Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]2[O:22][CH:21]=[C:20]([C:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=3)[C:15]=2[CH:16]=[N:17][C:18]=1[NH2:19])[CH3:11].[S:29](N)([NH2:32])(=[O:31])=[O:30]>O1CCOCC1>[NH2:19][C:18]1[N:17]=[CH:16][C:15]2[C:20]([C:23]3[CH2:24][CH2:25][N:26]([S:29]([NH2:32])(=[O:31])=[O:30])[CH2:27][CH:28]=3)=[CH:21][O:22][C:14]=2[C:13]=1[O:12][C@@H:10]([C:3]1[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[Cl:1])[CH3:11]
Reactant: NS(N)(=O)=O
Reactant: C[C@@H](Oc1c(N)ncc2c(C3=CCNCC3)coc12)c1c(Cl)ccc(F)c1Cl
Solvent: C1COCCO1
Product: C[C@@H](Oc1c(N)ncc2c(C3=CCN(S(N)(=O)=O)CC3)coc12)c1c(Cl)ccc(F)c1Cl

Procedure:
A mixture of 7-[(R)-1-(2,6-Dichloro-3-fluorophenyl)-ethoxy]-3-(1,2,3,6-tetrahydropyridin-4-yl)-furo[3,2-c]pyridin-6-ylamine (0.0300 g, 0.071 mmol) and Sulfamide (0.00819 g, 0.0852 mmol) in 1,4-Dioxane (2 mL) was stirred under reflux for 7 h. The reaction mixture was directly loaded onto prep TLC for purification (silica gel, eluting with 4% MeOH in DCM) to afford the title compound as a yellow solid. 1H-NMR (CD3OD, 400 MHz): δ=1.87 (d, J=6.6 Hz, 3H), 2.60 (d, J=1.5 Hz, 2H), 3.36 (t, J=5.7 Hz, 2H), 3.85 (d, J=2.8 Hz, 2H), 6.29 (br. s., 1H), 6.49 (q, 1H), 7.21 (t, J=8.7 Hz, 1H), 7.39 (dd, J=9.0, 4.9 Hz, 1H), 7.64 (s, 1H), 8.19 (s, 1H). MS (ES+): m/z 500.98 (MH+, 35Cl, 37Cl), 502.88 (MH+, 37Cl, 37Cl). HPLC: tR=2.92 min (polar—5 min, ZQ3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][NH:6][C:7]([C:9]1O[CH:11]=[C:12]([Br:24])[C:13](=[O:23])[C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:8].C(O)C.[CH3:31][O:32][CH:33]([O:36][CH3:37])[CH2:34][NH2:35]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][NH:6][C:7]([C:9]1[N:35]([CH2:34][CH:33]([O:36][CH3:37])[O:32][CH3:31])[CH:11]=[C:12]([Br:24])[C:13](=[O:23])[C:14]=1[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:8]
Reactant: COC(CN)OC
Reactant: O=C(NCc1cccc(Cl)c1)c1occ(Br)c(=O)c1OCc1ccccc1
Solvent: CCO
Solvent: C1CCOC1
Product: COC(Cn1cc(Br)c(=O)c(OCc2ccccc2)c1C(=O)NCc1cccc(Cl)c1)OC
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 3-benzyloxy-5-bromo-4-oxo-4H-pyran-2-carboxylic acid 3-chlorobenzylamide (1.50 g) in tetrahydrofuran (10 ml)-ethanol (10 ml) was added aminoacetaldehyde dimethyl acetal (0.73 ml) and the mixture was stirred at 60° C. for 1 hr. The solvent was evaporated and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:3–1:2) to give 3-benzyloxy-5-bromo-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (1.35 g).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([OH:10])=O.ClCCCl.[F:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][C:26](=[O:37])[NH:27][C@H:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:29][CH3:30])[C:17]=1[C:18]([OH:20])=O.C(N(CC)CC)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[F:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[C:18](=[O:20])[O:37][C:26]([NH:27][C@H:28]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:29][CH3:30])=[C:25]2[C:8](=[O:10])[CH2:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1]
Reactant: CC[C@H](NC(=O)Cc1cccc(F)c1C(=O)O)c1ccccc1
Reactant: O=C(O)CN1CCCC1=O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC[C@H](Nc1oc(=O)c2c(F)cccc2c1C(=O)CN1CCCC1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
To a solution of 2-oxo-pyrrolidin-1-yl-acetic acid (1.56 g, 10.9 mmol) in 1,2-dichloroethane (40 ml) oxalyl chloride (0.95 ml, 10.9 mmol) and DMF (1 drop) were added with gas evolution observed. After stirring at r.t. for 1 hour, 2-fluoro-6-[((S)-1-phenyl-propylcarbamoyl)-methyl]-benzoic acid (1.56 g, 4.95 mmol), triethylamine (2.1 ml, 14.9 mmol) and DMAP (85 mg, 0.1 eq.) were added and stirred at r.t. overnight. It was partitioned between mixture of 0.2 M aq. HCl (100 ml)—brine (100 ml) and ethyl acetate (250 ml), washed with water and evaporated to give 1.89 g of crude title compound used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][CH3:10])[CH:3]=1.[ClH:11].[Cl:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17]Cl.O.Cl>C1(C)C(C)=CC=CC=1.CO>[ClH:12].[ClH:11].[F:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: ClCCNCCCl
Reactant: COc1cc(F)ccc1N
Agent: Cl
Solvent: CO
Solvent: Cc1ccccc1C
Solvent: O
Product: COc1cc(F)ccc1N1CCNCC1
Yield: 51.5 %

Procedure:
To a solution of 4-fluoro-2-methoxyaniline (3.0 g) in orthoxylene (50 ml) was added bis(2-chloroethyl)amine hydrochloride (3.8 g) and the mixture was refluxed under heating for 13 hr. The reaction mixture was poured into water and washed with isopropyl ether. To the aqueous layer was added an aqueous sodium hydroxide solution to make it alkaline (pH 12) and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate and the solvent was evaporated to give a black oil. The oil was dissolved in methanol and conc. hydrochloric acid was added and the mixture was concentrated. To this concentrated solution added tetrahydrofuran to give the title compound (3.1 g) as pale-purple crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:32]=[CH:31][C:14]([O:15][C:16]3[CH:25]=[C:24]4[C:19]([CH:20]([C:26]([O:28]C)=[O:27])[CH2:21][CH2:22][O:23]4)=[CH:18][C:17]=3[Cl:30])=[C:13]([N+:33]([O-:35])=[O:34])[CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[OH-].[Na+].O.CO>C1COCC1.C(OCC)(=O)C.Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:32]=[CH:31][C:14]([O:15][C:16]3[CH:25]=[C:24]4[C:19]([CH:20]([C:26]([OH:28])=[O:27])[CH2:21][CH2:22][O:23]4)=[CH:18][C:17]=3[Cl:30])=[C:13]([N+:33]([O-:35])=[O:34])[CH:12]=2)=[O:10])=[CH:36][CH:37]=1
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(Cl)cc4)cc3[N+](=O)[O-])c(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(NCCc1ccc(Cl)cc1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)c([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 36.9 %

Procedure:
To a stirred solution of methyl 7-(4-((4-chlorophenethyl)carbamoyl)-2-nitrophenoxy)-6-chlorochroman-4-carboxylate (5 mg, 0.00917 mmol) in THF (200 uL) was added NaOH (0.0183 ml, 0.0917 mmol) followed by water and methanol (100 uL each). After stirring for 2 hours, the reaction was diluted with ethyl acetate and 2N HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated to yield 7-(4-((4-chlorophenethyl)carbamoyl)-2-nitrophenoxy)-6-chlorochroman-4-carboxylic acid (1.8 mg, 37.0% yield). LCMS (apci/pos)=533.0 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:17]2[CH:18]=[N:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)O1.C([O-])([O-])=O.[K+].[K+].C1COCC1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:17]2[CH:18]=[N:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:3][CH:4]=1
Reactant: CC1(C)OB(c2cnc3ccccc3c2)OC1(C)C
Reactant: Brc1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: Brc1ccc(-c2cnc3ccccc3c2)nc1
Temperature: 100 °C
Yield: 107.4 %

Procedure:
1.1 g (4.7 mmol) of 2,5-dibromo-pyridin, 1.0 g (3.92 mmol) of 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline, 0.45 g of tetrakis(triphenylphosphine)palladium(0), 7.84 ml of 2M K2CO3 and 1.26 g of tetrabutylammoniumbromide were added to a 100 ml round-bottom flask in an argon atmosphere, and 30 ml of THF and 15 ml of toluene were added thereto. Then, the mixture was refluxed at 100° C. for 16 hours. When the mixture solution turned dark brown, water was added thereto and the mixture was subject to extraction using chloroform. Then, an organic layer extracted therefrom was dried using anhydrous magnesium sulfate and filtered. A solvent was removed and the resultant was separated using a silica gel column chromatography to obtain 1.2 g of white solid 3-(5-bromo-pyridin-2-yl)-quinoline which was identified by APCI using LCMS. As a result, a main peak was observed at [M+H]+=285.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[CH:6]1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2([OH:27])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[N:5]1([CH2:4][CH2:3][CH2:2][N:24]2[CH2:23][CH2:22][C:21]([C:18]3[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=3)([OH:27])[CH2:26][CH2:25]2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[CH:6]1
Reactant: ClCCCn1cnc2ccccc21
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: OC1(c2ccc(Cl)cc2)CCN(CCCn2cnc3ccccc32)CC1
Yield: 67.6 %

Procedure:
A mixture of 4.86 parts of 1-(3-chloropropyl)-1H-benzimidazole, 4.24 parts of 4-(4-chlorophenyl)-4-piperidinol, 5.3 parts of sodium carbonate, 0.1 parts of potassium iodide and 200 parts of 4-methyl-2-pentanone is stirred and refluxed for 20 hours with water-separator. The reaction mixture is cooled, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and dried, yielding 5 parts (67.6%) of 1-[3-(1H-benzimidazol-1-yl)propyl]-4-(4-chlorophenyl)-4-piperidinol; mp. 160° C.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18]C(C)(C)C)=[O:17])=[O:12]>>[Cl:8][C:9]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:24]=[CH:23][C:15]=1[C:16]([OH:18])=[O:17])=[O:12]
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1NC(=O)c1c(Cl)cccc1Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(CCc2ccccc2)cc1NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.0 mL of trifluoroacetic acid was added to the obtained tert-butyl 2-(2,6-dichlorobenzamido)-4-phenethylbenzoate and stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure and diisopropyl ether was added to the obtained residue and a solid substance was separated by filtration to obtain 18 mg of 2-(2,6-dichlorobenzamido)-4-phenethylbenzoic acid as white solid.
Reaction SMILES: C[O:2][C:3](=[O:7])[CH2:4][CH2:5][NH2:6].[Cl:8][C:9]1[C:10]([F:34])=[N:11][C:12](NCC(OC)=O)=[C:13]([Cl:27])[C:14]=1[O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22]C)=[C:18]([CH:24]([CH3:26])[CH3:25])[CH:17]=1>>[Cl:8][C:9]1[C:10]([F:34])=[N:11][C:12]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:7])=[C:13]([Cl:27])[C:14]=1[O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH:24]([CH3:26])[CH3:25])[CH:17]=1
Reactant: COC(=O)CCN
Reactant: COC(=O)CNc1nc(F)c(Cl)c(Oc2ccc(OC)c(C(C)C)c2)c1Cl
Product: CC(C)c1cc(Oc2c(Cl)c(F)nc(NCCC(=O)O)c2Cl)ccc1O

Procedure:
By use of β-alanine methyl ester in place of glycine methyl ester for the preparation of Compound 1e followed by deprotection as described for example 2.
Reaction SMILES: [OH:1][C:2]1[C:10]([OH:11])=[C:9]([O:12][CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:14]([N:17]1[CH2:22][CH2:21][C:20](OC)(OC)[CH2:19][CH2:18]1)(=[O:16])[CH3:15].C(N1CC=C(OC)CC1)(=O)C>>[CH3:13][O:12][C:9]1[C:10]2[O:11][C:20]3([O:1][C:2]=2[C:3]([C:4]([OH:6])=[O:5])=[CH:7][CH:8]=1)[CH2:21][CH2:22][N:17]([C:14](=[O:16])[CH3:15])[CH2:18][CH2:19]3
Reactant: COc1ccc(C(=O)O)c(O)c1O
Reactant: COC1(OC)CCN(C(C)=O)CC1
Agent: COC1=CCN(C(C)=O)CC1
Product: COc1ccc(C(=O)O)c2c1OC1(CCN(C(C)=O)CC1)O2
Temperature: 180 °C
Yield: 26.3 %

Procedure:
A mixture of 2,3-dihydroxy-4-methoxybenzoic acid (1.23 g, 6.67 mmol), 1-acetyl-4,4-dimethoxy-piperidine (1.4 g, 7.6 mmol) and 1-acetyl-1,2,3,6-tetrahydro-4-methoxy-pyridine (14.2 g, 91.5 mmol) was exposed to microwave heating (180° C., one hour) in a sealed reaction vessel. Filtration and subsequent standard HPLC purification afforded compound 508 (0.54 g, 26%). LC/MS (METHOD B): (m/z) 308.2 (MH+); RT=2.27 min; purity (UV)=95%.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:17][C@@H:16]([O:18]C(C)(C)C)[CH2:15][N:14]2[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:17][C@@H:16]([OH:18])[CH2:15][N:14]2[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)O[C@@H]1C[C@@H](C(=O)Nc2cc(C(C)(C)C)on2)N(c2ccc(Cl)cc2)C1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2C[C@@H](O)CN2c2ccc(Cl)cc2)no1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(2S,4R)-4-tert-Butoxy-1-(4-chloro-phenyl)-pyrrolidine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide (45 mg, 0.107 mmol) is dissolved in trifluoroacetic acid (0.5 mL, 6.49 mmol) at room temperature and the reaction is stirred at room temperature for 1 hour. The reaction is concentrated under reduced pressure and purification by chromatography on silica eluting with ethyl acetate/hexanes provides the title compound. ESI m/z 364 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][CH:9]=[CH:10][C:5]2=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[C:3]=1[CH:18]([CH2:23][CH2:24][CH3:25])[C:19]([O:21]C)=[O:20].[OH-].[Na+]>CO.C(O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][CH:9]=[CH:10][C:5]2=[C:4]([C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[C:3]=1[CH:18]([CH2:23][CH2:24][CH3:25])[C:19]([OH:21])=[O:20]
Reactant: CCCC(C(=O)OC)c1c(C)nc2sccc2c1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc2sccc2c1-c1ccc(C)cc1
Temperature: 25 °C
Yield: 55.2 %

Procedure:
To a solution of methyl 2-(6-methyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)pentanoate (0.051 g; 0.144 mmol) in methanol (3 mL) and ethanol (1.5 mL) was added a 5% sodium hydroxide solution (3.9 mL; 4.875 mmol). The reaction mixture was heated under reflux for 4 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was suspended in water, acidified with 1N HCl (pH˜2) and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was crystallized from a mixture of ethyl acetate/heptane to afford 0.027 g (55%) of the title compound as a white solid.
Reaction SMILES: [C:1](OC(=O)C)(=O)[CH3:2].[SH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1>>[CH2:1]([S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH3:2]
Reactant: Sc1ccccn1
Reactant: CC(=O)OC(C)=O
Product: CCSc1ccccn1

Procedure:
d. 2-Ethylthio-pyridine was prepared by the same method as used for compound (1) c., except that ethyl halide was used instead of methyl halide. The product had a b.p. of 77°-77.5° C./8 mm. Hg. (1) e. (Pyridyl-2)-thiol acetate was prepared by reacting acetic anhydride with 2-mercaptopyridine in alkaline medium according to the method described in Houben-Weyl, 4th ed., vol. 9, 753 (1955) and in J.A.C.S. 59, 1089 (1937). The product has a b.p. of 117°-118° C./9 mm. Hg.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[S:9][N:8]=[C:7]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][C@H:17]4[C@H:22]([CH2:23][N:24]5[C:34](=[O:35])[C@H:33]6[C@H:27]([C@H:28]7[CH2:32][C@@H:31]6[CH2:30][CH2:29]7)[C:25]5=[O:26])[CH2:21][CH2:20][CH2:19][CH2:18]4)[CH2:12][CH2:11]3)[C:5]=2[CH:6]=1.O.O.[C:38]([OH:43])(=[O:42])[C:39]([OH:41])=[O:40]>CC(C)=O>[CH:1]1[CH:2]=[CH:3][C:4]2[S:9][N:8]=[C:7]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][C@H:17]4[C@H:22]([CH2:23][N:24]5[C:34](=[O:35])[C@H:33]6[C@H:27]([C@H:28]7[CH2:32][C@@H:31]6[CH2:30][CH2:29]7)[C:25]5=[O:26])[CH2:21][CH2:20][CH2:19][CH2:18]4)[CH2:12][CH2:11]3)[C:5]=2[CH:6]=1.[C:38]([O-:43])(=[O:42])[C:39]([O-:41])=[O:40]
Reactant: O=C(O)C(=O)O
Agent: O=C1[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2C(=O)N1C[C@@H]1CCCC[C@H]1CN1CCN(c2nsc3ccccc23)CC1
Solvent: O
Solvent: CC(C)=O
Product: O=C([O-])C(=O)[O-]
Temperature: 25 °C

Procedure:
A mixture consisting of acetone (4750 mL) and lurasidone base (431 g) is refluxed until dissolved. Oxalic acid dihydrate (110 g) is added, and the mixture is cooled to ambient temperature, and then cooled for two hours at 10° C. The solid is filtered, and 435 g of substantially pure lurasidone oxalate is obtained after drying.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5](/[CH:7]=[CH:8]/[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][CH:3]=1.[CH3:16]C1SC(C2CC2C(OCCCC)=O)=CC=1>>[CH3:1][C:2]1[S:6][C:5]([CH:7]2[CH2:16][CH:8]2[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][CH:3]=1
Reactant: Cc1ccc(/C=C/C(=O)OC(C)(C)C)s1
Reactant: CCCCOC(=O)C1CC1c1ccc(C)s1
Product: Cc1ccc(C2CC2C(=O)OC(C)(C)C)s1

Procedure:
tert-Butyl (2E)-3-(5-methylthien-2-yl)prop-2-enoate was cyclopropanated according to the procedure described for EXAMPLE 136, STEP 2, providing, after chromatography, ten-butyl 2-(5-methylthien-2-yl)cyclopropanecarboxylate.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][S:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([OH:20])=[O:19])=[CH:16][C:3]1=2.Cl.[CH2:22](O)[CH3:23]>>[CH2:22]([O:19][C:18](=[O:20])[CH2:17][C:15]1[CH:14]=[CH:13][C:4]2[S:5][CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:2](=[O:1])[C:3]=2[CH:16]=1)[CH3:23]
Reactant: O=C(O)Cc1ccc2c(c1)C(=O)c1ccccc1CS2
Reactant: CCO
Agent: Cl
Product: CCOC(=O)Cc1ccc2c(c1)C(=O)c1ccccc1CS2

Procedure:
40 g of 6,11-dihydro-11-oxo-dibenzo[b,e]thiepine-2-acetic acid are boiled at reflux for 45 minutes together with 400 cc of 3 N hydrochloric acid in ethanol. The reaction mixture is completely concentrated by evaporation at reduced pressure and the oily residue is divided between ethyl acetate and water; the organic phase is washed with a 10% sodium bicarbonate solution and with water. After drying over sodium sulphate and concentrating, 6,11-dihydro-11-oxo-dibenzo[b,e]thiepine-2-acetic acid ethyl ester crystallizes by the addition of ether. (M.P. 98°-100°).
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.Cl[C:55]1[C:64]2[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=2[F:65])[N:58]=[C:57]([C:67]2[CH:68]=[N:69][C:70]([C:73]([F:76])([F:75])[F:74])=[CH:71][CH:72]=2)[C:56]=1[CH3:77].CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH:47][C:55]3[C:64]4[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=4[F:65])[N:58]=[C:57]([C:67]4[CH:68]=[N:69][C:70]([C:73]([F:74])([F:76])[F:75])=[CH:71][CH:72]=4)[C:56]=3[CH3:77])=[CH:45][C:44]([N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: Cc1c(-c2ccc(C(F)(F)F)nc2)nc2cc(F)cc(F)c2c1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccc(C(F)(F)F)nc2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
The Buchwald coupled product was prepared according to Procedure H using dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.021 g, 0.045 mmol), 2,5-dimorpholinopyridin-3-amine (0.088 g, 0.34 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(6-(trifluoromethyl)pyridin-3-yl)quinoline (0.1 g, 0.28 mmol), Pd2dba3 (0.010 g, 0.011 mmol) and sodium tert-butoxide (0.079 g, 0.82 mmol) in toluene (2.8 mL) at 120° C. for 43 h. The crude product was purified by column chromatography on basic alumina (0 to 50% hexanes/EtOAc) to give the desired product N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(6-(trifluoromethyl)-pyridin-3-yl)quinolin-4-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.04 (1H, d, J=1.8 Hz), 8.35 (1H, dd, J=7.8, 1.6 Hz), 8.11 (1H, d, J=8.0 Hz), 7.86 (1H, d, J=6.1 Hz), 7.69 (1H, m), 7.56 (1H, d, J=2.5 Hz), 7.53, (1H, ddd, J=12.9, 9.0, 2.5 Hz), 6.51 (1H, d, J=2.5 Hz), 3.67 (8H, m), 3.17 (2H, br. s), 3.02 (4H, m), 2.85 (2H, br. s), 2.06 (3H, s). Mass Spectrum (ESI) m/e=587.2 (M+1).
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[C:11]12[O:22][CH2:21][CH2:20][CH2:19][O:18]1.Cl[CH2:24][C:25]([CH3:29])([CH3:28])[C:26]#[N:27].O>CS(C)=O>[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:24][C:25]([CH3:29])([CH3:28])[C:26]#[N:27])[C:12](=[O:17])[C:11]12[O:22][CH2:21][CH2:20][CH2:19][O:18]1
Reactant: CC(C)(C#N)CCl
Reactant: O=C1Nc2ccc(Cl)cc2C12OCCCO2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C#N)CN1C(=O)C2(OCCCO2)c2cc(Cl)ccc21
Temperature: 125 °C
Reaction time: 0.17 h
Yield: 68 %

Procedure:
To a stirred solution of potassium t-butoxide (0.561 g, 5.00 mmol, 1.2 eq) in anhydrous DMSO (16 mL) was added 5′-chlorospiro[1,3-dioxane-2,3′-indol]-2′(1′H)-one (1.00 g, 4.17 mmol) all in one portion. After stirring 10 min. 3-chloro-2,2-dimethylpropionitrile (0.981 g, 8.34 mmol, 2 eq) was added in one portion at room temperature under a dry N2 atmosphere. The reaction was heated at 125° C. for 22 hr, cooled to room temperature, poured into H2O (180 mL) and extracted with Et2O (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated. The crude product was purified on Biotage KP silica gel eluting with 100% CH2Cl2 to give the title compound as a white solid (0.91 g, 68% yield). Anal. Calc'd for C16H17ClN2O3: C, 59.91; H, 5.34; N, 8.73. Found: C, 59.79; H, 5.26; N, 8.57. NMR (300 Mz, DMSO-d6): consistent. IR: consistent. MS: (ES+) m/z 321 [M+H]; one Cl pattern observed. m.p.: 114-115.5° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([F:10])([F:9])[F:8])[C:4]([C:11]([O:13]CC)=[O:12])=[CH:3]1.[OH-].[Na+]>C(O)C.O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]([F:9])([F:10])[F:8])[C:4]([C:11]([OH:13])=[O:12])=[CH:3]1
Reactant: CCOC(=O)c1cn(C)cc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1cc(C(=O)O)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of ethyl 1-methyl-4-(trifluoromethyl)pyrrole-3-carboxylate (4.4 g, 0.02 mol) and 4N sodium hydroxide (5 ml, 0.02 mol) in ethanol is stirred for 24 hours at room temperature, diluted with water and extracted with ether. The aqueous phase is acidified with 10% HCl and filtered. The filter cake is washed with water and dried in vacuo at 45° C. to afford the title compound as an off-white solid, 2.4 g (62%), mp 210°-212° C.