Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5](COCC[Si](C)(C)C)[C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([CH:25]([F:27])[F:26])[CH:22]=[C:21]([C:28]#[N:29])[CH:20]=2)[C:12]=1[F:30])=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([CH:25]([F:26])[F:27])[CH:22]=[C:21]([C:28]#[N:29])[CH:20]=2)[C:12]=1[F:30])=[O:8]
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(C#N)cc(C(F)F)c2)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)cc(C(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.1 %

Procedure:
To a solution of 4-chloro-N-[(4-chloro-3-{[3-cyano-5-(difluoromethyl)phenyl]oxy}-2-fluorophenyl)methyl]-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (81 mg, 0.138 mmol) dissolved in DCM (5 ml) was added TFA (2.00 ml) and the reaction mixture was stirred at RT for 2 hours. The solvent was removed and the crude material was purified via reverse phase HPLC to give 4-chloro-N-[(4-chloro-3-{[3-cyano-5-(difluoromethyl)phenyl]oxy}-2-fluorophenyl)methyl]-1H-imidazole-5-carboxamide (56 mg, 0.123 mmol, 89% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.77 (s, 1H), 7.65 (s, 1H), 7.23-7.50 (m, 4H), 6.81 (t, 1H), 4.64 (s, 2H). LC-MS (ES+) m/z 454.97, [M+H].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][N:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[N:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)([N:29]1C=CN=C1)=O.N.S(=O)(=O)(O)O>C(#N)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][N:14]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[N:16]=[CH:17][CH:18]=[CH:19][N:20]=1)[C:10]([NH2:29])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CN(c1ccccc1)c1ncccn1)C(=O)O
Agent: N
Agent: O=S(=O)(O)O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](CN(c1ccccc1)c1ncccn1)C(N)=O
Reaction time: 2 h
Yield: 95.2 %

Procedure:
A suspension of (S)-2-tert-butoxycarbonylamino-3-(phenyl-pyrimidin-2-ylamino)-propanoic acid (11.9 g, 33.2 mmol, >99.9% ee) in acetonitrile (36 ml) is admixed at −15° C. with a solution of 1,1′-carbonyldiimidazole (8.36 g, 51.6 mmol) in acetonitrile (125 ml), and the reaction mixture is stirred for 2 h at this temperature. Ammonia (4.0 g, 222 mmol) is then introduced, and the mixture is stirred for further 1 h and then adjusted to pH 4.5 using 2N sulfuric acid. Acetonitrile is distilled off, and the precipitated solid is filtered off with suction and dried to give (S)-2-tert-butoxycarbonylamino-3-(phenyl-pyrimidin-2-ylamino)-propanoic acid amide (11.3 g, 95%, >99.9% ee) as a colorless solid.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([CH2:11][CH3:12])=[C:9]([CH3:13])[Se:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:14][C:15]1[CH:19]=[C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[Se:17][C:16]=1[C:24]([NH2:26])=[O:25].CN(C=O)C.[OH-].[Na+]>>[CH2:11]([C:10]1[C:3]2[C:2]([NH:14][C:15]3[CH:19]=[C:18]([C:20]([CH3:23])([CH3:21])[CH3:22])[Se:17][C:16]=3[C:24]([NH2:26])=[O:25])=[N:7][CH:6]=[N:5][C:4]=2[Se:8][C:9]=1[CH3:13])[CH3:12]
Reactant: CCc1c(C)[se]c2ncnc(Cl)c12
Reactant: CC(C)(C)c1cc(N)c(C(N)=O)[se]1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCc1c(C)[se]c2ncnc(Nc3cc(C(C)(C)C)[se]c3C(N)=O)c12

Procedure:
The reaction of 4-chloro-5-ethyl-6-methylselenopheno[2,3-d]pyrimidine with 3-amino-5-tert-butylselenophene-2-carboxamide in the presence of DMF/NaOH as described in Example 1 gave title compound as a pale yellow color solid, mp 258-260° C. IR (KBr) vmax 3321, 3149, 2960, 1666, 1582, 1384, 1356, 1224, 1187, 1129, 1042, 1020, 925, 838, 810 cm−1; 1H NMR (400 MHz, CDCl3): δ 10.96 (1H, s, exchangeable with D2O), 8.51 (1H, s), 8.49 (1H, s), 5.44 (2H, br s, exchangeable with D2O), 3.13 (2H, q, J=7.6 Hz), 2.57 (3H, s), 1.44 (9H, s), 1.24 (3H, t, J=7.6 Hz); 13C NMR (100 MHz, CDCl3): δ 172.1, 167.9, 167.1, 153.4, 151.2, 146.9, 135.6, 133.4, 122.8, 120.8, 110.6, 37.0, 32.6, 21.8, 15.8, 15.3; LC-MS (negative ion mode): m/z 465, 467, 469 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]([CH:13]([CH3:16])[CH2:14]O)[CH:7]=[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]2=[O:22].S(Cl)([Cl:25])=O>C(Cl)(Cl)Cl>[Cl:25][CH2:14][CH:13]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([F:1])=[C:11]([F:12])[CH:10]=2)[C:5](=[O:22])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:7]1)[CH3:16]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1cn(C(C)CO)c2cc(F)c(F)cc2c1=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(C(C)CCl)c2cc(F)c(F)cc2c1=O

Procedure:
4.45 gm (14.3 mmol) of ethyl 6,7-difluoro-1,4-dihydro-1-(1-hydroxyprop-2-yl)-4-oxoquinoline-3-carboxylate and 5.10 gm (42.9 mmol) of thionyl chloride were dissolved into 130 ml of chloroform for reaction with heating under refluxing for 1 hour. After cooling, the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (chloroform:methanol=100:1), and recrystallized from ethanol to obtain 3.53 gm of colorless, needlelike crystals of ethyl 1-(1-chloroprop-2-yl)-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:42])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C@H:14]2[C@H:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=3[F:26])[C@:17]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=3[F:36])([C:27]#[N:28])[C@H:16]([CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[NH:15]2)=[O:13])=[CH:7][CH:6]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:53](I)[CH3:54]>C1COCC1.[Cl-].[NH4+]>[CH3:1][O:2][C:3](=[O:42])[CH:4]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([C@H:14]2[C@H:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=3[F:26])[C@:17]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=3[F:36])([C:27]#[N:28])[C@H:16]([CH2:37][C:38]([CH3:39])([CH3:41])[CH3:40])[NH:15]2)=[O:13])=[CH:9][CH:10]=1)[CH2:53][CH3:54]
Reactant: CCI
Reactant: COC(=O)Cc1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(C(=O)OC)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 53.6 %

Procedure:
A mixture of chiral (4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-phenyl)-acetic acid methyl ester (22 mg, 0.036 mmol) was dissolved in THF (1 mL) and cooled to −78° C., then LHMDS (1 mL, 1M in THF) was added and the mixture stirred 15 min at −78° C. Ethyl iodide (0.1 mL, 0.107 mmol) was added and stirred for 1 h at −78° C., then warmed to 1 h at room temperature. The mixture was diluted with sat'd ammonium chloride solution extracted with ethyl acetate, the organic layer was separated then concentrated under reduced pressure to afford an oil that was purified by silica column chromatography (4 g Analogix column, 1-100% EtOAc/heptane) to afford 2-(4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-phenyl)-butyric acid methyl ester as a light yellow foam (12.4 mg, 53.9%). LCMS (ES+) m/z Calcd for C34H35Cl2F2N3O3+H [(M+H)+]: 641.20. found: 642.2.
Reaction SMILES: [C:1]([OH:15])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].S(Cl)([Cl:18])=O>C1CCCCC1>[C:1]([Cl:18])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCCC(=O)O
Reactant: O=S(Cl)Cl
Solvent: C1CCCCC1
Product: CCCCCCCCCCCCC(=O)Cl
Temperature: 80 °C
Yield: 101.4 %

Procedure:
In a one L (liter) two-necked flask were placed 158.7 g (0.74 mol) of tridecanoic acid and 200 milliliter (mL) of cyclohexane, and the flask was equipped with a 100 mL dropping funnel containing 83.3 g (0.7 mol) of thionyl chloride and a reflux tube. Then, the tridecanoic acid was completely dissolved under heating and stirring of the flask in an oil bath at 80° C. Thereafter the thionyl chloride was added dropwise over a period of 2 hours, and further the oil bath was maintained at 80° C. for one hour. From the resultant reaction solution were removed the cyclohexane and the thionyl chloride under reduced pressure by means of an aspirator. The resultant reaction mixture was subjected to vacuum distillation. Thus 166.0 g (0.71 mol) of tridecanoyl chloride was obtained in a yield of 95.9% based on the fed tridecanoic acid.
Reaction SMILES: C(O)C.[CH2:4]([C:14]1[CH:24]=[CH:23][C:17]([C:18](OCC)=[O:19])=[CH:16][CH:15]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].O.[NH2:26][NH2:27]>O>[CH2:4]([C:14]1[CH:24]=[CH:23][C:17]([C:18]([NH:26][NH2:27])=[O:19])=[CH:16][CH:15]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: NN
Reactant: CCCCCCCCCCc1ccc(C(=O)OCC)cc1
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCc1ccc(C(=O)NN)cc1
Yield: 72.9 %

Procedure:
18 ml of ethanol was added to 10.0 g of ethyl 4-decylbenzoate, and then 20 g of 80%-hydrazine hydrate was added thereto, followed by refluxing for 16 hours. After the reaction, the reaction mixture was poured into 200 ml of iced water to precipitate a crystal. The crystal was recovered by filtration and recrystallized from ethanol to obtain 6.93 g of 4-decylbenzohydrazide (Yield: 72.9%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[S:10](=[O:12])(=[O:11])[CH2:9][C:8]3[C:13]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:14][N:15]([CH:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[C:7]=3[C:5]=2[N:6]=1.C(N(CC)CC)C.[C:34](Cl)(=[O:36])[CH3:35].O>C(Cl)Cl>[C:34]([NH:1][C:2]1[S:3][C:4]2[S:10](=[O:12])(=[O:11])[CH2:9][C:8]3[C:13]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:14][N:15]([CH:16]4[CH2:17][CH2:18][O:19][CH2:20][CH2:21]4)[C:7]=3[C:5]=2[N:6]=1)(=[O:36])[CH3:35]
Reactant: CCOC(=O)c1nn(C2CCOCC2)c2c1CS(=O)(=O)c1sc(N)nc1-2
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nn(C2CCOCC2)c2c1CS(=O)(=O)c1sc(NC(C)=O)nc1-2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To suspension of ethyl 7-amino-1-(tetrahydro-2H-pyran-4-yl)-1,4-dihydropyrazolo[3′,4′:4,5]thiopyrano[3,2-d][1,3]thiazole-3-carboxylate 5,5-dioxide (71 mg; 0.18 mmol; 1 eq.) and triethylamine (98.8 μL; 0.71 mmol; 4 eq.) in DCM (710 μL) at 0° C. is added acetylchloride (30 μL; 0.46 mmol; 2.5 eq.). The suspension is stirred at rt overnight then heated up to 100° C. for 1 day. Water is added to reacture mixture and the product is extracted with DCM (×2). The combined organic layers are washed with brine, dried over Na2SO4 then concentrated under vacuum affording a beige solid residue. The residue is triturated then sonicated in Et2O and the solid is filtered-off to afford the title compound. HPLC (max plot) 98.8%; Rt 3.28 min. MS (ESI+): 441.1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[CH:18][C:19]([F:23])=[C:20]([NH2:22])[CH:21]=2)[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[CH3:30][N:31]1[CH:35]=[C:34]([S:36](Cl)(=[O:38])=[O:37])[N:33]=[CH:32]1>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[CH:18][C:19]([F:23])=[C:20]([NH:22][S:36]([C:34]3[N:33]=[CH:32][N:31]([CH3:30])[CH:35]=3)(=[O:38])=[O:37])[CH:21]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: CC(C)c1nc(-c2ccc(F)c(N)c2)c(-c2ccnc(Cl)n2)s1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3cn(C)cn3)c2)c(-c2ccnc(Cl)n2)s1
Temperature: 45 °C
Reaction time: 0.08 h
Yield: 66.3 %

Procedure:
{5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}amine (160 mg, 0.459 mmol) was dissolved in DMF (3 mL) and added pyridine (0.074 mL; 0.917 mmol). The reaction was stirred 5 min and added 1-methylimidazole-4-sulfonyl chloride (83 mg, 0.459 mmol). The reaction mixture was heated at 45° C. for two days. The reaction mixture was cooled to rt, added silica gel, and concentrated. The crude product was chromatographed on silica gel eluting with 100% DCM to 100% EtOAc to obtained the title compound as a white solid (150 mg, 66% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.12 (br. s., 1H), 8.49 (d, J=5.4 Hz, 1H), 7.52-7.83 (m, 2H), 7.51 (d, J=1.8 Hz, 1H), 7.28-7.43 (m, 1H), 7.25 (t, J=9.3 Hz, 1H), 7.05 (d, J=5.3 Hz, 1H), 3.58 (s, 3H), 3.00-3.23 (m, 1H), 1.35 (d, J=6.9 Hz, 6H).
Reaction SMILES: O[C:2]1[C:3](C)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].O[N:13]1C2C=CC=CC=2N=N1.C(Cl)CCl.C(OCC)(=O)C>CN(C)C=O>[C:5]([NH2:13])(=[O:6])[C:4]1[CH:8]=[CH:9][CH:10]=[CH:2][CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: Cc1c(O)cccc1C(=O)O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=O)c1ccccc1
Reaction time: 0.33 h
Yield: 183 %

Procedure:
To a solution of 175 mg (1.15 mmol) of 3-hydroxy-2-methylbenzoic acid and 203 mg (1.5 mmol) of N-hydroxybenzotriazole in 6 mL of anhydrous N,N-dimethylformamide at 0° C., was added 220 mg (1.15 mmol) of EDC. After 20 minutes of activation at 0° C. and 1 hour at room temperature, 392 mg (1.0 mmol) of 2R-hydroxy-3-[(2-methylpropyl)(4-aminophenyl)sulfonyl]amino-1S-(phenylmethyl)propylamine was added. After 15 hours at room temperature, ethyl acetate was added, washed with 5% citric acid, saturated sodium bicarbonate, brine, dried, filtered and concentrated to afford 590 mg of crude material. This was chromatographed on silica gel using 50-80% ethyl acetate/methylene chloride as eluent to afford 255 mg of pure benzamide, N-[2R-hydroxy-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3-hydroxy-2-methyl, m/e=526(M+H).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C@H:5]1[CH2:9][CH2:8][N:7]([CH2:10][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)O)[CH2:6]1.COCO[C@H]1CCN([C@H](C2C=CC=CC=2)CO)C1.[CH3:37][O:38][C:39]1[CH:40]=[C:41]([CH:46]=[CH:47][C:48]=1[NH:49][CH3:50])[C:42]([O:44][CH3:45])=[O:43]>>[CH3:37][O:38][C:39]1[CH:40]=[C:41]([CH:46]=[CH:47][C:48]=1[N:49]([C@@H:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10][N:7]1[CH2:8][CH2:9][C@H:5]([O:4][CH2:3][O:2][CH3:1])[CH2:6]1)[CH3:50])[C:42]([O:44][CH3:45])=[O:43]
Reactant: COCO[C@H]1CCN(C[C@@H](O)c2ccccc2)C1
Reactant: CNc1ccc(C(=O)OC)cc1OC
Agent: COCO[C@H]1CCN([C@@H](CO)c2ccccc2)C1
Product: COCO[C@H]1CCN(C[C@H](c2ccccc2)N(C)c2ccc(C(=O)OC)cc2OC)C1
Yield: 60 %

Procedure:
This was prepared from 2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethanol and 2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-2-(R)-phenylethanol and methyl 3-methoxy-4-methylaminobenzoate in 60% yield according to a procedure similar to that described in Example 1 (i).
Reaction SMILES: [CH3:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].C([O:16][N:17]=O)(C)(C)C.O1CCCC1.Cl.C(=O)([O-])[O-].[Na+].[Na+].CC1CCCCC1>[Cl-].[Na+].O>[Cl:11][C:8]1[CH:7]=[CH:6][C:5]([C:3](=[O:4])/[C:2](=[N:17]/[OH:16])/[CH3:1])=[CH:10][CH:9]=1
Reactant: CCC(=O)c1ccc(Cl)cc1
Reactant: CC(C)(C)ON=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC1CCCCC1
Solvent: O
Solvent: C1CCOC1
Product: C/C(=N\O)C(=O)c1ccc(Cl)cc1
Reaction time: 2 h
Yield: 91.1 %

Procedure:
To a solution of 440 g (2.437 mol) of 4-chloropropiophenone and 335 g (2.925 mol) t-butylnitrite in 700 g of tetrahydrofurane 97.8 g (2.681 mol) of gaseous hydrochloric acid is dosed over 2 hours at +25° C. to +40° C. Following the end of the addition the batch is stirred for two hours at +15° C. to +30° C. The reaction mixture is neutralized by adding 630.5 g of 20% sodium carbonate solution at +25° C. Some brine and methylcyclohexane is added and the phases are separated. The product crystallizes from the organic phase when concentrated. The product is isolated by filtration and the filter cake is washed with 75 g of methylcyclohexane at 0° C.: 438.9 g of (E)-1-(4-chlorophenyl)-propan-1,2-dione-2-oxime (m.p. 115-115C.) are obtained in 91.1% yield.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([C:25](=[O:29])[C:26]([NH2:28])=[O:27])=[C:9]([CH2:23][CH3:24])[N:10]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=1.CO.[Na]>[OH-].[Na+]>[NH2:28][C:26](=[O:27])[C:25]([C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[CH:14][C:6]=2[O:5][CH2:4][C:3]([OH:30])=[O:2])[N:10]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[C:9]=1[CH2:23][CH3:24])=[O:29]
Reactant: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)OC)cccc2n1Cc1cccc(Cl)c1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CO
Product: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)O)cccc2n1Cc1cccc(Cl)c1
Yield: 64.6 %

Procedure:
Using the procedure described in Example 2, Part E, 418 mg (1 mmol) of [[3-(2-amino-1,2-dioxoethyl)1-[(3-chlorophenyl)methyl]-2-ethyl-1H-indol-4-yl]oxy]acetic acid methyl ester was hydrolyzed in 5 mL of 1N NaOH and 15 mL of MeOH to give 268 mg (61% yield) of [[3-(2-amino-1,2-dioxoethyl)1-[(3-chlorophenyl)methyl]-2-ethyl-1H-indol-4-yl]oxy]acetic acid, sodium salt, mp, >265° C.
Reaction SMILES: CO.[OH-].[Na+].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[C:13]1[C:17]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:27]=[C:28]4[C:33](=[CH:34][CH:35]=3)[C:32]([C:36]([O:38]C)=[O:37])=[CH:31][CH:30]=[CH:29]4)=[CH:22][CH:21]=2)=[C:16]([CH:40]([CH3:42])[CH3:41])[O:15][N:14]=1>O1CCCC1>[Cl:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([Cl:5])[C:7]=1[C:13]1[C:17]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:27]=[C:28]4[C:33](=[CH:34][CH:35]=3)[C:32]([C:36]([OH:38])=[O:37])=[CH:31][CH:30]=[CH:29]4)=[CH:22][CH:21]=2)=[C:16]([CH:40]([CH3:42])[CH3:41])[O:15][N:14]=1
Reactant: COC(=O)c1cccc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3c(C(=O)O)cccc3c2)cc1
Temperature: 25 °C
Yield: 91.2 %

Procedure:
Methanol (380 mL) and 5 N sodium hydroxide solution (190 mL) were added to a stirred solution of methyl 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthalenecarboxylate (190 g, 0.35 mol) in tetrahydrofuran (1 L). The resulting solution was heated to reflux for 1.5 h. The mixture was cooled to room temperature and concentrated to remove methanol and tetrahydrofuran. The residue was diluted with water (500 mL), acidified with 6 N HCl and the supernatant was decanted from the taffy-like solid. The solid was crystallized from ethyl acetate (1 L) to give 170 g of the product as off-white crystals. 1H NMR (DMSO-d6): δ 9.02 (d, J=9 Hz, 1H), 8.01 (s, 1H), 7.80 (d, J=8 Hz, 1H), 7.73 (d, J=7 Hz, 1H), 7.68-7.61 (m, 5H), 7.53 (dd, J=7, 9 Hz, H), 7.38 (t, J=8, 15 Hz, 1H), 6.88 (d, J=9 Hz, 2H), 4.85 (s, 2H), 3.46 (septet, J=7 Hz, 1H), 1.32 (d, J=7 Hz, 6H). ESI-LCMS m/z 532 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[C:6]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:11]([C:21]3[CH:26]=[CH:25][C:24]([C:27]#[CH:28])=[CH:23][CH:22]=3)[C:10](=[O:29])[C:7]=2[NH:8][N:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:31](=[N:37][OH:38])[C:32]([O:34][CH2:35][CH3:36])=[O:33].C(N(CC)CC)C>C1COCC1>[C:1]([C:5]1[C:6]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:11]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[O:38][N:37]=[C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:28]=4)=[CH:23][CH:22]=3)[C:10](=[O:29])[C:7]=2[NH:8][N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1ccc(N2C(=O)c3[nH]nc(C(C)(C)C)c3C2c2ccccc2OC)cc1
Reactant: CCOC(=O)C(Cl)=NO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(-c2ccc(N3C(=O)c4[nH]nc(C(C)(C)C)c4C3c3ccccc3OC)cc2)on1
Temperature: 0 °C
Reaction time: 4 h
Yield: 64.5 %

Procedure:
To a mixture of 3-t-butyl-5-(4-ethynylphenyl)-4-(2-methoxyphenyl)-4,5-dihydro-1H-pyrrolo[3,4-c]pyrazol-6-one (1.51 g, 3.9 mmol), ethyl 2-chloro-2-hydroxyiminoacetate (1.19 g, 7.8 mmol) and THF (4 mL), triethylamine (1.09 mL, 7.8 mmol) in THF (3 mL) was added dropwise under ice-cooling conditions, and the mixture was stirred at 0° C. for 4 hr. Ethyl 2-chloro-2-hydroxyiminoacetate (1.19 g, 7.8 mmol) was added, and further triethylamine (0.81 mL, 5.9 mmol) in THF (3 mL) was added dropwise. The mixture was stirred at 0° C. for 2 hr and left stand overnight. The precipitate was removed by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane) to give 3-t-butyl-5-[4-(3-ethoxycarbonyl-5-isoxazolyl)phenyl]-4-(2-methoxyphenyl)-4,5-dihydro-1H-pyrrolo[3,4-c]-pyrazol-6-one (1.26 g, 64%) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:7](OC)([O:10]C)[CH2:8][F:9])=[CH:5][CH:6]=1.Cl.CCCCCC>CC#N.C(Cl)Cl>[Br:1][C:2]1[S:3][C:4]([C:7](=[O:10])[CH2:8][F:9])=[CH:5][CH:6]=1
Reactant: COC(CF)(OC)c1ccc(Br)s1
Agent: Cl
Solvent: ClCCl
Solvent: CC#N
Solvent: CCCCCC
Product: O=C(CF)c1ccc(Br)s1
Reaction time: 3 h
Yield: 83.5 %

Procedure:
To a stirred solution of 2-bromo-5-(2-fluoro-1,1-dimethoxy-ethyl)-thiophene (9.4 g, 35 mmol) in MeCN (100 mL) was added 10% aq. HCl (50 mL) at 20° C. and the reaction mixture was stirred at ° C. for 3 h. Solvent was removed in vacuo to afford a residue, which was partitioned between DCM and water, the aqueous layer was extracted with DCM. The combined organic layers were washed with water, sat aq. NaHCO3 and brine, dried over sodium sulfate and evaporated in vacuo to give a white solid. It was dissolved in minimum volume of DCM, and a large volume of hexane was added. After evaporation of most of the solvent, solid precipitated and was then collected with filtration, washed with hexane and dried under high vacuum to afford 1-(5-bromo-thiophen-2-yl)-2-fluoro-ethanone (6.52 g, 84%). 1H-NMR (CDCl3): δ 7.64 (d, 1H), 7.15 (d, 1H), 5.26 (d, 2H).
Reaction SMILES: B([O-])=O.[Na+].[Cl:5][CH:6]([Cl:27])[C:7]([CH3:26])([CH3:25])[C:8](=[O:24])[CH:9]([O:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23])[N:10]1[CH:14]=[N:13][CH:12]=[N:11]1.C(O)(=O)C>CO>[Cl:27][CH:6]([Cl:5])[C:7]([CH3:25])([CH3:26])[CH:8]([OH:24])[CH:9]([O:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23])[N:10]1[CH:14]=[N:13][CH:12]=[N:11]1
Reactant: CC(C)(C(=O)C(Oc1ccc(Cl)cc1Cl)n1cncn1)C(Cl)Cl
Agent: O=B[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C(Cl)Cl)C(O)C(Oc1ccc(Cl)cc1Cl)n1cncn1
Temperature: 50 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
1.5 g (0.04 mole) of sodium boranate are added in portions to a solution of 8 g (0.02 mole) of 4,4-dichloro-1-(2,4-dichlorophenoxy)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-one in 80 ml of methanol at 20°-30° C., while stirring. After two hours, the mixture is brought to pH 6 by addition of acetic acid. The solution is evaporated under reduced pressure, the residue is taken up in 200 ml of methylene chloride and the mixture is washed three times with 400 ml of water each time and dried over sodium sulphate. After evaporating the solution and removing the residual solvent by warming the residue at 50° C. under 0.01 bar for two hours, 6 g (75% of theory) of 4,4-dichloro-1-(2,4-dichlorophenoxy)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-ol are obtained as a 3:1 mixture of the two diastereomers in the form of a highly viscous oil.