Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[CH:8]1[C:13]([OH:14])=[CH:12][CH:11]=[C:10]([CH3:15])[CH:9]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:14][C:13]1[CH:12]=[CH:11][C:10]([CH3:15])=[CH:9][CH:8]=1)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: Cc1ccc(O)cc1
Reactant: CCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(=O)Oc1ccc(C)cc1

Procedure:
Pentanoyl chloride (39.8 g) in dichloromethane (50 ml) was added slowly to a solution of p-cresol (32.4 g) and triethylamine (36.4 g) in dichloromethane (250 ml) with ice cooling. After 1 hour the reaction mixture was washed with brine, dried over magnesium sulfate, filtered and evaporated under reduced pressure to give 4-methylphenyl pentanoate.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([NH:14][C:15](=[O:34])[NH:16][C@@H:17]([CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[C:35]([O:39][C:40](=[O:68])[CH2:41][N:42]1[CH:46]=[CH:45][N:44]=[C:43]1[CH2:47][N:48]([CH2:57][C:58]1[CH:63]=[CH:62][C:61]([O:64][CH2:65][C:66]#[CH:67])=[CH:60][CH:59]=1)[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][C:54](O)=[O:55])([CH3:38])([CH3:37])[CH3:36].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>ClCCCl>[C:35]([O:39][C:40](=[O:68])[CH2:41][N:42]1[CH:46]=[CH:45][N:44]=[C:43]1[CH2:47][N:48]([CH2:57][C:58]1[CH:63]=[CH:62][C:61]([O:64][CH2:65][C:66]#[CH:67])=[CH:60][CH:59]=1)[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][C:54](=[O:55])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C@@H:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[NH:14][C:15](=[O:34])[NH:16][C@H:17]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])([CH3:36])([CH3:38])[CH3:37]
Reactant: C#CCOc1ccc(CN(CCCCCC(=O)O)Cc2nccn2CC(=O)OC(C)(C)C)cc1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCN)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: C#CCOc1ccc(CN(CCCCCC(=O)NCCCC[C@H](NC(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)Cc2nccn2CC(=O)OC(C)(C)C)cc1
Yield: 57.1 %

Procedure:
A solution of (S)-di-tert-butyl 2-(3-((S)-6-amino-1-(tert-butoxy)-1-oxohexan-2-yl)ureido)pentanedioate (0.480 g, 1.0 mmol), 6-(((1-(2-(tert-butoxy)-2-oxoethyl)-1H-imidazol-2-yl)methyl)(4-(prop-2-yn-1-yloxy)benzyl)amino)hexanoic acid (0.220 g, 0.468 mmol), EDCI (0.191 g, 1.0 mmol), HOBt (0.135 g, 1.0 mmol) and DIPEA (0.40 mL) in DCE (10.0 mL) was stirred at room temperature for 3 h. The solvent was evaporated to give a residue, which was purified by Biotage eluting with DCM/MeOH to give (14S,18S)-tri-tert-butyl 1-(1-(2-(tert-butoxy)-2-oxoethyl)-1H-imidazol-2-yl)-8,16-dioxo-2-(4-(prop-2-yn-1-yloxy)benzyl)-2,9,15,17-tetraazaicosane-14,18,20-tricarboxylate (0.251 g, 57%). MS (ESI), 939.5 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([C:12]1[CH:13]=[C:14]([Si:17]([CH3:20])([CH3:19])[CH3:18])[O:15][CH:16]=1)[CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1>[C:21]([O:1][CH:2]([C:12]1[CH:13]=[C:14]([Si:17]([CH3:20])([CH3:19])[CH3:18])[O:15][CH:16]=1)[CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:23])[CH3:22]
Reactant: C[Si](C)(C)c1cc(C(O)CCCc2ccccc2)co1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC(CCCc1ccccc1)c1coc([Si](C)(C)C)c1

Procedure:
A solution of 4-(1-hydroxy-4-phenylbutyl)-2-trimethylsilylfuran (0.249 g., 0.862 mmol), acetic anhydride (1 ml, excess) and pyridine (3 to 4 drops, excess) was stirred at room temperature until no starting material remained (as monitored by TLC). The reaction mixture was then partitioned between ethyl ether and a 5% ammonium chloride solution. The organic portion was washed repeatedly with saturated sodium bicarbonate solution, twice with aqueous cupric sulfate solution, water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give a pale yellow oil (0.396 g). This material was further purified by flash chromatography (silica, 5% ethyl acetate/hexane) to give the desired acetate.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[C:12]4[O:33][C:32]5[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=5[C:13]=4[N:14]([CH2:21][C:22]4[CH:27]=[CH:26][C:25]5[O:28][CH2:29][O:30][C:24]=5[CH:23]=4)[C:15](=[O:20])[C:16]=3[C:17](O)=[O:18])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.CN(C1C=CC=CN=1)C.S(Cl)(Cl)=O.[C:51]1([S:57]([NH2:60])(=[O:59])=[O:58])[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>N1C=CC=CC=1>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[C:12]4[O:33][C:32]5[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=5[C:13]=4[N:14]([CH2:21][C:22]4[CH:27]=[CH:26][C:25]5[O:28][CH2:29][O:30][C:24]=5[CH:23]=4)[C:15](=[O:20])[C:16]=3[C:17]([NH:60][S:57]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)(=[O:59])=[O:58])=[O:18])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: O=C(O)c1c(-c2ccc3c(c2)OCCO3)c2oc3ccccc3c2n(Cc2ccc3c(c2)OCO3)c1=O
Agent: CN(C)c1ccccn1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: O=C(NS(=O)(=O)c1ccccc1)c1c(-c2ccc3c(c2)OCCO3)c2oc3ccccc3c2n(Cc2ccc3c(c2)OCO3)c1=O
Reaction time: 10 h

Procedure:
A solution of 4.85 g of 4-(1,4-benzodioxan-6-yl)-1,2-dihydro-1-(3,4-methylenedioxybenzyl)-2-oxobenzofuro-[3,2-b]pyridine-3-carboxylic acid and 0.2 g of dimethylaminopyridine in 50 ml of pyridine is treated with 5 ml of thionyl chloride and 1.57 g of phenylsulfonamide. The mixture is stirred for 10 hours and worked up in the customary manner, and 4-(1,4-benzodioxan-6-yl)-1,2-dihydro-1-(3,4-methylenedioxybenzyl)-2-oxo-3-(phenylsulfonamidocarbonyl)benzofuro[3,2-b]pyridine is obtained.
Reaction SMILES: Cl.[F:2][C:3]1[CH:24]=[C:23]([NH:25][C:26]([NH:28][C:29](=[O:37])[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[S:27])[CH:22]=[CH:21][C:4]=1[O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:19][CH3:20])=[C:13]([C:16](O)=[O:17])[CH:14]=2)[N:9]=[CH:8][CH:7]=1.[CH3:38][S:39]([CH2:42][CH2:43][NH2:44])(=[O:41])=[O:40].C(N(CC)CC)C>C(O)C>[F:2][C:3]1[CH:24]=[C:23]([NH:25][C:26]([NH:28][C:29](=[O:37])[CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[S:27])[CH:22]=[CH:21][C:4]=1[O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:19][CH3:20])=[C:13]([C:16]([NH:44][CH2:43][CH2:42][S:39]([CH3:38])(=[O:41])=[O:40])=[O:17])[CH:14]=2)[N:9]=[CH:8][CH:7]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2cc1C(=O)O
Reactant: CS(=O)(=O)CCN
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2cc1C(=O)NCCS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
Similar to the synthesis of Example 1, compound 1e (25 mg), 2-(methylsulfonyl)ethaneamine (6 mg), triethylamine (19 μL), and DMTMM•n-hydrate (20 mg) were dissolved in ethanol (1 mL), and the solution was stirred at room temperature for 1 hour, to thereby yield the titled compound 27 (20.6 mg, yield: 73%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[CH:27][C:26]([C:29]2[N:30]=[N:31][N:32]([CH2:34][CH2:35][OH:36])[CH:33]=2)=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[N:30]=[N:31][N:32]([CH2:34][CH2:35][OH:36])[CH:33]=3)=[CH:27][N:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: OCCn1cc(-c2ccc(Cl)nc2)nn1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccc(-c4cn(CCO)nn4)cn3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (100 mg, 0.32 mmol) and 2-[4-(6-chloropyridin-3-yl)-1H-1,2,3-triazol-1-yl]ethanol (72 mg, 0.32 mmol) as starting materials.
Reaction SMILES: [OH-].[NH4+:2].C(OC([NH:10][C@H:11]([C:17]1[NH:21][C:20]2[CH:22]=[CH:23][C:24]([C:26]3[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[C:28]([F:34])[CH:27]=3)=[CH:25][C:19]=2[N:18]=1)[C@@H:12]([CH3:16])[C:13](O)=[O:14])=O)(C)(C)C>C(Cl)Cl.C1CCCCC1>[NH2:10][C@H:11]([C:17]1[NH:21][C:20]2[CH:22]=[CH:23][C:24]([C:26]3[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[C:28]([F:34])[CH:27]=3)=[CH:25][C:19]=2[N:18]=1)[C@@H:12]([CH3:16])[C:13]([NH2:2])=[O:14]
Reactant: [NH4+]
Reactant: C[C@@H](C(=O)O)[C@H](NC(=O)OC(C)(C)C)c1nc2cc(-c3ccc(C#N)c(F)c3)ccc2[nH]1
Agent: [OH-]
Solvent: C1CCCCC1
Solvent: ClCCl
Product: C[C@@H](C(N)=O)[C@H](N)c1nc2cc(-c3ccc(C#N)c(F)c3)ccc2[nH]1

Procedure:
The title compound was prepared according to Preparation 28 using ammonium hydroxide and (2R,3S)-3-[(tert-butoxycarbonyl)amino]-3-[5-(4-cyano-3-fluorophenyl)-1H-benzimidazol-2-yl]-2-methylpropanoic acid (Preparation 32). The residue was sonicated in DCM:cyclohexane 5:1 to afford the boc protected amide intermediate. The residue was dissolved in 4M HCl in dioxane and stirred at room temperature for 3 hours. The solvent was removed in vacuo and the residue dissolved in MeOH and passed through an SCX cartridge eluting first with MeOH followed by 3M NH3 in MeOH. The residue was purified using silica gel column chromatography eluting with DCM:MeOH:NH3 (90:10:0.5) to afford the title compound (55 mg, 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([NH2:16])=[CH:11][CH:12]=[C:13]([CH3:15])[CH:14]=2)=[CH:4][CH:3]=1.[C:17](OCC)(=[O:21])[C:18]([CH3:20])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9]3[C:10](=[CH:11][CH:12]=[C:13]([CH3:15])[CH:14]=3)[N:16]=[C:18]([CH3:20])[C:17]2=[O:21])=[CH:4][CH:3]=1
Reactant: Cc1ccc(N)c(Nc2ccc(Cl)cc2)c1
Reactant: CCOC(=O)C(C)=O
Product: Cc1ccc2nc(C)c(=O)n(-c3ccc(Cl)cc3)c2c1

Procedure:
Preparation as in Example 1 but using N-(4-chlorophenyl)-5-methylbenzene-1,2-diamine and ethyl pyruvate gave the title compound mp 144°-145° C.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:23])([CH3:22])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([O:19][CH2:20][CH3:21])[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]([Cl:29])([Cl:28])[CH2:26]O.C(Cl)CCl.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:24][C:25]([Cl:29])([Cl:28])[CH2:26][O:17][C:16](=[O:18])[CH:15]([O:19][CH2:20][CH3:21])[CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]([CH3:22])([CH3:23])[O:6][SiH2:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:9][CH:10]=1
Reactant: CCOC(Cc1ccc(C(C)(C)O[SiH2]C(C)(C)C)cc1)C(=O)O
Reactant: OCC(Cl)(Cl)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOC(Cc1ccc(C(C)(C)O[SiH2]C(C)(C)C)cc1)C(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Under nitrogen atmosphere 3-[4-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-2-ethoxy-propionic acid (0.135 g, 0.4 mmol) and 2,2,2-trichloro ethanol (0.06 g, 0.4 mmol) were dissolved in dry DCM (5 mL) and DMAP (2 mg, 0.02 mmol) was added followed by EDC×HCl (0.092 g, 0.48 mmol) at 0° C. The mixture was stirred for 18 h at ambient temperature, then diluted with DCM and extracted with aq. HCl (2N) and water. The organic layer was separated, dried (MgSO4) and evaporated to afford the crude product which was used in the next step without further purification (0.176 g, 93.6%). 1H NMR (400 MHz, CDCl3): δ 7.12-7.19 (m, 4H), 4.62-4.71 (q, 2H), 4.63 (s, 2H), 4.05-4.08 (m, 1H), 3.55-3.59 (m, 1H), 3.27-3.31 (m, 1H), 2.92-3.03 (m, 2H), 1.08 (t, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1.C(N(C(C)C)C(C)C)C.Cl.[O:26]1[CH2:31][CH2:30][CH2:29][CH2:28][NH:27]1.C([O-])(O)=O.[Na+]>O1CCCC1>[O:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1
Reactant: CCCNc1nc(Cl)nc(NCCC)n1
Reactant: C1CCONC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCNc1nc(NCCC)nc(N2CCCCO2)n1
Temperature: 100 °C
Yield: 89 %

Procedure:
An ACE® pressure tube was charged with 2-chloro-N-(4,6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV) (1.50 g, 6.53 mmol), N-ethyldiisopropylamine (19.59 mmol), 1,2-oxazinane hydrochloride (1.61 g, 13.06 mmol) and tetrahydrofuran. The reaction mixture was heated at 100° C. for 2 h, then cooled and poured into saturated NaHCO3 solution (50 mL). The suspension was extracted with EtOAc (3×25 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography using gradient elution from CH2Cl2/EtOH (99:1) to CH2Cl2/EtOH (95:5) to yield 6-[1,2]oxazinan-2-yl-N,N′-dipropyl-[1,3,5]triazine-2,4-diamine (LVII) (1.63 g, 89%). ESI-MS (m/z): 281 [M+H]+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1OS(C1C=CC(C)=CC=1)(=O)=O)(=[O:3])[CH3:2].[C:22]([C:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]=1)#[CH:23]>CCCCCCC.CCOC(C)=O>[C:24]1([C:22]#[C:23][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:1](=[O:3])[CH3:2])[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]=1
Reactant: CC(=O)Nc1ccccc1OS(=O)(=O)c1ccc(C)cc1
Reactant: C#CC1=CCCCC1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC(=O)Nc1ccccc1C#CC1=CCCCC1

Procedure:
This product was prepared from toluene-4-sulfonic acid 2-acetylamino-phenyl ester and 1-ethynyl-cyclohexene following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane/EtOAc 9:1; yield (115 mg, 96%); 1H NMR δ (CDCl3): 8.39 (d, J=8.53 Hz, 1H), 7.9 (br s, 1H), 7.37 (dm, 1H), 7.31-7.23 (m, 1H), 7.02 (t, J=7.22 Hz, 1H), 6.25 (m, 1H), 2.32-2.12 (m, 7H), 1.76-1.6 (m, 4H); LCMS m/z: 239.
Reaction SMILES: [F:1][C:2]([F:15])([O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[O:11])[CH:3]([F:5])[F:4].[C-:16]#[N:17].[K+].OS([O-])=O.[Na+]>C(OCC)(=O)C.O>[OH:11][CH:10]([C:9]1[CH:12]=[CH:13][CH:14]=[C:7]([O:6][C:2]([F:15])([F:1])[CH:3]([F:4])[F:5])[CH:8]=1)[C:16]#[N:17]
Reactant: O=Cc1cccc(OC(F)(F)C(F)F)c1
Reactant: [C-]#N
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: N#CC(O)c1cccc(OC(F)(F)C(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (222 mg, 1.0 mmol) in ethyl acetate (5 mL) was added a solution of KCN (195 mg, 3.0 mmol) and NaHSO3 (312 mg, 3.0 mmol) dissolved in H2O (10 mL). The reaction was stirred at rt for 8 h. Another portion of KCN (195 mg, 3.0 mmol) and NaHSO3 (312 mg, 3.0 mmol) dissolved in H2O (10 mL) was added. It was left stirring overnight before it was extracted with ethyl acetate (2×50 mL). The combined organic extracts were dried and concentrated to give 130A as an oil. It was used for next step without purification. 1H NMR (400 MHz, CDCl3) δ ppm 5.57 (s, 1H) 5.78-6.04 (m, 1H) 7.28 (d, J=6.15 Hz, 1H) 7.39 (s, 1H) 7.43-7.52 (m, 2H). 19F NMR (376 MHz, CDCl3) δ ppm −136.72, −88.04.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[N+:8]([C:7]1[C:2]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cccnc1Nc1ccccc1
Yield: 33.9 %

Procedure:
A procedure similar to that described in Preparation 66 was repeated, except that 15 g of 2-chloro-3-nitro-pyridine, 13.22 g of aniline and 25.07 g of sodium carbonate were reacted in 180 ml of toluene. After working up the product as described in Preparation 66, the resulting crude product was purified by column chromatography through silica gel, using a 1:5 by volume mixture of ethyl acetate and hexane, to give 6.9 g of the title compound, melting at 66°-68° C.
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: 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: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([OH:10])=O)([CH3:4])([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.C(N(CC)CC)C.[C:41]1([NH2:48])[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[NH2:47]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[NH2:47][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=1[NH:48][C:8](=[O:10])[C:7]1[CH:6]=[C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])[C:13]([OH:14])=[C:12]([C:15]([CH3:17])([CH3:16])[CH3:18])[CH:11]=1
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Reactant: Nc1ccccc1N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(C(=O)Nc2ccccc2N)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.4 %

Procedure:
To a solution of 3,5-di-t-butyl-4-hydroxybenzoic acid (5.0 g) in methylene chloride (20 ml) was added dicyclohexylcarbodiimide (2.17 g) and the mixture was stirred overnight at room temperature. Subsequently, triethylamine (2.1 ml), 4-dimethylaminopyridine (0.37 g) and o-phenylenediamine (1.08 g) were added and the mixture was stirred overnight at room temperature. The insolubles was filtered off and the filtrate was concentrated to dryness. The residue was purified by a silica gel column chromatography (chloroform:ethyl acetate=20:1) and crystallized from diisopropyl ether to give N-(2-aminophenyl)-3,5-di-t-butyl-4-hydroxybenzamide (1.10 g, 32%).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.Cl.N([O-])=O.[Na+].[O:14]1[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15]1>O.CC(C)=O>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]2[O:14][CH:18]=[CH:17][C:16]=2[C:19]([OH:21])=[O:20])=[CH:3][CH:4]=1
Reactant: O=C(O)c1ccoc1
Reactant: Cc1ccc(N)cc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccc(-c2occc2C(=O)O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 15.1 %

Procedure:
70.7 g of p-toluidine, cooled with a bath of water and ice, are treated with 205 ml of 36% HCl. The mixture is then stirred at 55°-60° C. for 30 min before being cooled to 0° C. again. A solution of 45 g of NaNO2 in 220 ml of water is then introduced. The mixture is stirred for 1 h at 0° C. This cold solution is introduced into a mixture of 49.3 g of 3-furanoic acid, 220 ml of acetone, 23.4 g of CuCl2 and 6.3 g of water, cooled to -5° C. The whole is stirred at 0° C. for 2 h and then at room temperature for 48 h. It is extracted twice with ether and the organic phase is decanted, dried and concentrated to give an oil, which gives crystals when treated with water. The crystals are filtered off and washed with 50 ml of a 50% methanol/water mixture to give 13.4 g of 2-(4-methylphenyl)-3-furanoic acid.
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].[S:6]([Cl:12])([N:9]=[C:10]=[O:11])(=[O:8])=[O:7]>C1C=CC=CC=1>[Cl:12][S:6]([NH:9][C:10](=[O:11])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:8])=[O:7]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C)O
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)NS(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butanol (3.2 g, 36.9 mmol) in benzene (13 mL) was added sulfurisocyanatidoyl chloride (3.5 mL, 36.6 mmol). After stirring at rt for 2 h, the reaction mixture was quenched with hexane. The mixture was cooled in an ice-bath, resulted in white solid precipitation. The solid was filtered, washed with hexane, dried and used in the next step immediately (3.2 g, 41%).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][C:6](=[CH2:8])[CH2:5][C@H:4]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].CCN(C(C)C)C(C)C.Cl>C(Cl)Cl>[Si:15]([O:1][CH2:2][C@@H:3]1[CH2:7][C:6](=[CH2:8])[CH2:5][C@H:4]1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: C=C1C[C@@H](CO)[C@H](c2ccccc2)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=C1C[C@@H](CO[Si](C)(C)C(C)(C)C)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (+−)-trans-1-hydroxymethyl-4-methylene-2-phenylcyclopentane from Step B (2.5 g, 13.3 mmol) in methylene chloride (50 mL) was added t-butyldimethylsilyl chloride (3.0 g, 20 mmol) and DIPEA (4.7 mL, 27 mmol). The reaction was stirred at RT for 16 h, poured into dilute aq. HCl and extracted twice with ether. The organic layers were washed with brine, dried over sodium sulfate, combined and concentrated. The residue was purified by FC (5% ethyl acetate in hexanes) to afford the title product. (4.2 g) as a oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([Br:21])(C)C>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][Br:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1cccc(OCc2ccccc2)c1
Reactant: C[Si](C)(C)Br
Solvent: ClCCl
Product: BrCc1cccc(OCc2ccccc2)c1

Procedure:
A solution of 3-benzyloxybenzyl alcohol (9.54 g) in methylene chloride (40 ml) with TMSBr (2.5 eq, 13 mL) was heated at reflux for 1 hr. After cooling, the reaction was concentrated and then reconcentrated 2 × with methylene chloride (40 ml). The residue was chromatographed on silica gel eluting first with hexane followed by 10% methylene chloride in hexane to afford 3-benzyloxybenzyl bromide which solidifies on cooling . 5.75 g m.p. 38°-40°.
Reaction SMILES: Cl[CH2:2][C:3]1[N:13]=[CH:12][C:11]([CH2:14][CH3:15])=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:16][C@@:17]([C:22]([NH2:24])=[O:23])([CH:19]([CH3:21])[CH3:20])[NH2:18].C(=O)(O)[O-].[Na+]>CS(C)=O>[C:22]([C:17]([NH:18][CH2:2][C:3]1[N:13]=[CH:12][C:11]([CH2:14][CH3:15])=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6])([CH3:16])[CH:19]([CH3:21])[CH3:20])(=[O:23])[NH2:24]
Reactant: CCOC(=O)c1cc(CC)cnc1CCl
Reactant: CC(C)[C@](C)(N)C(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)c1cc(CC)cnc1CNC(C)(C(N)=O)C(C)C

Procedure:
A mixture of 77 g of ethyl 2-chloromethyl-5-ethylnicotinate (0.338 mol), 44 g of α-methylvalinamide (0.338 mol) and 33.5 g of sodium bicarbonate (0.4 mol) in 60 mL dimethylsulfoxide is stirred and heated at 80° for 16 hours. The reaction is partitioned between 1:1 ethylacetate-hexane and water. The organic layer is washed thoroughly with water, dried, and concentrated in vacuo to a gum. Chromatography of this gum on silica gel using hexane-ethyl acetate mixtures as eluant affords the title product, mp 68°-72°.