Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([O:11]CC)=[O:10].C(Cl)Cl.[Li+].[OH-].Cl>CO>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)c1[nH]c(C)c(Cl)c1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: Cc1[nH]c(C(=O)O)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.5 %

Procedure:
Ethyl 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylate (Intermediate 2; 7.765 g, 0.03496 mol) was dissolved in MeOH (80 ml) and DCM (10 ml) and slowly added to a 70° C. solution of 2 N LiOH (105 ml, 0.21 mol). After 2 h, the reaction mixture was cooled to room temperature and then in an ice bath, followed by acidification with 2 N HCl. The mixture was stirred at 0° C. for 1 h, and a purple solid was filtered, washed with water and lyophilized overnight to give 4.314 g (0.0222 mol, 64% yield) of the desired product. MS (ES−): 192.13, 194.13 for C6H5Cl2NO2; NMR: 2.17 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][OH:11])[CH:6]=[CH:7][CH:8]=1.FC(F)(F)C(O)=O.[F:19][C:20]1([F:39])[CH2:25][N:24]([C:26]([C:28]2[S:29][C:30]([CH3:33])=[CH:31][CH:32]=2)=[O:27])[CH2:23][C:22]2([CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[O:21]1.C(N(CC)CC)C>C(#N)C>[F:39][C:20]1([F:19])[CH2:25][N:24]([C:26]([C:28]2[S:29][C:30]([CH3:33])=[CH:31][CH:32]=2)=[O:27])[CH2:23][C:22]2([CH2:34][CH2:35][N:36]([CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH2:10][OH:11])[CH:4]=3)[CH2:37][CH2:38]2)[O:21]1
Reactant: OCCc1cccc(CBr)c1
Reactant: Cc1ccc(C(=O)N2CC(F)(F)OC3(CCNCC3)C2)s1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(=O)N2CC(F)(F)OC3(CCN(Cc4cccc(CCO)c4)CC3)C2)s1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
2-(3-(Bromomethyl)phenyl)ethanol (example 6, step a) (0.095 g) was added to a solution of (2,2-difluoro-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(5-methylthiophen-2-yl)methanone trifluoroacetate (example 37, step e) (0.19 g) and triethylamine (0.185 mL) in acetonitrile (10 mL) and the reaction mixture stirred at 20° C. for 3 hours. The solvent was evaporated under reduced pressure and the residue partitioned between ethyl acetate and brine, the organic layer was dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 2.5% methanol in dichloromethane with 1% triethylamine as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.188 g.
Reaction SMILES: [OH2:1].C([C@@:10]([C:25]([OH:27])=[O:26])([OH:24])[C@@:11](C(=O)C1C=CC=CC=1)([OH:15])[C:12]([OH:14])=[O:13])(=O)C1C=CC=CC=1.[Br:28][C:29]1[CH:30]=[N:31][CH:32]=[C:33]([C@@H:35]2[CH2:39][CH2:38][CH2:37][N:36]2[CH3:40])[CH:34]=1.[CH2:41]([OH:43])[CH3:42]>>[C:41]([O:15][C@H:11]([C@@H:10]([O:24][C:34](=[O:1])[C:33]1[CH:32]=[CH:37][CH:38]=[CH:39][CH:35]=1)[C:25]([OH:27])=[O:26])[C:12]([OH:14])=[O:13])(=[O:43])[C:42]1[CH:39]=[CH:35][CH:33]=[CH:34][CH:29]=1.[Br:28][C:29]1[CH:30]=[N:31][CH:32]=[C:33]([C@@H:35]2[CH2:39][CH2:38][CH2:37][N:36]2[CH3:40])[CH:34]=1
Reactant: O
Reactant: CCO
Reactant: O=C(O)[C@@](O)(C(=O)c1ccccc1)[C@@](O)(C(=O)O)C(=O)c1ccccc1
Agent: CN1CCC[C@H]1c1cncc(Br)c1
Product: O=C(O[C@@H](C(=O)O)[C@@H](OC(=O)c1ccccc1)C(=O)O)c1ccccc1
Reaction time: 18 h
Yield: 84 %

Procedure:
A solution of (−)-dibenzoyl-L-tartaric acid monohydrate (2.11 g, 5.89 mmol, 1.0 equiv) in ethanol (22 mL) was added to (S)-3-bromo-5-(1-methylpyrrolidin-2-yl)pyridine (III) (5.88 mmol, 1.0 equiv) dissolved in ethanol (22 mL) at 20° C. Solids precipitated and the mixture was granulated 18 hours. The light yellow solids filtered from the mixture were washed with ethanol and dried on the filter, giving (S)-3-bromo-5-(1-methylpyrrolidin-2-yl)pyridine (2R,3R)-2,3-bis (benzoyloxy) succinate (IIIB) (2.9556 g, 84%, 99.5% ee).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:11]O>C(O)(=O)C>[C:1]([C:5]1[CH:10]=[CH:9][N+:8]([O-:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OO
Reactant: CC(C)(C)c1ccncc1
Solvent: CC(=O)O
Product: CC(C)(C)c1cc[n+]([O-])cc1
Yield: 88 %

Procedure:
To a solution of 4-tert-butylpyridine (44.3 ml, 300 mmol) in glacial acetic acid (200 ml) was added hydrogen peroxide (37.1 ml of a 27.5% aqueous solution, 300 mmol), and the resulting mixture heated at reflux overnight. The cooled mixture was evaporated to dryness. The residue was dissolved in dichloromethane (200 ml), and washed with brine (50 ml), then dried (Na2SO4) and evaporated to give the title compound (40 g, 88%) as a white solid.
Reaction SMILES: CN(C)CC(C)(C)CNC[CH2:8][CH2:9][O:10][C:11]1[CH:35]=[CH:34][C:14]([CH2:15][C:16]2[CH:17]=[C:18]([C@H:23]3[C@H:28]([OH:29])[C@@H:27]([OH:30])[C@H:26]([OH:31])[C@@H:25]([S:32][CH3:33])[O:24]3)[CH:19]=[CH:20][C:21]=2[CH3:22])=[CH:13][CH:12]=1.[NH2:39][C:40]1([C:45]([NH2:47])=[O:46])[CH2:44][CH2:43][CH2:42][CH2:41]1>>[CH3:22][C:21]1[CH:20]=[CH:19][C:18]([C@H:23]2[C@H:28]([OH:29])[C@@H:27]([OH:30])[C@H:26]([OH:31])[C@@H:25]([S:32][CH3:33])[O:24]2)=[CH:17][C:16]=1[CH2:15][C:14]1[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][NH:39][C:40]2([C:45]([NH2:47])=[O:46])[CH2:44][CH2:43][CH2:42][CH2:41]2)=[CH:35][CH:34]=1
Reactant: NC(=O)C1(N)CCCC1
Reactant: CS[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(OCCCNCC(C)(C)CN(C)C)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Product: CS[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(OCCNC4(C(N)=O)CCCC4)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
The same procedure was employed as for amine 50, using 1-aminocyclopentanecarboxamide, to provide the product 52. 1H NMR (400 MHz, MeOH-d4) δ ppm 7.11-7.21 (m, 3 H), 7.06 (d, J=8.3 Hz, 2 H), 6.85 (m, J=8.6 Hz, 2 H), 4.39 (d, J=9.6 Hz, 1H), 4.12 (d, J=9.3 Hz, 1 H), 4.06 (t, J=4.9 Hz, 2 H), 3.94 (s, 2 H), 3.34-3.54 (m, 3 H), 2.92 (t, J=4.8 Hz, 2 H), 2.20 (s, 3 H), 2.14 (s, 3 H), 2.06-2.13 (m, 2 H), 1.75-1.83 (m, 6 H); MS (ES+) [M+H]+=531.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH2:10][CH3:11])[N:5]=[C:4]([C:12]([OH:14])=O)[CH:3]=1.ClC1C=CC(C(O)=O)=CC=1OC.Cl.Cl.Cl.[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]1[S:37][C:38]([CH2:41][N:42]2[CH2:47][CH2:46][CH:45]([CH2:48][NH2:49])[CH2:44][CH2:43]2)=[CH:39][N:40]=1>>[NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH2:10][CH3:11])[N:5]=[C:4]([C:12]([NH:49][CH2:48][CH:45]2[CH2:46][CH2:47][N:42]([CH2:41][C:38]3[S:37][C:36]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][N:30]=4)=[N:40][CH:39]=3)[CH2:43][CH2:44]2)=[O:14])[CH:3]=1
Reactant: NCC1CCN(Cc2cnc(-c3ccccn3)s2)CC1
Reactant: CCOc1nc(C(=O)O)cc(N)c1Cl
Agent: COc1cc(C(=O)O)ccc1Cl
Agent: Cl
Product: CCOc1nc(C(=O)NCC2CCN(Cc3cnc(-c4ccccn4)s3)CC2)cc(N)c1Cl

Procedure:
According to the same procedure described in Example 16 and starting with 4-amino-5-chloro-6-ethoxypicolinic acid (prepared according to the reported preparation in J. Med. Chem. 2006, 49, 4455) instead of 4-chloro-3-methoxybenzoic acid and the compound prepared in Example 214 instead of the compound prepared in Example 9, the title compound having the following physical data was obtained. 1H NMR (DMSO-d6): δ 8.61 (d, J=4.7 Hz, 1H), 8.33 (t, J=6.4 Hz, 1H), 8.09 (d, J=7.9 Hz, 1H), 7.94 (td, J=1.7, 7.7 Hz, 2H), 7.78 (s, 1H), 7.47 (ddd, J=1.1, 4.8, 7.5 Hz, 1H), 7.09 (s, 1H), 6.50 (s, 1H), 4.45 (q, J=7.0 Hz, 2H), 3.73 (s, 2H), 3.16 (t, J=6.5 Hz, 2H), 2.85-2.88 (m, 2H), 1.97 (t, J=10.7 Hz, 2H), 1.60-1.63 (m, 2H), 1.50-1.55 (m, 1H), 1.31 (t, J=7.0 Hz, 3H), 1.15-1.24 (m, 2H);
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH2:11][C:12]#[N:13])[CH:5]=1)#[N:2].Cl.N[C:16]1[C:21]([F:22])=[C:20]([F:23])[CH:19]=[C:18]([F:24])[C:17]=1[SH:25]>C(O)C>[F:22][C:21]1[C:16]2[N:13]=[C:12]([CH2:11][C:6]3[CH:5]=[C:4]([CH2:3][C:1]#[N:2])[CH:9]=[C:8]([CH3:10])[CH:7]=3)[S:25][C:17]=2[C:18]([F:24])=[CH:19][C:20]=1[F:23]
Reactant: Nc1c(F)c(F)cc(F)c1S
Reactant: Cc1cc(CC#N)cc(CC#N)c1
Agent: Cl
Solvent: CCO
Product: Cc1cc(CC#N)cc(Cc2nc3c(F)c(F)cc(F)c3s2)c1
Yield: 32.9 %

Procedure:
A solution of 1,3-biscyanomethyl-5-methylbenzene (2.89 g, 17 mmol) and 2-amino-3,4,6-trifluorothiophenol hydrochloride (3.66 g, 17 mmol) in absolute ethanol was heated at 170° C. for 15 hours under a nitrogen stream in an autoclave. After the reaction, evaporation of the solvent left a residue, which was purified on a silica gel column and recrystallized from ethyl acetate-hexane to obtain 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]-5-methylphenylacetonitrile (1.86 g, 33%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[CH:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][C:10]=2[C:18]([F:21])([F:20])[F:19])[CH2:4][CH2:3]1.S(Cl)([Cl:24])=O>>[ClH:24].[CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[CH:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([Cl:24])=[O:14])=[CH:11][C:10]=2[C:18]([F:21])([F:20])[F:19])[CH2:4][CH2:3]1
Reactant: O=S(Cl)Cl
Reactant: CN1CCC(=Cc2ccc(C(=O)O)cc2C(F)(F)F)CC1
Product: CN1CCC(=Cc2ccc(C(=O)Cl)cc2C(F)(F)F)CC1
Product: Cl

Procedure:
This compound was prepared in the same manner as in Reference Example 1 (step 7), except that 4-(1-methylpiperidin-4-ylidenemethyl)-3-trifluoromethylbenzoic acid obtained in the step 3 was used, and that treatment after the reaction was that thionyl chloride was distilled off under reduced pressure, and then the operation of adding of toluene to the residue, followed by azeotropic removal of thionyl chloride was repeated three times.
Reaction SMILES: [Cl:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]2[N:6]([CH2:20][O:21][CH3:22])[C:7]([C:9]3[NH:10][C:11]4[C:16]([CH:17]=3)=[CH:15][C:14]([CH:18]=[O:19])=[CH:13][CH:12]=4)=[N:8][C:4]=2[CH:3]=1.IC.[CH3:28]C(C)([O-])C.[K+].O>CN(C)C=O>[Cl:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]2[N:6]([CH2:20][O:21][CH3:22])[C:7]([C:9]3[N:10]([CH3:28])[C:11]4[C:16]([CH:17]=3)=[CH:15][C:14]([CH:18]=[O:19])=[CH:13][CH:12]=4)=[N:8][C:4]=2[CH:3]=1
Reactant: COCn1c(-c2cc3cc(C=O)ccc3[nH]2)nc2cc(Cl)c(Cl)cc21
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COCn1c(-c2cc3cc(C=O)ccc3n2C)nc2cc(Cl)c(Cl)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.8 %

Procedure:
To a solution of 5,6-dichloro-2-[5-formylindol-2-yl]-1-(methoxymethyl)benzimidazole obtained in Example 47 (32 mg, 0.086 mmol) in dimethylformamide (2 mL) were added iodomethane (0.027 mL, 0.43 mmol) and potassium tert-butoxide (19 mg, 0.17 mmol) under nitrogen atmosphere, and the mixture was stirred at room temperature for 18 h. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure to afford 5,6-dichloro-2-[5-formyl-1-methylindol-2-yl]-1-methoxymethylbenzimidazole (30 mg, 90%).
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]([C:17]2[NH:18][C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([Cl:26])=[CH:21][CH:20]=3)=[O:16])[CH2:9]1.[N+](C1C=CC([O:36][C:37](=O)[NH:38][C:39]2[CH:44]=[CH:43][C:42]([N:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]3=[O:51])=[CH:41][C:40]=2[F:52])=CC=1)([O-])=O>>[F:52][C:40]1[CH:41]=[C:42]([N:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]2=[O:51])[CH:43]=[CH:44][C:39]=1[NH:38][C:37]([N:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]([C:17]2[NH:18][C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([Cl:26])=[CH:21][CH:20]=3)=[O:16])[CH2:9]1)=[O:36]
Reactant: O=C(NC[C@H]1CCNC1)c1cc2cc(Cl)ccc2[nH]1
Reactant: O=C(Nc1ccc(-n2ccccc2=O)cc1F)Oc1ccc([N+](=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC[C@H]1CCN(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C1)c1cc2cc(Cl)ccc2[nH]1

Procedure:
69.3 Using general method H, 5-chloro-1H-indole-2-carboxylic acid ((S)-1-pyrrolidin-3-ylmethyl)-amide trifluoro acetate was reacted with [2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-carbamic acid 4-nitro-phenyl ester (prepared according to example 54.3) to give 5-chloro-1H-indole-2-carboxylic acid {(R)-1-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-pyrrolidin-3-ylmethyl}-amide. Pale yellow solid. MS 506.1 ([M−H]−)
Reaction SMILES: Cl.[O:2]=[C:3]1[CH2:7][NH:6][C@H:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4]1.[CH3:18][O:19][C:20]([NH:22][C@@H:23]([CH:27]([CH3:29])[CH3:28])[C:24](O)=[O:25])=[O:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH3:18][O:19][C:20]([NH:22][C@@H:23]([CH:27]([CH3:29])[CH3:28])[C:24]([N:6]1[CH2:7][C:3](=[O:2])[CH2:4][C@H:5]1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])=[O:25])=[O:21]
Reactant: O=C1CN[C@H](C(=O)OCc2ccccc2)C1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CC(=O)C[C@H]1C(=O)OCc1ccccc1)C(C)C
Reaction time: 2 h

Procedure:
(S)-Benzyl 4-oxopyrrolidine-2-carboxylate hydrochloride (1.92 g, 8.8 mmol), the acid (in this case (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid) (1.84 g, 10.56 mmol) and HATU (5.02 g, 13.2 mmol) were weighed out in a round bottom flask and dissolved in anhydrous DMF (44 mL). To this mixture was added DIPEA (6.82 g, 52.8 mmol) at room temperature and the mixture was stirred for 2 h. The crude mixture was diluted with EtOAc and washed respectively with brine, 10% Na2CO3 and brine again, and the mixture was dried over MgSO4, after filtration the mixture was concentrated down on rotovap. The residue was then purified on normal phase chromatography. (2.45 g, 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][C:17]=1[OH:26]>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][C:17]=1[O:26][C:7]1[CH:6]=[CH:5][C:4]([S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])=[CH:3][C:2]=1[Cl:1]
Reactant: CN(C)S(=O)(=O)c1ccc(F)c(Cl)c1
Reactant: O=C(O)Cc1ccc(Cl)c(O)c1
Product: CN(C)S(=O)(=O)c1ccc(Oc2cc(CC(=O)O)ccc2Cl)c(Cl)c1

Procedure:
The title compound was prepared by the method of example 2 step (iii) using 3-chloro-4-fluoro-N,N-dimethylbenzenesulfonamide and the product of example 1 step (iii).
Reaction SMILES: O(C[C@H:10]([OH:12])C)[Si](C(C)(C)C)(C)C.N[C:14]1SN=C(C)N=1.[CH3:20][O:21][C:22](=[O:43])[C:23]1[CH:28]=[C:27]([OH:29])[CH:26]=[C:25]([O:30][C:31]2[CH:36]=[CH:35][C:34]([CH2:37][NH:38][C:39]([O:41][CH3:42])=[O:40])=[CH:33][CH:32]=2)[CH:24]=1>>[CH3:20][O:21][C:22](=[O:43])[C:23]1[CH:28]=[C:27]([O:29][CH2:14][O:12][CH3:10])[CH:26]=[C:25]([O:30][C:31]2[CH:32]=[CH:33][C:34]([CH2:37][NH:38][C:39]([O:41][CH3:42])=[O:40])=[CH:35][CH:36]=2)[CH:24]=1
Reactant: C[C@@H](O)CO[Si](C)(C)C(C)(C)C
Reactant: Cc1nsc(N)n1
Reactant: COC(=O)NCc1ccc(Oc2cc(O)cc(C(=O)OC)c2)cc1
Product: COCOc1cc(Oc2ccc(CNC(=O)OC)cc2)cc(C(=O)OC)c1

Procedure:
The compound of Production Example 127 was obtained as a colorless amorphous substance by the same method as in Production Example 2, a corresponding method, or a combination thereof with an ordinary method, using (2R)-1-(t-butyldimethylsiloxy)-2-hydroxypropane, 5-amino-3-methyl-[1,2,4]-thiadiazole and 3-(4-methoxycarbonylaminomethylphenoxy)-5-hydroxy-benzoic acid methyl ester obtained by deprotection of the methoxymethyl group of 3-(4-methoxycarbonylaminomethylphenoxy)-5-methoxymethoxy-benzoic acid methyl ester obtained by the same method as in Production Example 59, using 5-hydroxy-3-methoxymethoxybenzoic acid methyl ester instead of 5-hydroxy-3-isopropoxybenzoic acid methyl ester.
Reaction SMILES: [CH3:1][N:2]([C:7](=[S:10])[NH:8][CH3:9])[C:3](=O)[O:4]C.C([O-])(=O)C.[Na+].[F:16][C:17]1([F:39])[O:22][C:21]2[CH:23]=[C:24]([F:37])[C:25]([NH:27][C:28](=[O:36])OC3C=CC=CC=3)=[CH:26][C:20]=2[NH:19][C:18]1=[O:38]>CN(C=O)C>[CH3:1][N:2]1[C:7](=[S:10])[N:8]([CH3:9])[C:28](=[O:36])[N:27]([C:25]2[C:24]([F:37])=[CH:23][C:21]3[O:22][C:17]([F:16])([F:39])[C:18](=[O:38])[NH:19][C:20]=3[CH:26]=2)[C:3]1=[O:4]
Reactant: O=C(Nc1cc2c(cc1F)OC(F)(F)C(=O)N2)Oc1ccccc1
Reactant: CNC(=S)N(C)C(=O)OC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=S)n(C)c(=O)n(-c2cc3c(cc2F)OC(F)(F)C(=O)N3)c1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
0.97 g (5.0 mmol) methyl N-methyl-N-(methylcarbamothioyl)carbamate with a purity of 83.3% was dissolved in 4.2 g DMF. 0.14 g (1.7 mmol) sodium acetate was added. The mixture was stirred at 60° C. at a pressure of 25 mbar. Via syringe a solution of 1.32 g (3.7 mmol) phenyl N-(2,2,7-trifluoro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (purity 95.7%) in 4.2 g DMF was added within 2 h. From time to time fresh DMF was added to maintain the solvent volume. After a poststirring period of 1 h, a chemical yield 73% was determined by quantitative HPLC analytics (HPLC-method A; tR=4.9 min) of the product solution.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([CH2:35][C@H:36]([OH:63])/[CH:37]=[CH:38]\[C@H:39]([CH3:62])[C@H:40]([O:54][Si:55]([C:58]([CH3:61])([CH3:60])[CH3:59])([CH3:57])[CH3:56])[C@@H:41]([CH3:53])[CH2:42][CH2:43][CH2:44][O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[C@H:10]([CH3:34])/[CH:11]=[CH:12]/[CH2:13][O:14][C:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:64](OS(C(F)(F)F)(=O)=O)([C:67]([CH3:70])([CH3:69])[CH3:68])([CH3:66])[CH3:65].N1C(C)=CC=CC=1C>CCOC(C)=O.CCCCCC>[Si:1]([O:8][C@@H:9]([CH2:35][C@H:36]([O:63][Si:64]([C:67]([CH3:70])([CH3:69])[CH3:68])([CH3:66])[CH3:65])/[CH:37]=[CH:38]\[C@H:39]([CH3:62])[C@H:40]([O:54][Si:55]([C:58]([CH3:60])([CH3:59])[CH3:61])([CH3:57])[CH3:56])[C@@H:41]([CH3:53])[CH2:42][CH2:43][CH2:44][O:45][Si:46]([C:49]([CH3:50])([CH3:51])[CH3:52])([CH3:48])[CH3:47])[C@H:10]([CH3:34])/[CH:11]=[CH:12]/[CH2:13][O:14][C:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C[C@H](/C=C/COC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@H](C[C@H](O)/C=C\[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)CCCO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCCCCC
Solvent: Cc1cccc(C)n1
Solvent: CCOC(C)=O
Product: C[C@H](/C=C/COC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@H](C[C@@H](/C=C\[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)CCCO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Yield: 95529.9 %

Procedure:
The procedure for 35 was used with alcohol 66 (1.70 g, 1.85 μmol), TBSOTf (0.94 mL, 4.07 mmol) and 2,6-lutidine (0.51 mL, 4.44 mmol) to yield 67 (1.82 g, 96%) by flash column chromatography (EtOAc/hexane 1:19) as a colorless oil: IR (CHCl3) 2956, 2856, 1471, 1448, 1254, 1092, 1004, 836, 773 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.77-7.75 (m, 6H), 7.57-7.47 (m, 9H), 6.02-5.87 (m, 2H), 5.76 (t, J=10.8 Hz, 1H), 5.61 (dd, J=10.8, 8.5 Hz, 1H), 4.88 (m, 1H), 4.24 (m, 1H), 3.88 (m, 4H), 3.75 (m, 1H), 2.94 (m, 1H), 2.73 (m, 1H), 1.83 (m, 2H), 1.75 (m, 2H), 1.57 (m, 1H), 1.46-1.41 (m, 2H), 1.31 (d, J=6.8 Hz, 3H), 1.30(d, J=6.3 Hz, 3H), 1.24-1.13 (m, 39H), 0.44-0.34 (m, 24H); 13C NMR (75 MHz, CDCl3) δ 144.4, 134.4, 132.9, 132.2, 128.7, 127.7, 126.8, 86.8, 80.2, 72.3, 66.6, 65.1, 63.6, 42.4, 41.6, 38.4, 35.7, 31.6, 29.9, 26.3, 26.0, 19.6, 18.5, 18.4, 18.2, 15.1, 13.2, −2.9, −3.6, −3.7, −4.2, −5.2; LRMS (ESI) 1051.6 [M+Na]+, 918.6, 769.5, 637.4, 413.2; HRMS (ESI) calcd for C61H104O5Si4Na 1051.6859 [M+Na]+, found 1051.6848 [α]20D−8.3 (c 2.4, CHCl3).
Reaction SMILES: [Cl-].[Na+].[Cl:3][S:4]([OH:7])(=O)=[O:5].[CH3:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1>>[Cl:3][S:4]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:9]=1[CH3:8])[C:13]([OH:15])=[O:14])(=[O:7])=[O:5]
Reactant: O=S(=O)(O)Cl
Reactant: Cc1ccc(C(=O)O)cc1
Agent: [Cl-]
Agent: [Na+]
Product: Cc1ccc(C(=O)O)cc1S(=O)(=O)Cl
Temperature: 122 °C

Procedure:
Sodium chloride (8 g, 138 mmol) is added to chlorosulfonic acid (30 mL, 451 mmol) and in small portions 4-methyl-benzoic acid (4 g, 29 mmol) is added to the stirred mixture. After complete addition, the reaction is heated at 122° C. for 16 h. The reaction mixture is cooled and poured into ice-water. The organic material is extracted with ethyl acetate. The organic layer is washed with a saturated sodium chloride solution, dried over magnesium sulfate, filtered, and the solvent is removed in vacuo. The residue is used as is in the next step.
Reaction SMILES: O.[S:2]([O-:6])([O-:5])(=[O:4])=[O:3].[Zn+:7].[NH4+].N>>[S:2]([O-:6])([O-:5])(=[O:4])=[O:3].[Zn+2:7].[S:2](=[O:4])(=[O:3])([OH:6])[OH:5]
Reactant: [Zn+]
Agent: N
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: O
Product: O=S(=O)(O)O
Product: [Zn+2]

Procedure:
The present invention comprises the use of ammonium zinc sulfate hydrate to selectively recover ammonia from an aqueous solution in a solid crystalline form. The water and ammonia may then be recovered by heating the crystals and recovering the water and ammonia in the off gases. This process would then leave behind zinc sulfate and sulfuric acid, which can be resolubilized and recycled.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([N:28]=[C:29]=[O:30])[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([NH:28][C:29](=[O:30])[O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]3)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: Oc1ccc2c(c1)CCN2Cc1ccccc1
Reactant: COc1ccc(N=C=O)cc1OC
Product: COc1ccc(NC(=O)Oc2ccc3c(c2)CCN3Cc2ccccc2)cc1OC

Procedure:
The title compound was synthesized from 1-benzylindolin-5-ol (30.0 mg, 0.133 mmol) using the same procedure employed for Example 2 (2), but with 3,4-dimethoxyphenylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (26.9 mg, 50%) having the following characteristics.
Reaction SMILES: [F:1][C:2]([F:22])([C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]#[N:14])=[CH:8][CH:7]=1)=[O:4].[N-:23]=[N+:24]=[N-:25].[Na+].[Cl-].[NH4+].O>CN(C)C=O>[F:1][C:2]([F:22])([C:15]([F:20])([F:21])[C:16]([F:19])([F:18])[F:17])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[NH:25][N:24]=[N:23][N:14]=2)=[CH:8][CH:7]=1)=[O:4]
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCc1ccc(NC(=O)C(F)(F)C(F)(F)C(F)(F)F)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc(Cc2nnn[nH]2)cc1)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C

Procedure:
A mixture of 2,2,3,3,4,4,4-heptafluoro-N-[4-(cyanomethyl)phenyl]butanamide (17.5 g.), sodium azide (17.3 g.) and ammonium chloride (14.1 g.) was heated in dimethylformamide (250 ml.) at 130°-135° C. (oil bath) under a nitrogen atmosphere for 20 hours. Enough water was then added to the hot reaction mixture to dissolve all suspended salts and the mixture was allowed to cool to room temperature. Additional water was then added to produce a white precipitate which was filtered, washed with water and dried under vacuum. The white solid 2,2,3,3,4,4,4-heptafluoro-N-[4-(1H-tetrazol-5-ylmethyl)phenyl]butanamide product (8.7 g., 44%, mp 176°-179° C.) was analytically pure as isolated. A sample recrystallized from acetone (minimum amount)/diethyl ether melted at 176°-178° C.