Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8](I)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15].[CH3:17][N:18]1[C:22]([Sn](CCCC)(CCCC)CCCC)=[CH:21][CH:20]=[N:19]1>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:22]2[N:18]([CH3:17])[N:19]=[CH:20][CH:21]=2)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15]
Reactant: COC(=O)c1cc(I)c(C(F)(F)F)cc1N
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1C
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccnn2C)c(C(F)(F)F)cc1N
Temperature: 100 °C
Reaction time: 18 h
Yield: 75.8 %

Procedure:
2-Amino-5-iodo-4-trifluoromethyl-benzoic acid methyl ester (7 g, 20.29 mmol) and 1-methyl-5-tributylstannanyl-1H-pyrazole (9.03 g, 1.2 equiv) were weighed in air and added in a flame-dried flask. Bis(triphenylphosphine)palladium (II) dichloride (2.18 g, 0.15 equiv) and dioxane (100 mL) were added and the mixture was stirred for 18 h at 100° C. The mixture was evaporated to dryness. The crude product was purified by flash chromatography (hexanes to EtOAc/hexanes (4:6)) to provide 2-amino-4-trifluoromethyl-5-(2-methyl-2H-pyrazol-3-yl)-benzoic acid methyl ester (4.6 g, 76%) as an orange solid. (ESI-MS: m/z 300.3 [M+H]+, rt 5.15 min).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[N:22]=[CH:21][N:20]=[C:19]3[C:15]=1[N:16]=[CH:17][NH:18]3)[CH2:9][CH2:8]2)=[O:4].[NH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([NH2:30])[CH2:26][CH2:25]1>O>[NH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([NH:30][C:21]2[N:20]=[C:19]3[C:15]([N:16]=[CH:17][NH:18]3)=[C:14]([N:10]3[C:11]4[C:7](=[CH:6][C:5]([C:3](=[O:4])[CH3:2])=[CH:13][CH:12]=4)[CH2:8][CH2:9]3)[N:22]=2)[CH2:26][CH2:25]1
Reactant: O=C(CCl)c1ccc2c(c1)CCN2c1ncnc2[nH]cnc12
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: O
Product: CC(=O)c1ccc2c(c1)CCN2c1nc(N[C@H]2CC[C@H](N)CC2)nc2[nH]cnc12
Temperature: 140 °C
Reaction time: 48 h

Procedure:
1.88 g of product obtained in stage 1 above are mixed with 4.8 g of trans-1,4-diaminocyclohexane, and the mixture is then heated at 140° C. for approximately 72 hours. The mixture is allowed to return to ambient temperature for 48 hours. A paste is formed in water, and drying is carried out under vacuum at 50° C. 2.7 g of expected product are obtained, in the form of a beige powder.
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH3:7])[CH2:5][NH2:6])[CH3:2].C([N:16]=[C:17]=[S:18])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].S(=O)(=O)(O)O>C(Cl)(Cl)Cl>[CH2:1]([O:3][CH:4]([CH3:7])[CH2:5][NH:6][C:17]([NH2:16])=[S:18])[CH3:2]
Reactant: CCOC(C)CN
Reactant: O=C(N=C=S)c1ccccc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CCOC(C)CNC(N)=S
Temperature: 75 °C
Yield: 68 %

Procedure:
2-Ethoxy-propylamine (1.50 g, 14.5 mmol) and benzoylisothiocyanate (2.61 g, 16.0 mmol) in chloroform (50 mL) were heated at 75° C. for 1 h. The solvent was removed under reduced pressure and methanol (15 mL) and water (30 mL) were added. Potassium carbonate (2.0 g, 14.5 mmol) was added and the mixture was heated at 75° C. for 2 h. After cooling to room temperature, the mixture was neutralized with 2M sulphuric acid and the solvent was removed under reduced pressure. The crude product was dissolved in methanol and insoluble material was removed by filtration. The solvent was distilled off and the resulting solid was washed with dichloromethane and dissolved in ethanol. Insoluble material was removed by filtration and the solvent was removed under reduced pressure. This gave the title compound as a white solid (1.6 g, 59% yield).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:23])[C:10]2[CH:15]=[C:14]([O:16][C@@H:17]([CH3:21])[CH2:18][O:19][CH3:20])[CH:13]=[C:12]([OH:22])[CH:11]=2)=[N:4]1)[CH3:2].[N:24]1([C:28]([C:30]2[CH:35]=[CH:34][C:33](Br)=[CH:32][N:31]=2)=[O:29])[CH2:27][CH2:26][CH2:25]1>>[N:24]1([C:28]([C:30]2[N:31]=[CH:32][C:33]([O:22][C:12]3[CH:11]=[C:10]([CH:15]=[C:14]([O:16][C@@H:17]([CH3:21])[CH2:18][O:19][CH3:20])[CH:13]=3)[C:9]([NH:8][C:5]3[CH:6]=[CH:7][N:3]([CH2:1][CH3:2])[N:4]=3)=[O:23])=[CH:34][CH:35]=2)=[O:29])[CH2:27][CH2:26][CH2:25]1
Reactant: CCn1ccc(NC(=O)c2cc(O)cc(O[C@@H](C)COC)c2)n1
Reactant: O=C(c1ccc(Br)cn1)N1CCC1
Product: CCn1ccc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)nc3)cc(O[C@@H](C)COC)c2)n1

Procedure:
The preparation of N-(1-ethyl-1H-pyrazol-3-yl)-3-hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzamide and 2-(azetidin-1-ylcarbonyl)-5-bromopyridine was described earlier.
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:38][C:39]1[C:44]([CH3:45])=[CH:43][C:42]([C:46](=[O:48])[NH2:47])=[CH:41][C:40]=1[CH3:49])[C:10]([N:12]([CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:36][CH3:37])=[C:31]([CH:35]=1)[C:32]([OH:34])=[O:33])[CH:13]([C:15]1[NH:16][CH:17]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:19]=1)[CH3:14])=[O:11])=O)(C)(C)C.CC(C)=O.Cl.[OH-].[Na+]>O>[NH2:8][CH:9]([CH2:38][C:39]1[C:44]([CH3:45])=[CH:43][C:42]([C:46](=[O:48])[NH2:47])=[CH:41][C:40]=1[CH3:49])[C:10]([N:12]([CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:36][CH3:37])=[C:31]([CH:35]=1)[C:32]([OH:34])=[O:33])[CH:13]([C:15]1[NH:16][CH:17]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:19]=1)[CH3:14])=[O:11]
Reactant: COc1ccc(CN(C(=O)C(Cc2c(C)cc(C(N)=O)cc2C)NC(=O)OC(C)(C)C)C(C)c2nc(-c3ccccc3)c[nH]2)cc1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(CN(C(=O)C(N)Cc2c(C)cc(C(N)=O)cc2C)C(C)c2nc(-c3ccccc3)c[nH]2)cc1C(=O)O
Temperature: 45 °C
Reaction time: 2 h

Procedure:
A 1 L three-necked round-bottomed flask equipped with a mechanical stirrer, addition funnel and a thermocouple was charged without agitation. 34.2 g of 5-({[2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid (see Example 9 of US 2005/0203143), 340 ml of acetone, and 17 ml of 204 mmolar concentrated HCl were combined in the flask. The stirring was started and the resulting slurry formed a clear solution. This solution was heated to 45° C. under vigorous stirring and aged at this temperature for a period of two hours. After the completion, the reaction mass was cooled to ambient temperature and the supernatant was removed by suction. The vessel along with the residue was rinsed with 20 ml of acetone and then removed as previously. 170 ml of water was added and the reaction mass and was aged under stirring until a homogeneus solution resulted. This solution was then added over a period of ˜½ hr to a solution of 90 ml of 1N NaOH and water. The pH was adjusted to 6.5-7.0 accordingly. The resulting slurry was aged for about 2 hrs at ambient temperature, cooled to 10-15° C., aged at that temperature for about 1 hr, and then filtered. The solid was washed with 10 ml water, air-dried for a period of 4 to 5 hrs, and then placed in a vacuum oven at 50-55° C. until the water content was less than 3%.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[N:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13](=[O:24])[CH2:14][C:15]1[C:20]([F:21])=[CH:19][C:18]([F:22])=[CH:17][C:16]=1[F:23])=[O:5])C.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CO>[F:21][C:20]1[CH:19]=[C:18]([F:22])[CH:17]=[C:16]([F:23])[C:15]=1[CH:14]1[C:13](=[O:24])[NH:12][C:11]2[CH:10]=[CH:9][N:8]=[N:7][C:6]=2[C:4]1=[O:5]
Reactant: CCOC(=O)c1nnccc1NC(=O)Cc1c(F)cc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C1Nc2ccnnc2C(=O)C1c1c(F)cc(F)cc1F
Reaction time: 18 h
Yield: 97.2 %

Procedure:
The product from Step 2 (0.307 g) and potassium carbonate (0.25 g) were stirred in dry DMF (10 ml) at 110° C. for 2 hours and then cooled and stood for 18 hours. The DMF was evaporated and the resulting brown solid was triturated with diethyl ether and the organic phase decanted. The solid was dissolved in water then acidified with dilute hydrochloric acid to neutrality. Most of the aqueous phase was then evaporated, leading to precipitation of a black solid that was filtered, and the yellow/brown aqueous phase was evaporated to dryness, affording a residue that was dissolved in methanol, the insoluble inorganic salts were filtered and the organic phase was evaporated to dryness to give 7-(2,4,6-trifluorophenyl)-5H-pyrido[3,2-c]pyridazine-6,8-dione as a light brown/beige solid (0.258 g).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]([CH3:19])[CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)=[CH:4][CH:3]=1.[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[C:29]=1B(O)O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[C:29]=1[C:2]1[N:7]=[N:6][C:5]([N:8]([CH3:19])[CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)=[CH:4][CH:3]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CN(c1ccc(Cl)nn1)C1CC(C)(C)NC(C)(C)C1
Reactant: COc1cccc(OCc2ccccc2)c1B(O)O
Product: COc1cccc(OCc2ccccc2)c1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1

Procedure:
Intermediate 1-1 (391 mg, 1.384 mmol) and (2-(benzyloxy)-6-methoxyphenyl)boronic acid (500 mg, 1.94 mmol) were reacted according to GENERAL METHOD 1-5 for Suzuki coupling. 6-(2-(Benzyloxy)-6-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine was obtained as a beige solid (358 mg, 56% yield) after flash column chromatography purification. MS (M+1)=461.5.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[NH:13][C:14](=[O:19])[CH2:15][CH2:16][CH2:17][CH3:18])[C:7]([OH:9])=O)([O-:3])=[O:2].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.[NH:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1>O1CCCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[NH:13][C:14](=[O:19])[CH2:15][CH2:16][CH2:17][CH3:18])[C:7]([N:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1)=[O:9])([O-:3])=[O:2]
Reactant: C1COCCN1
Reactant: CCCCC(=O)Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCCCC(=O)Nc1ccc(C(=O)N2CCOCC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In tetrahydrofuran (800 ml), 3-nitro-4-valeramidobenzoic acid ([1]-(11)-1) (20.0 g) was dissolved. Dicyclohexylcarbodiimide (17.1 g) and 1-hydroxybenzotriazole (11.2 g) were added to the solution, and the mixture was stirred at room temperature for 15 minutes. Morpholine (7.27 g) was further added to the solution. The mixture was stirred for 16 hours. After the insolubles were removed from the reaction solution, the solution was concentrated and dried. The crude product was dissolved in chloroform, and the insolubles were removed, and the solution was purified by silica gel column chromatography (Kieselgel 60=400 g, chloroform/methanol=30/1) to obtain the compound ([1]-(12)-1) (22.95 g) as yellow needle crystals.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[C:7]([O:16]C(OC(C)(C)C)=O)[C:6]([C:24]([F:27])([F:26])[F:25])=[CH:5][CH:4]=1.[OH:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:40]=[CH:39][C:38]([CH2:41][C:42]([O:44][CH2:45][CH:46]=[CH2:47])=[O:43])=[CH:37][N:36]=2)=[CH:31][CH:30]=1>>[CH2:45]([O:44][C:42]([CH2:41][C:38]1[CH:37]=[N:36][C:35]([C:32]2[CH:31]=[CH:30][C:29]([O:28][CH2:2][C:3]3[C:8]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])=[C:7]([OH:16])[C:6]([C:24]([F:26])([F:25])[F:27])=[CH:5][CH:4]=3)=[CH:34][CH:33]=2)=[N:40][CH:39]=1)=[O:43])[CH:46]=[CH2:47]
Reactant: C=CCOC(=O)Cc1cnc(-c2ccc(O)cc2)nc1
Reactant: CC(C)(C)OC(=O)Oc1c(C(F)(F)F)ccc(CBr)c1C(=O)OC(C)(C)C
Product: C=CCOC(=O)Cc1cnc(-c2ccc(OCc3ccc(C(F)(F)F)c(O)c3C(=O)OC(C)(C)C)cc2)nc1
Yield: 28 %

Procedure:
According to a method similar to Example (2-3) and Example (33-5), from tert-butyl 6-(bromomethyl)-2-[(tert-butoxycarbonyl)oxy]-3-(trifluoromethyl)benzoate (412 mg, 0.92 mmol) obtained in Example (28-5) and allyl [2-(4-hydroxyphenyl)-5-pyrimidinyl]acetate (250 mg, 0.92 mmol), tert-butyl 6-{[4-(5-{[(allyloxy)carbonyl]methyl}-2-pyrimidinyl)phenoxy]methyl}-2-hydroxy-3-(trifluoromethyl)benzoate was obtained (140 mg, two-step total yield: 28%).
Reaction SMILES: [CH2:1]([C:3]1[NH:12][C:6]2=[CH:7][N:8]=[C:9](Cl)[CH:10]=[C:5]2[CH:4]=1)[CH3:2].[NH3:13].O>CCO>[CH2:1]([C:3]1[NH:12][C:6]2=[CH:7][N:8]=[C:9]([NH2:13])[CH:10]=[C:5]2[CH:4]=1)[CH3:2]
Reactant: N
Reactant: CCc1cc2cc(Cl)ncc2[nH]1
Solvent: O
Solvent: CCO
Product: CCc1cc2cc(N)ncc2[nH]1
Temperature: 200 °C
Reaction time: 10 h
Yield: 16 %

Procedure:
A suspension of 2-ethyl-5-chloro-1H-pyrrolo[2,3-c]pyridine (1.3 g, 7.19 mmol) in EtOH (20 mL), CuSO4.5H2O (179 mg, 0.72 mmol) and NH3—H2O (60 ml) was added into an autoclave (100 mL). The reaction was stirred at 200° C. and 2 MPa for 10 h. The reaction was cooled to 25° C. and was quenched with water and extracted with ethyl acetate (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 10/1) to give 2-ethyl-1H-pyrrolo[2,3-c]pyridin-5-amine (190 mg, 16%). 1H-NMR (CDCl3, 300 MHz) δ 10.71 (brs, H), 8.00 (s, 1H), 6.39 (s, 1H), 5.87 (s, 1H), 4.89 (br s, 2H), 2.65 (q, J=7.5 Hz, 2H), 1.22 (t, J=7.5 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH2:22][CH3:23])=[CH:20][C:19]([CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:25])[CH:3]=1.[CH3:26][C:27]1([CH3:33])[O:31][C:30](=[O:32])[NH:29][CH2:28]1>>[CH2:22]([C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:29]4[CH2:28][C:27]([CH3:33])([CH3:26])[O:31][C:30]4=[O:32])=[CH:3][C:4]=3[F:25])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:24])[CH:20]=1)[CH3:23]
Reactant: CC1(C)CNC(=O)O1
Reactant: CCc1cc(C)cnc1N1CCN(C(=O)c2ccc(Br)cc2F)CC1
Product: CCc1cc(C)cnc1N1CCN(C(=O)c2ccc(N3CC(C)(C)OC3=O)cc2F)CC1
Yield: 49.1 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-fluorophenyl)[4-(3-ethyl-5-methylpyridin-2-yl)piperazin-1-yl]methanone (539 mg) described in Preparation Example 104 and 5,5-dimethyloxazolidin-2-one (276 mg) described in Preparation Example 43, the title compound (287 mg) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:30]=[N:31][CH:32]=[C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:34]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:30]=[N:31][CH:32]=[C:33]([C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=5)[CH:34]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Brc1cncc(-c2ccccc2)c1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cncc(-c5ccccc5)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 3-bromo-5-phenyl-pyridine.
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: O=C1NC(=O)[C@H]2[C@@H]3CC[C@@H](C3)[C@@H]12
Reactant: c1ccc2c(N3CC[N+]4(CC3)C[C@@H]3CCCC[C@H]3C4)nsc2c1
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Solvent: CC(C)O
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][C@H:2]1[CH2:8][S:7][C@H:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][N:4]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:3]1=[O:23].Br[CH:25]([CH2:31][CH2:32][CH2:33][CH2:34][N:35]1[C:39](=[O:40])[C:38]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:37]2[C:36]1=[O:45])[C:26]([O:28][CH2:29][CH3:30])=[O:27].C(=O)([O-])[O-].[Na+].[Na+]>>[CH2:29]([O:28][C:26]([CH:25]([NH:1][C@H:2]1[CH2:8][S:7][C@H:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][N:4]([CH2:15][C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[C:3]1=[O:23])[CH2:31][CH2:32][CH2:33][CH2:34][N:35]1[C:39](=[O:40])[C:38]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:37]2[C:36]1=[O:45])=[O:27])[CH3:30]
Reactant: CC(C)(C)OC(=O)CN1C[C@@H](c2ccccc2)SC[C@H](N)C1=O
Reactant: CCOC(=O)C(Br)CCCCN1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)C(CCCCN1C(=O)c2ccccc2C1=O)N[C@H]1CS[C@H](c2ccccc2)CN(CC(=O)OC(C)(C)C)C1=O

Procedure:
By following the same procedure as described in Example 4, a condensation reaction was carried out between 336 mg of t-butyl rel-α-[6(R)-amino-5-oxo-2(R)-phenylperhydro-1,4-thiazepin-4-yl]acetate and 552 mg of ethyl 2-bromo-6-phthalimidohexanoate in the presence of 318 mg of sodium carbonate to give two diastereoisomers. These isomers were separated by column chromatography through silica gel using a mixture of cyclohexane and ethyl acetate in the ratio 5:1 by volume as the eluent.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][NH:20][C:21](=[O:57])[C@@H:22]([NH2:56])[CH2:23][S:24][CH2:25][C@H:26]([O:42][C:43](=[O:55])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:27][O:28][C:29](=[O:41])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].N1C=CC=CC=1.[C:64](Cl)(=[O:80])[CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH3:79]>C(Cl)Cl>[C:43]([O:42][C@H:26]([CH2:27][O:28][C:29](=[O:41])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:25][S:24][CH2:23][C@H:22]([NH:56][C:64](=[O:80])[CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH3:79])[C:21](=[O:57])[NH:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][P:4]([O:5][CH2:6][CH3:7])([O:3][CH2:1][CH3:2])=[O:8])(=[O:55])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](N)C(=O)NCCOCCOCCOCCP(=O)(OCC)OCC)OC(=O)CCCCCCCCCCC
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCC)OC(=O)CCCCCCCCCCC)C(=O)NCCOCCOCCOCCP(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of (14R,18R)-14-amino-18-(dodecanoyloxy)-13,21-dioxo-3,6,9,20-tetraoxa-16-thia-12-azadotriacontylphosphonic acid diethyl ester (1 eq, from example 18, step 6) in DCM (0.1 M) was cooled in an ice bath. Pyridine (1.2 eq) was added followed by palmitoyl chloride (1.1 eq). The reaction mixture was stirred for 10 minutes then warmed up to room temperature, and stirred for 2 hours. The reaction mixture was diluted with DCM, washed with saturated aqueous NH4Cl. The aqueous phase was back extracted with DCM. The combined organic phases were washed with brine, dried over anhydrous Na2SO4 and concentrated en vaccuo. The resulting crude was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-10% MeOH/DCM to give the title product as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH:7]([NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH2:6]2)#[N:2].[H-].[Na+].C[Si](C)(C)CCO[CH2:30][Cl:31]>CN(C=O)C>[Cl:31][C:30]1[CH:11]=[C:12]([N:9]2[C:10]3[C:5](=[CH:4][C:3]([C:1]#[N:2])=[CH:12][CH:11]=3)[CH2:6][CH:7]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH2:8]2)[CH:3]=[CH:4][CH:5]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: N#Cc1ccc2c(c1)CC(NS(=O)(=O)c1ccccc1)CN2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)CC(NS(=O)(=O)c1ccccc1)CN2c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 146.3 %

Procedure:
To a solution of 153A (627 mg, 2 mmol) in DMF (5 mL) at RT was added NaH (96 mg, 2.4 mmol) in portions. After addition, the reaction was stirred at RT for 30 min, and then 2-(trimethylsilyl)ethoxymethyl chloride (0.37 mL, 2.10 mmol) was added dropwise. After addition, the reaction was stirred at RT for 1 h, then quenched carefully with water. The mixture was extracted with EtOAc (3×30 mL), and the combined extracts washed with brine, dried (Na2SO4), and concentrated. The resulting residue was chromatographed (silica gel) eluting with EtOAc (0-60%) in hexane to give the title compound as a white powder (620 mg, 70%).
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[C:5]1[CH:10]=[C:9]([Cl:11])[N:8]=[C:7]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:6]=1>O1CCCC1.C(N(CC)C(C)C)(C)C>[Cl:11][C:9]1[N:8]=[C:7]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:6]=[C:5]([N:2]([CH3:3])[CH3:1])[CH:10]=1
Reactant: Clc1cc(Cl)nc(Nc2ccccc2)n1
Reactant: CNC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)c1cc(Cl)nc(Nc2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
Dimethylamine in tetrahydrofuran (2M, 15 mL) was added to a solution of 4,6-dichloro-N-phenyl-2-pyrimidinamine (0.715 g, 2.97 mmol) in tetrahydrofuran (30 mL) and N,N-diisopropylethylamine (0.52 mL). The resulting mixture was stirred at room temperature overnight. The solvent was removed and the crude material was purified by flash chromatography on silica gel, eluting with ethyl acetate/hexane (1:9). The eluent was removed, giving 6-chloro-N4,N4-dimethyl-N2-phenyl-2,4-pyrimidinediamine (0.592 g, 2.39 mmol, 80%, Rf=0.3).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[CH:13]1(Br)[CH2:17][CH2:16][CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(O)cc1Cl
Reactant: BrC1CCCC1
Product: O=C(O)c1ccc(OC2CCCC2)cc1Cl

Procedure:
Using methyl 2-chloro-4-hydroxybenzoate and cyclopentyl bromide, 2-chloro-4-cyclopentyloxybenzoic acid was obtained in the same manner as in Example 277b).