl>C(#N)C.O>[CH3:26][O:25][C:23]1[CH:24]=[C:19]([O:18][CH3:17])[N:20]=[C:21]([NH:27][C:28]([NH:16][S:13]([C:8]2[C:7]([S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5])=[CH:12][CH:11]=[CH:10][N:9]=2)(=[O:15])=[O:14])=[O:29])[N:22]=1
Reactant: CCCS(=O)(=O)c1cccnc1S(N)(=O)=O
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCCS(=O)(=O)c1cccnc1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
To a stirred suspension of 0.4 g (0.0015 mol) of the product from Example 4 and 0.63 g (0.0023 mol) of phenyl (4,6-dimethoxypyrimidin-2-yl)carbamate in 4 mls acetonitrile was added 0.35 g (0.0023 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene and stirred for 30 minutes. The solution was diluted with water and acidified with 1 normal hydrochloric acid. The resulting precipitate was collected and washed with water and ether to afford 0.45 g (67%) white solid: m.p. 168°-170°; NMR (CDCl3, 200 MHz), 1.07 (3H, t, J=7 Hz), 1.85 (2H, m), 3.7 (2H, m), 3.97 (6H, s), 5.8 (1H, s), 7.26 (NH), 7.8 (1H, m), 8.6 (1H, m), 8.9 (1H, m), 12.9 (NH); IR (nujol) 3320, 1740, 1610, 1580, 1375, 1195, 1170 cm-1.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][CH2:5][C:6]1(O)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2.N.[Li]>CCOCC.O>[CH3:22][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]1[C:12]2[CH2:13][CH:14]=[CH:15][CH2:16][C:11]=2[CH2:10][CH2:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2
Reactant: CN(C)CCCC1(O)c2ccccc2CCc2ccccc21
Agent: N
Agent: [Li]
Solvent: CCOCC
Solvent: O
Product: CN(C)CCCC1C2=C(CC=CC2)CCc2ccccc21
Reaction time: 0.33 h
Yield: 98.3 %

Procedure:
5-[3-(Dimethylamino)propyl]-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ol (50.2 g) is partially dissolved in 350 ml of ether and added to 2 liters of liquid ammonia. Lithium ribbon (4.73 g) is then added portionwise over a period of 15 minutes. After stirring for 20 minutes, absolute alcohol is added dropwise until the color is discharged (about 90 ml added over a period of 1 hour). More ether is added and the ammonia is boiled off. While cooling in an ice bath the mixture is diluted slowly with 1 liter of water. The layers are separated and the aqueous layer is reextracted with ether. The combined organic layers are dried over potassium carbonate, filtered, and the solvent is removed in vacuo, leaving 47.0 g of an oil. NMR indicates this is about 50% of the desired diene (the bulk of remaining material being unreduced starting material).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][N:5]([CH3:21])[C:6]1[CH:11]=[CH:10][C:9]([B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]2)=[CH:8][CH:7]=1.I[C:24]1C=CC(N2CC[C@@H](N(C)C)C2)=CC=1>>[CH3:1][N:2]([CH3:22])[C@@H:3]1[CH2:24][CH2:21][N:5]([C:6]2[CH:7]=[CH:8][C:9]([B:12]3[O:16][C:15]([CH3:17])([CH3:18])[C:14]([CH3:20])([CH3:19])[O:13]3)=[CH:10][CH:11]=2)[CH2:4]1
Reactant: CN(C)[C@@H]1CCN(c2ccc(I)cc2)C1
Reactant: CN(C)CCN(C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CN(C)[C@@H]1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C1

Procedure:
The title compound was synthesized according to the synthesis of N,N,N′-trimethyl-N′-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethane-1,2-diamine, substituting (R)-1-(4-iodophenyl)-N,N-dimethylpyrrolidin-3-amine (300 mg, 0.95 mmol). The title compound was purified by silica gel chromatography (MeOH/CH2Cl2, 2:98 to 12:88) as a yellow solid (95 mg, 32%). 1H NMR (400 MHz, MeOD) δ 7.58 (d, J=7.6 Hz, 2H), 6.52 (d, J=7.8 Hz, 2H), 3.55-3.51 (m, 1H), 3.48-3.43 (m, 1H), 3.32-3.26 (m, 1H), 3.15-3.11 (m, 1H), 2.92-2.86 (m, 1H), 2.55 (s, 3H), 2.32 (s, 6H), 2.28-2.22 (m, 1H), 1.94-1.86 (m, 1H); MS ESI 317.2 [M+H]+, calcd for [C18H29BN2O2+H]+ 317.23.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([S:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C1C=C(Cl)C=C(C(OO)=[O:28])C=1.C([O-])(O)=O.[Na+].CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([S:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:28])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc2c(Sc3ccccc3)ccnc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2c(S(=O)c3ccccc3)ccnc2c1
Temperature: 25 °C
Yield: 93.7 %

Procedure:
To 7-methoxy-4-(phenylthio)quinoline (1.38 g, 5.16 mmol) in CH2Cl2 (50 mL) at −78° C. was added m-CPBA (77%) (1.25 g, 7.23 mmol) portionwise. The mixture was allowed to slowly warm to RT (3 hrs). The reaction mixture was diluted with CH2Cl2 then neutralized with NaHCO3 (sat.). The aqueous phase was extracted three times with CH2Cl2 then the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude mixture was purified by silica gel chromatography using 0-10% CH2Cl2:MeOH to afford 7-methoxy-4-(phenylsulfinyl)quinoline (1.37 g, 94% yield) as a off-white foam. MH+=284.0.
Reaction SMILES: [OH:1][CH:2]([CH2:10][OH:11])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[CH3:12][O:13][C:14]([C:16]1[C:21]([Cl:22])=[N:20][CH:19]=[CH:18][N:17]=1)=[O:15]>O1CCOCC1>[ClH:22].[ClH:22].[CH3:12][O:13][C:14]([C:16]1[C:21]([N:7]2[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[CH2:10][OH:11])[CH2:5][CH2:6]2)=[N:20][CH:19]=[CH:18][N:17]=1)=[O:15]
Reactant: OCC(O)CN1CCNCC1
Reactant: COC(=O)c1nccnc1Cl
Solvent: C1COCCO1
Product: COC(=O)c1nccnc1N1CCN(CC(O)CO)CC1
Product: Cl

Procedure:
Grams 20.5 of 1-(2,3-dihydroxypropyl)piperazine and 11 g of 3-chloropyrazine-2-carboxylic acid methyl ester in 100 ml dioxane were refluxed for one hour. The reaction mixture was cooled and settled, the solvent evaporated and the obtained residue dissolved in concentrated hydrochloric acid and the solution diluted with isopropanol until incipient precipitation. After resting, 12.7 g of 3-[4-(2,3-dihydroxypropyl)piperazin-1-yl]pyrazine-2-carboxylic acid methyl ester dihydrochloride melting at 195°-197° C. (with decomposition), were obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([N+:10]([O-])=O)=[CH:4][CH:3]=1.[NH4+].[Cl-].CC(=O)OCC>CO.O.[Fe]>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([NH2:10])=[CH:4][CH:3]=1
Reactant: CNc1nc(Cl)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CNc1nc(Cl)ccc1N
Reaction time: 3 h
Yield: 59.7 %

Procedure:
To a solution of 6-chloro-N-methyl-3-nitropyridin-2-amine (630 mg, 3.36 mmol) in MeOH (10 ml) and water (10 ml) was added Fe (940.8 mg, 16.8 mmol) and NH4Cl (898.8 mg, 168 mmol) at 20° C. The mixture was stirred for 3 hours under reflux temperature until TLC (PE: EA=3:1) showed that the reaction was complete. The mixture was filtered, the filtrate concentrated and residue treated with water (10 ml) and extracted with ethyl acetate (2×20 ml). The combined organic layers were washed with brine (30 ml), dried over Na2SO4 and concentrated to give the desired product (316 mg, 59.7%) as a yellow solid which was used in next step without further purification. LCMS (m/z): 158.1 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C:3](=[S:5])[NH2:4].[Cl:7][CH2:8][C:9]([CH2:11]Cl)=O.[O-]S([O-])(=O)=O.[Mg+2]>CC(C)=O>[ClH:7].[Cl:7][CH2:8][C:9]1[N:4]=[C:3]([CH:2]([CH3:6])[CH3:1])[S:5][CH:11]=1
Reactant: O=C(CCl)CCl
Reactant: CC(C)C(N)=S
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(C)=O
Product: CC(C)c1nc(CCl)cs1
Product: Cl

Procedure:
A mixture of 94.0 g (0.91 mol) of 2-methylpropane-thioamide, 115.7 g (0.91 mol) of 1,3-dichloroacetone, and 109.7 g (0.91 mol) of MgSO4 in 1.6 liters of acetone was heated at reflux for 3.5 h. The resulting mixture was allowed to cool, filtered, and the solvent was removed in vacuo to provide the crude desired compound as a yellow oil. 1H NMR (DMSO-d6) δ 1.32 (d, J=7 Hz, 6 H), 3.27 (heptet, J=7 Hz, 1 H), 4.78 (s, 2 H), 7.61 (s, 1 H). Mass spectrum: (M+H)+ =176.
Reaction SMILES: [C:1]([S:4][CH2:5][C@H:6]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]([C:16](N2[C@H](CC3C=CC=CC=3)COC2=O)=[O:17])[NH:8][C:7]1=[O:31])(=[O:3])[CH3:2].[OH2:32].[OH-].[Li+]>O1CCCC1.O>[C:1]([S:4][CH2:5][C@H:6]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]([C:16]([OH:17])=[O:32])[NH:8][C:7]1=[O:31])(=[O:3])[CH3:2]
Reactant: CC(=O)SC[C@H]1CCCCCC[C@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)NC1=O
Reactant: O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=O)SC[C@H]1CCCCCC[C@H](C(=O)O)NC1=O
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
The more polar major chiral isomer of N-[[trans 3-(acetylthiomethyl)-2-oxo-1-azacyclodecan-10-yl]-carbonyl]-(R)-4-benzyl-2-oxazolidinone (1.23 g, 2.75 mmol) is dissolved in tetrahydrofuran (45.0 mL) and water (15.0 mL), and the reaction is cooled to 0° C. Lithium hydroxide hydrate (0.116 g, 2.75 mmol) is added, and the reaction is stirred at 0° C. for 45 minutes. The solvent is then evaporated, and the residue is partitioned between saturated sodium bicarbonate and methylene chloride. The aqueous layer is extracted several times with methylene chloride, and then the aqueous layer is acidified with 2.5N hydrochloric acid to pH=3. The aqueous layer is extracted several times with ethyl acetate, the combined organic layers dried (MgSO4) and the solvent is evaporated, to give one enantiomer of trans 3-(acetylthiomethyl)-2-oxo-1-azacyclodecane-10-carboxylic acid, m.p. 144°-145° C.; [α]D +88.36° (c=6.9 mg/ml, CH2Cl2), which is assigned the 3R, 10S configuration.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=O)[C:4]([C:9]([F:12])([F:11])[F:10])=[N:3]1.[ClH:13].Cl.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:24][CH:25]=[CH:26][N:27]=2)=[CH:18][CH:17]=1.C(N(CC)CC)C.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[ClH:13].[ClH:13].[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([N:28]3[CH2:29][CH2:30][N:31]([CH2:7][C:5]4[C:4]([C:9]([F:12])([F:11])[F:10])=[N:3][N:2]([CH3:1])[CH:6]=4)[CH2:32][CH2:33]3)=[N:24][CH:25]=[CH:26][N:27]=2)=[CH:18][CH:17]=1
Reactant: Cn1cc(C=O)c(C(F)(F)F)n1
Reactant: Fc1ccc(-c2nccnc2N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: Cn1cc(CN2CCN(c3nccnc3-c3ccc(F)cc3)CC2)c(C(F)(F)F)n1
Reaction time: 0.25 h
Yield: 149.2 %

Procedure:
Combine 1-methyl-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde (0.17 g, 0.97 mmol) and 3′-(4-fluorophenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl dihydrochloride (0.35 g, 1.06 mmol) in DCM (20 mL) and treat with triethylamine (0.30 mL, 2.12 mmol). After stirring for 15 min, add glacial acetic acid (0.08 mL, 1.46 mmol) then sodium triacetoxyborohydride (0.31 g, 1.46 mmol). Stir at room temperature for 18 hr. Concentrate and purify using SCX chromatography and further purify using silica gel chromatography (5% 7 M ammonia in methanol/DCM). Dissolve the free base in methanol (5 mL) and treat with ammonium chloride (0.107 g). Concentrate the resulting solution to give the title compound (0.39 g, 81%). MS: m/z=421.3 [M+H]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([NH:18][C@@H:19]([CH2:24][CH:25]1[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]1)[C:20]([O:22][CH3:23])=[O:21])=[O:17])([CH3:14])([CH3:13])[CH3:12].C([O-])(O)=O.[Na+]>C(Cl)Cl.CCN(CC)CC>[C:11]([O:15][C:16]([NH:18][C@@H:19]([CH2:24][CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]1)[C:20]([O:22][CH3:23])=[O:21])=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: COC(=O)[C@H](CC1CCC(O)CC1)NC(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: COC(=O)[C@H](CC1CCC(=O)CC1)NC(=O)OC(C)(C)C
Temperature: -40 °C
Reaction time: 5 h
Yield: 67 %

Procedure:
To a solution of oxalyl dichloride (49.5 g, 0.39 mol) in dry CH2Cl2 (480 mL) was added dropwise a solution of dry DMSO (60.8 g, 0.78 mol) in dry CH2Cl2 (200 mL) at −65° C. for about 0.5-1 hr. Then a solution of (S)-methyl 2-(tert-butoxycarbonylamino)-3-(4-hydroxycyclohexyl)propanoate (59.5 g, 0.197 mol) in dry CH2Cl2 (600 mL) was added dropwise to the above mixture for about 0.5-1 hr. It was allowed to stir for 4-6 hr at −50-−30° C. Upon completion of the reaction, 158 mL of Et3N was added dropwise and the mixture was warmed to rt. The solution was added sat. NaHCO3, extracted by EtOAc, washed with H2O, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatograph to give (S)-methyl 2-(tert-butoxycarbonylamino)-3-(4-oxocyclohexyl)propanoate (39.5 g, 67%). 1H NMR (CDCl3, 400 MHz) δ 5.00 (d, J=8.0H, 1H), 4.39 (m, 1H), 3.74 (s, 3H), 2.40-1.30 (m, 11H), 1.44 (s, 9H). MS ESI +ve m/z 301 (M+1).
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([CH2:10]O)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:14])=O>ClCCl>[ClH:14].[C:1]([N:5]1[CH:9]=[C:8]([CH2:10][Cl:14])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1cc(CO)cn1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)n1cc(CCl)cn1
Product: Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.77 g of (1-t-butyl-1H-pyrazol-4-yl)methanol was dissolved in 25 ml of dichloromethane, and 1.7 ml of thionyl chloride was added. The mixture was stirred at room temperature for 5 hours. Thereafter, the reaction mixture was concentrated under reduced pressure to obtain 1.12 g of 1-t-butyl-4-(chloromethyl)-1H-pyrazole hydrochloride.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7](=[O:28])[CH2:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@H:4]([C:29]([N:31]2[CH2:35][CH2:34][CH2:33][C@@H:32]2[C:36]([NH:38][CH2:39][C@H:40]2[CH2:45][CH2:44][CH2:43][NH:42][CH2:41]2)=[O:37])=[O:30])[CH2:3]1.[CH3:46][CH:47]([CH2:50][CH3:51])[CH:48]=O>>[OH:1][C@H:2]1[CH2:6][N:5]([C:7](=[O:28])[CH2:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@H:4]([C:29]([N:31]2[CH2:35][CH2:34][CH2:33][C@@H:32]2[C:36]([NH:38][CH2:39][C@H:40]2[CH2:45][CH2:44][CH2:43][N:42]([CH2:46][CH:47]([CH3:48])[CH2:50][CH3:51])[CH2:41]2)=[O:37])=[O:30])[CH2:3]1
Reactant: O=C(NC[C@H]1CCCNC1)[C@H]1CCCN1C(=O)[C@@H]1C[C@@H](O)CN1C(=O)CC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCC(C)C=O
Product: CCC(C)CN1CCC[C@H](CNC(=O)[C@H]2CCCN2C(=O)[C@@H]2C[C@@H](O)CN2C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1

Procedure:
The title compound was prepared by a method similar to Step 3 of Example 17, using (2R)-1-{(2S,4R)-4-hydroxy-1-(3,3,3-triphenylpropanoyl)pyrrolidin-2-yl}carbonyl-N-((3S)-3-piperidylmethyl)pyrrolidine-2-carboxamide and 2-methylbutanal. The compound was obtained as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:14]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.C1(S(Cl)(=O)=O)C=CC=CC=1.[OH-].[NH4+:49]>>[CH3:1][C:2]1[N:3]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[C:6]([NH2:49])[C:5]=2[N:14]=1
Reactant: Cc1nc2cnc3ccccc3c2n1CCCCC(=O)N1CCOCC1
Reactant: [NH4+]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S(=O)(Cl)c1ccccc1
Agent: [OH-]
Product: Cc1nc2c(N)nc3ccccc3c2n1CCCCC(=O)N1CCOCC1

Procedure:
2-Methyl-1-(5-morpholin-4-yl-5-oxopentyl)-1H-imidazo[4,5-c]quinoline (8.4 g, 24 mmol) was treated with mCPBA (7.19 g, 41.7 mmol), ammonium hydroxide (40 mL), and benzenesulfonyl chloride (5.93 mL, 46.5 mmol) according to the method described in Part D of Example 36. The crude product was purified by column chromatography on silica gel (eluting with 90:10 dichloromethane:methanol). The resulting product was triturated with 10% aqueous sodium hydroxide, isolated by filtration, washed with water, and dried overnight in a vacuum oven to provide 0.487 g of 2-methyl-1-(5-morpholin-4-yl-5-oxopentyl)-1H-imidazo[4,5-c]quinolin-4-amine as an off-white powder, mp 218-219° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C@H:14]2[C@H:10]([C:11]([C:16]3C=N[C:19](OC)=[CH:20][CH:21]=3)=[N:12][O:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:25]=[C:26](Cl)C1C=CC=CN=1>CO.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:15][C@H:14]2[C@H:10]([C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:26][N:25]=3)=[N:12][O:13]2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(C2=NO[C@H]3CN(C(=O)OC(C)(C)C)C[C@@H]23)cn1
Reactant: ON=C(Cl)c1ccccn1
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H]2ON=C(c3ccccn3)[C@@H]2C1

Procedure:
The title compound was prepared in an analogous manner as the 4-methoxy-3-pyridyl cycloadduct 3c using chloro oxime 2e. 3e was isolated as a white solid after chromatography with 1.5% methanol/methylene chloride.
Reaction SMILES: S([O-])(=O)(=O)C.[S:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8]([N:15]2[CH2:20][CH2:19][N+:18]3([CH2:28][C@H:27]4[C@@H:22]([CH2:23][CH2:24][CH2:25][CH2:26]4)[CH2:21]3)[CH2:17][CH2:16]2)=[N:7]1.[C:29]1(=[O:40])[C@H:37]2[C@H:32]([C@H:33]3[CH2:38][C@@H:36]2[CH2:35][CH2:34]3)[C:31](=[O:39])[NH:30]1.C(=O)([O-])[O-].[K+].[K+].C1(C)C(C)=CC=CC=1>C(O)(C)C>[CH:13]1[CH:12]=[CH:11][C:10]2[S:6][N:7]=[C:8]([N:15]3[CH2:16][CH2:17][N:18]([CH2:21][C@H:22]4[C@H:27]([CH2:28][N:30]5[C:31](=[O:39])[C@H:32]6[C@H:37]([C@H:36]7[CH2:38][C@@H:33]6[CH2:34][CH2:35]7)[C:29]5=[O:40])[CH2:26][CH2:25][CH2:24][CH2:23]4)[CH2:19][CH2:20]3)[C:9]=2[CH:14]=1
Reactant: c1ccc2c(N3CC[N+]4(CC3)C[C@@H]3CCCC[C@H]3C4)nsc2c1
Reactant: O=C1NC(=O)[C@H]2[C@@H]3CC[C@@H](C3)[C@@H]12
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: Cc1ccccc1C
Product: O=C1[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2C(=O)N1C[C@@H]1CCCC[C@H]1CN1CCN(c2nsc3ccccc23)CC1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
100 g (3aR,7aR)-4′-(benzo[d]isothiazol-3-yl)octahydrospiro[isoindole-2,1′-piperazin]-1′-ium mesylate of Formula (G) and 55 g (3aS,4R,7S,7aR)-hexahydro-4,7-methano-1H-isoindole-1,3-(2H)-dione of Formula (E), 55 g potassium carbonate, 400 mg dibenzo-18-crown-ether and 1000 mL xylene were added to round bottom flask at 25 to 35° C. The reaction mass was heated to 130° C. to 140° C. and stirred for 3 hours and cooled to 65° C. The reaction mixture was filtered and washed with 50 mL of xylene. The wet-cake was treated with 200 mL xylene at 65° C. for 30 min. The reaction mixture was cooled to 25° C. and filtered. The filtrate was washed with water and separated organic layer was dried over sodium sulfate, charcoalized and distilled under vacuum below 70° C. to obtain residue. The residue was treated with 200 mL isopropanol at 80 to 85° C. The reaction mass cooled to 25 to 35° C. and cooled to 0 to 5° C. The product was filtered and washed with isopropanol to afford the title compound as lurasidone free base of Formula (H). X-ray powder diffraction pattern (FIG. 3), DSC (FIG. 4).
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].Cl.Cl[C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=1.CCN(C(C)C)C(C)C>CC#N>[C:6]([O:5][C:3](=[O:4])[CH2:2][NH:1][C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)CNc1ncccc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 102.9 %

Procedure:
To a suspension of H-Gly-OtBu.HCl (1.57 g) in MeCN (35 mL) was added 2-chloro-3-nitropyridine (1.5 g) and DIPEA (4.01 mL). The resulting yellow solution was heated up to 80° C. for 14 h. The reaction mixture was evaporated to dryness. The residue was taken up in DCM, washed with water and brine and the aq. phases were extracted with DCM. The combined org. layers were dried (MgSO4), filtrated off and evaporated in vacuo to afford 2.44 g of yellow solid. LC-MS (C): tR=0.81 min; [M+H]+: 254.27