Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[F:6][C:7]([F:18])([F:17])[C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](Cl)=[O:12]>C1C=CC=CC=1.ClCCl>[C:1]([NH:5][C:11](=[O:12])[C:10]1[CH:14]=[CH:15][CH:16]=[C:8]([C:7]([F:6])([F:17])[F:18])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)N
Solvent: c1ccccc1
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To tert-butylamine (2.0 eq) in 75 mL of benzene is added 3-trifluoromethylbenzoyl chloride (1.0 eq). The temperature is maintained below 15° C. during the addition and then the reaction mixture is allowed to warm to ambient temperature and stirred for 3 hours. The solvent is then stripped and the residue is dissolved in 75 mL of dichloromethane. This solution is washed with 5% hydrochloride acid (2×75 mL), water (2×75 mL), dried over MgSO4 and then the solvent is removed in vacuo to provide the title compound.
Reaction SMILES: O.[OH-].[Li+].[C:4]([C:12]1[N:17]=[C:16]2[S:18][C:19]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][N:28]4[CH2:31][CH:30]([C:32]([O:34]C)=[O:33])[CH2:29]4)=[CH:23][C:22]=3[F:36])=[N:20][C:15]2=[CH:14][CH:13]=1)(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.P([O-])([O-])([O-])=O>C1COCC1.O>[C:4]([C:12]1[N:17]=[C:16]2[S:18][C:19]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][N:28]4[CH2:31][CH:30]([C:32]([OH:34])=[O:33])[CH2:29]4)=[CH:23][C:22]=3[F:36])=[N:20][C:15]2=[CH:14][CH:13]=1)(=[O:11])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)C1CN(Cc2ccc(-c3nc4ccc(C(=O)c5ccccc5)nc4s3)c(F)c2)C1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(c1ccccc1)c1ccc2nc(-c3ccc(CN4CC(C(=O)O)C4)cc3F)sc2n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of lithium hydroxide hydrate (66.4 mg, 1582 μmol) and methyl 1-((4-(5-benzoylthiazolo[5,4-b]pyridine-2-yl)-3-fluorophenyl)methyl)azetidine-3-carboxylate (233.0 mg, 505 μmol) in THF (12.6 mL) and water (1.7 mL) was stirred at 25° C. for 1.5 h. The reaction mixture was then diluted with water (1.0 mL), acidified with 1.0N HCl (1.58 mL), brought to pH 6 with 0.05M phosphate buffer (1.0 mL), and partially concentrated in vacuo. The resulting precipitate was collected by vacuum filtration, washed with water (3.0 mL), and dried in vacuo to afford 1-((4-(5-benzoylthiazolo[5,4-b]pyridine-2-yl)-3-fluorophenyl)methyl)-azetidine-3-carboxylic acid as a colorless solid. MS (ESI) m/z: Calculated: 447.1; Observed: 448.0 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:5][C:3]=1[NH2:4].[C:15]1(=O)[O:20][C:18](=[O:19])[C:17]2[CH2:21][CH2:22][CH2:23][CH2:24][C:16]1=2.O>C(O)(=O)C>[F:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:5][C:3]=1[N:4]1[C:18](=[O:19])[C:17]2[CH2:21][CH2:22][CH2:23][CH2:24][C:16]=2[C:15]1=[O:20]
Reactant: Nc1cc(OC2CCCC2)ccc1F
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: CC(=O)O
Solvent: O
Product: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)ccc1F
Temperature: 25 °C
Yield: 34 %

Procedure:
2-Fluoro-5-cyclopentyloxyaniline (330 mg, 1.69 mmol), 3,4,5,6-tetrahydrophthalic anhydride (258 mg, 1.70 mmol) and acetic acid (10 ml) as a solvent were placed in a round bottom flask (50 cc) followed by heating under refluxing for 5 hours. After completion of the reaction, the reaction solution was cooled to room temperature, water was added thereto, and the mixture was extracted with ethyl acetate (20 ml×3 portions). The organic layers were combined, and, after washing with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate. After removing the drying agent, the solvent was distilled off under reduced pressure. The resulting dark red oily substance (345 mg) was isolated and purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=4/1) to obtain the desired N-(2-fluoro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide as a light yellow oily substance (171 mg, 0.575 mmol, 34% yield).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH3:10][C@@:11]12[C@@H:19]([OH:20])[CH2:18][CH2:17][C@H:16]1[C@@H:15]1[CH2:21][CH2:22][C:23]3[CH:28]=[C:27]([OH:29])[CH:26]=[CH:25][C:24]=3[C@H:14]1[CH2:13][CH2:12]2>N1C=CC=CC=1>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:1]([O:29][C:27]2[CH:26]=[CH:25][C:24]3[C@@H:14]4[C@H:15]([C@H:16]5[C@@:11]([CH2:12][CH2:13]4)([CH3:10])[C@@H:19]([O:20][C:1]([C:2]4[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=4)=[O:8])[CH2:18][CH2:17]5)[CH2:21][CH2:22][C:23]=3[CH:28]=2)=[O:8])[CH:3]=1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Reactant: O=C(Cl)c1cccnc1
Solvent: c1ccncc1
Product: C[C@]12CC[C@@H]3c4ccc(OC(=O)c5cccnc5)cc4CC[C@H]3[C@@H]1CC[C@@H]2OC(=O)c1cccnc1
Temperature: 0 °C
Yield: 90.3 %

Procedure:
To 5.3 g (0.03 mol) of nicotinoyl chloride in 30 mL of dry pyridine at 0° C. were added 2.0 g (0.0073 mol) of β-estradiol. The reaction mixture was refluxed for 1 hour, then was poured over 100 mL of ice water, and the resulting precipitate was collected by filtration. The precipitate was dried in vacuo over P2O5, affording 3.18 g (90%) of the title compound melting at 148°-150° C.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([C:6]1[C:7]([CH3:16])=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[O:10][CH2:9]2)[O:4][CH3:5].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.O>C(Cl)Cl>[CH3:5][O:4][C@H:3]([C:6]1[C:7]([CH3:16])=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[O:10][CH2:9]2)[CH:2]=[O:1]
Reactant: CO[C@@H](CO)c1ccc2c(c1C)COC2=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: O
Product: CO[C@@H](C=O)c1ccc2c(c1C)COC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-5-(2-Hydroxy-1-methoxyethyl)-4-methylisobenzofuran-1(3H)-one (500 mg, 2.25 mmol) was dissolved in DCM (10 mL) and treated with Dess-Martin periodinane (954 mg, 2.25 mmol). The reaction mixture was stirred at room temperature under nitrogen overnight. The crude product was used directly. LC-MS (IE, m/z): 239.2 (M+H2O+1)+.
Reaction SMILES: C[Al](C)C.[CH2:5]([O:7][C:8]([C:10]1[C:11]([I:20])=[C:12]([S:16]([NH2:19])(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1)=[O:9])[CH3:6].[CH3:21][C:22]1[N:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24]([NH:30][C:31](=O)[O:32]C)[N:23]=1.Cl>CCCCCC.ClCCl>[I:20][C:11]1[C:12]([S:16]([NH:19][C:31]([NH:30][C:24]2[N:25]=[C:26]([O:28][CH3:29])[N:27]=[C:22]([CH3:21])[N:23]=2)=[O:32])(=[O:18])=[O:17])=[CH:13][CH:14]=[CH:15][C:10]=1[C:8]([O:7][CH2:5][CH3:6])=[O:9]
Reactant: CCOC(=O)c1cccc(S(N)(=O)=O)c1I
Reactant: COC(=O)Nc1nc(C)nc(OC)n1
Agent: C[Al](C)C
Agent: Cl
Solvent: CCCCCC
Solvent: ClCCl
Product: CCOC(=O)c1cccc(S(=O)(=O)NC(=O)Nc2nc(C)nc(OC)n2)c1I
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32.2 %

Procedure:
14 mmol of trimethylaluminum (7 ml of a 2M solution in hexane) are added dropwise under a nitrogen protective atmosphere to a suspension of 3.6 g of 3-ethoxycarbonyl-2-iodobenzenesulfonamide in 100 ml of absolute dichloromethane. The mixture is stirred at room temperature for 30 minutes, and 2.2 g of O-methyl (4-methyl-6-methoxy-1,3,5-triazin-2-yl)carbamate in 25 ml of dichloromethane are then added, and the mixture is refluxed for 13 hours. The solution is cooled to room temperature, 25 ml of 2N hydrochloric acid are added dropwise with ice-cooling, and the hydrochloric acid phase is extracted twice using dichloromethane. The organic phase is concentrated in vacuo, and the residue is treated with acetone and 100 ml of 10% aqueous sodium acetate solution. The mixture is stirred for 3 hours and then filtered off with suction, followed by a washing step with diethyl ether, the aqueous phase is brought to pH 2-3 using concentrated hydrochloric acid and stirred for 15 minutes, and the product is filtered off with suction. After drying in vacuo at 50° C., 1.7 g of ethyl 2-iodo-3-[[[[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)amino]carbonyl]amino]sulfonyl]-benzoate of m.p. 177°-9° C. are obtained.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:14][CH:13]=3)(O)[CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>>[N:1]1([CH2:6][CH:7]2[CH2:8][CH:9]([C:12]3[CH:13]=[CH:14][C:15]([CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:16][CH:17]=3)[CH2:10]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1(c2ccc(CN3CCCC3)cc2)CC(CN2CCCC2)C1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: c1cc(C2CC(CN3CCCC3)C2)ccc1CN1CCCC1
Temperature: 25 °C
Yield: 31 %

Procedure:
Alternatively, to a stirring solution of 3-pyrrolidin-1-ylmethyl-1-(4-pyrrolidin-1-ylmethyl-phenyl)-cyclobutanol (Example 8, General procedure B, Step D) (1.1 g, 3.5 mmol) in TFA (5.4 mL, 70.1 mmol) was added triethyl silane (5.6 mL, 35.0 mmol). The reaction was then heated to 75 □C (oil bath) for 14 hours. The reaction was then cooled to rt and concentrated under reduced pressure. The residual was taken up in CH2Cl2 and washed with NaHCO3. The aqueous layer was back extracted with 3:1 (CH3Cl:isopropanol). The combined organic layers were dried over MgSO4, filtered though a fritted funnel and concentrated under reduced pressure. Purification of this material was accomplished by flash column chromatography using a 40 M Biotage column, eluting with a gradient of 10%–20% MeOH/CH2Cl2 with 0.3% NH4OH. The product containing fractions were collected and concentrated to give the title compound (324 mg, 18%) as the bis-TFA salt. To this material in EtOAc was added a solution of HCl (2 eq, 2M THF). The resulting solution was stirred over night, and then filtered through a fritted funnel. The solid was collected and dried under reduced pressure to yield the title compound as the bis-HCl salt and as a mixture of isomers.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[C:10]=2[CH3:18])=[N:5]1.[CH3:20][N:21]1[CH:25]=[C:24]([C:26](O)=[O:27])[N:23]=[CH:22]1>>[Cl:17][C:11]1[C:10]([CH3:18])=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:26]([C:24]3[N:23]=[CH:22][N:21]([CH3:20])[CH:25]=3)=[O:27])[CH3:19])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: Cn1cnc(C(=O)O)c1
Reactant: Cc1c(-c2ccn(C[C@H](C)N)n2)ccc(C#N)c1Cl
Product: Cc1c(-c2ccn(C[C@H](C)NC(=O)c3cn(C)cn3)n2)ccc(C#N)c1Cl
Yield: 38.7 %

Procedure:
(S)—N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-1-methyl-1H-imidazole-4-carboxamide was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile (300 mg, 1.092 mmol) and 1-methyl-1H-imidazole-4-carboxylic acid (207 mg, 1.638 mmol). The product was purified twice by Flash-chromatography (normal phase and reverse phase). Yield 38.7%. 1H-NMR (400 MHz; CDCl3): δ 1.26 (d, 3H), 2.56 (s, 3H), 3.74 (s, 3H), 4.30-4.43 (m, 2H), 4.49-4.61 (m, 1H), 6.41 (d, 1H), 7.35 (d, 1H), 7.39 (d, 1H), 7.49-7.56 (m, 3H), 7.60 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:18](O)=[O:19])=[C:15]3[C:10]([CH:11]=[C:12]([F:28])[C:13]([F:27])=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH2:33]([O:35][C:36](=[O:49])[C:37]([O:40][C:41]1[CH:46]=[CH:45][C:44]([NH2:47])=[C:43]([F:48])[CH:42]=1)([CH3:39])[CH3:38])[CH3:34]>CN(C1C=CN=CC=1)C>[CH2:33]([O:35][C:36](=[O:49])[C:37]([O:40][C:41]1[CH:46]=[CH:45][C:44]([NH:47][C:18](=[O:19])[CH:17]([C:16]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:9]=[C:10]3[C:15]=2[CH:14]=[C:13]([F:27])[C:12]([F:28])=[CH:11]3)[CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)=[C:43]([F:48])[CH:42]=1)([CH3:39])[CH3:38])[CH3:34]
Reactant: O=C(O)C(c1c2cc(F)c(F)cc2nn1-c1ccc(Cl)cc1)C1CCCCC1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(N)c(F)c1
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C(C)(C)Oc1ccc(NC(=O)C(c2c3cc(F)c(F)cc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(F)c1

Procedure:
In analogy to the procedure described in example 6, [rac]-[2-(4-chloro-phenyl)-5,6-difluoro-2H-indazol-3-yl]-cyclohexyl-acetic acid (example 24.7) was converted into the corresponding acid chloride with thionyl chloride which subsequently reacted with 2-(4-amino-3-fluoro-phenoxy)-2-methyl-propionic acid ethyl ester in the presence of DMAP to give the title compound as brown solid. MS: m/e=628.3 [M+H+].
Reaction SMILES: [Br:1][C:2]1[C:3]([F:18])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13](C)([CH3:15])[CH3:14])[C:8]([CH3:17])=[N:7]2.BrC1C(F)=CC=C2C=1NC(=O)C(C)=N2.C(N)(C)C>CS(C)=O>[Br:1][C:2]1[C:3]([F:18])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][CH:13]([CH3:14])[CH3:15])[C:8]([CH3:17])=[N:7]2
Reactant: Cc1nc2ccc(F)c(Br)c2nc1NC(C)(C)C
Agent: Cc1nc2ccc(F)c(Br)c2[nH]c1=O
Solvent: CC(C)N
Solvent: CS(C)=O
Product: Cc1nc2ccc(F)c(Br)c2nc1NC(C)C
Yield: 91 %

Procedure:
This compound (594 mg, 1.99 mmol, 91% yield) as an orange crystalline solid was prepared according to the procedure described for Intermediate 605a, using 5-bromo-3-chloro-6-fluoro-2-methylquinoxaline (600) (600 mg, 2.17 mmol) and isopropylamine (0.94 mL, 10.9 mmol) in DMSO (5.0 mL) as the starting materials. 1H NMR (400 MHz, CDCl3) δ ppm 7.73 (1H, dd, J=9.0, 5.9 Hz), 7.15 (1H, t, J=8.6 Hz), 4.68-4.82 (1H, m), 4.52 (1H, dq, J=13.2, 6.5 Hz), 2.53 (3H, s), 1.39 (6H, d, J=6.5 Hz). 19F NMR (376 MHz, CDCl3) δ ppm −103.43 (1F, s). m/z (ESI, +ve ion) 298.5/300.6 (M+H)+.
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:27][C@H:26]([CH2:28][O:29][C:30]5[CH:34]=[CH:33][O:32][N:31]=5)[O:25][C:24]4=[O:35])=[CH:19][C:18]=3[F:36])=[CH:13][CH2:12]2)=[O:10])[CH2:4][O:3]1.Cl.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[OH:6][C@@H:5]([CH2:4][OH:3])[CH2:7][O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][C@H:26]([CH2:28][O:29][C:30]4[CH:34]=[CH:33][O:32][N:31]=4)[O:25][C:24]3=[O:35])=[CH:19][C:18]=2[F:36])=[CH:13][CH2:12]1)=[O:10]
Reactant: CC1(C)OC[C@@H](COC(=O)N2CC=C(c3ccc(N4C[C@H](COc5ccon5)OC4=O)cc3F)CC2)O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(OC[C@@H](O)CO)N1CC=C(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 86.3 %

Procedure:
3-(4-(1-(2,2-Dimethyl-1,3-dioxolan-4(S)-ylmethoxycarbonyl)-1,2,5,6-tetrahydro-4-pyridinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one (130 mg, 0.25 mmol) was dissolved in tetrahydrofuran (5 ml), treated with 2 M aqueous hydrochloric acid (2 ml), and stirred at ambient temperature for 72 hours. Excess potassium carbonate was added to remove acid and water, and the solution filtered. The filtrate was evaporated, and the residue purified by chromatography on a 10 g silica Biotage column, eluting with a gradient increasing in polarity from 0 to 10% MeOH in dichloromethane. Relevant fractions were combined and evaporated to give the desired product (103 mg). MS (ESP): 478 (MH+) for C22H24FN3O8.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([O:8][CH2:9][CH:10]([OH:13])[CH2:11][OH:12])=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:15]=[CH:14][C:7]([O:8][CH2:9][CH:10]([OH:13])[CH2:11][OH:12])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(OCC(O)CO)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(OCC(O)CO)cc1

Procedure:
A solution of 3-(4-nitrophenoxy)propane-1,2-diol (5.0 g) in absolute ethanol (250 ml) was hydrogenated at atmospheric pressure in the presence of 10% palladium on charcoal (150 mg). After the uptake of hydrogen had ceased, the catalyst was removed by filtration. The filtrate was evaporated under reduced pressure to give 3-(4-aminophenoxy)propane-1,2-diol as a solid which was used without further purification.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[NH2:18].C[Al](C)C.O.Cl>C(Cl)Cl>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]2[S:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[C:3](=[O:2])[NH:18][C:12]=2[CH:13]=1
Reactant: COC(=O)c1ccccc1Sc1ccc(Cl)cc1N
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: O=C1Nc2cc(Cl)ccc2Sc2ccccc21
Temperature: 25 °C
Reaction time: 144 h
Yield: 28.5 %

Procedure:
A mixture of 2-(2-amino-4-chlorophenylsulfanyl)-benzoic acid methyl ester (189JO11) (149 mg, 0.51 mmol) and AlMe3 (355 μL, 0.71 mmol, 2 M in toluene) in CH2Cl2 (3 mL) was stirred at ambient temperature for six days, and then water was added carefully. The mixture was diluted with CH2Cl2, and was acidified with 2 M aqueous HCl. The organic phase was separated, dried (Na2SO4), concentrated and flash chromatographed (heptane:EtOAc, 5:1-3:1) to give 38 mg (29%) of the title compound (189JO13). MS (ESI) 262 (MH+).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([N:11]([CH:27]2[CH2:29][CH2:28]2)[C:12](=[O:26])[C:13]2[CH:18]=[CH:17][C:16]([C@@:19]([OH:25])([CH3:24])[C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)[CH2:7][CH2:6]1)#[N:2].[OH-].[K+].C([OH:36])CCC>O>[NH2:2][C:1](=[O:36])[CH2:3][CH2:4][CH:5]1[CH2:6][CH2:7][CH:8]([N:11]([CH:27]2[CH2:28][CH2:29]2)[C:12](=[O:26])[C:13]2[CH:14]=[CH:15][C:16]([C@@:19]([OH:25])([CH3:24])[C:20]([F:21])([F:22])[F:23])=[CH:17][CH:18]=2)[CH2:9][CH2:10]1
Reactant: CCCCO
Reactant: C[C@](O)(c1ccc(C(=O)N(C2CCC(CCC#N)CC2)C2CC2)cc1)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: C[C@](O)(c1ccc(C(=O)N(C2CCC(CCC(N)=O)CC2)C2CC2)cc1)C(F)(F)F
Temperature: 85 °C
Reaction time: 15 h

Procedure:
To (S)-N-(4-(2-cyanoethyl)cyclohexyl)-N-cyclopropyl-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamide prepared above (0.040 g, 0.098 mmol) and KOH (0.55 g, 0.98 mmol) was added tent-butanol (3.75 mL). The mixture was heated to 85° C. and stirred for 15 h. The solution was diluted with water (10 mL) and extracted with 10% MeOH in CH2Cl2 (2×15 mL). The combined organics were dried over Na2SO4 and removed in vacuo. Silica gel chromatography (gradient of 0-10% MeOH in CH2Cl2) afforded (S)-N-(4-(3-amino-3-oxopropyl)cyclohexyl)-N-cyclopropyl-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamide. 1H NMR (500 MHz, CD3OD): δ 0.45 (bs, 2H), 0.58 (bs, 2H), 1.05-1.15 (m, 2 H), 1.27-1.48 (m, 2H), 1.51-1.59 (m, 2H), 1.77 (s, 3H), 1.90-2.00 (m, 5H), 2.25-2.28 (m, 2H), 2.71 (bs, 1H), 4.00 (bs, 1H), 7.52 (d, J=8 Hz, 2H), 7.70 (d, J=8 Hz, 2H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][C@@H:10]1[C:33](=[O:34])[N:12]2[C:13]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=[O:21])=[C:14]([N:17]=[N+]=[N-])[CH2:15][S:16][C@H:11]12)=[O:8].[CH3:35][C:36](C)=[O:37]>C(O)C>[N+:30]([C:27]1[CH:28]=[CH:29][C:24]([CH2:23][O:22][C:20]([CH:13]2[N:17]=[C:14]([O:37][CH2:36][CH3:35])[CH2:15][S:16][CH:11]3[N:12]2[C:33](=[O:34])[CH:10]3[NH:9][C:7](=[O:8])[CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[O:21])=[CH:25][CH:26]=1)([O-:32])=[O:31]
Reactant: CC(C)=O
Reactant: [N-]=[N+]=NC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Solvent: CCO
Product: CCOC1=NC(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(NC(=O)Cc3cccs3)C2SC1

Procedure:
A solution of 2.53 g of p-nitrobenzyl 7β-[(2-thienylacetyl)amino]-3-azido-3-cephem-4-carboxylate in 50 ml. of acetone and 50 ml. of ethyl alcohol was heated at the reflux temperature for 1.25 hr. and thereafter the solution was evaporated to dryness. The crude product showed three spots on a thin layer chromatogram. The predominant 4-ethoxy-1,3-diaza isomer (title compound) was separated from the other isomer by chromatography over 15 g. of silica gel using 600 ml. of toluene vs 600 ml. of 75% ethyl acetate-toluene. The title compound was obtained crystalline as fine white needles (0.713 g.) melting at about 154° C. to about 155° C. after recrystallization from methylethyl ketone-hexane.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[CH3:16][C:17]1[CH:18]=[C:19]([CH2:29][NH2:30])[N:20]=[N:21][C:22]=1[O:23][CH2:24][C:25]([F:28])([F:27])[F:26]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:30]([CH2:29][C:19]3[N:20]=[N:21][C:22]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[C:17]([CH3:16])[CH:18]=3)[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: Cc1cc(CN)nnc1OCC(F)(F)F
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: Cc1cc(CN2Cc3c(ccnc3Cl)C2=O)nnc1OCC(F)(F)F
Yield: 51 %

Procedure:
The title compound is prepared in 51% yield (170 mg, off white solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (250 mg, 0.90 mmol, Step-1 of Intermediate-1) and (5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methanamine hydrochloride (230 mg, 0.90 mmol, Amine-50) in a similar manner to Intermediate-2.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1([CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.Cl[C:22]([O:24][CH:25]([Cl:27])[CH3:26])=[O:23].CN1CCOCC1>ClCCl>[Cl:27][CH:25]([O:24][C:22]([NH:2][CH2:3][C:4]1([CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)=[O:23])[CH3:26]
Reactant: NCC1(CC(=O)OCc2ccccc2)CCCCC1
Reactant: CC(Cl)OC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(Cl)OC(=O)NCC1(CC(=O)OCc2ccccc2)CCCCC1
Temperature: 15 °C
Yield: 100.6 %

Procedure:
In a 5-liter, 3-neck, round bottom flask, stirred mechanically and under nitrogen, was added dichloromethane (1.5 L), compound (6) (1.85 mol) and l-chloroethyl chloroformate (258 g, 1.81 mol). The resulting solution was cooled to 15° C. and N-methylmorpholine (396 mL, 3.60 mol) was added slowly, with cooling, over a one hour period. The resulting turbid solution was stirred for 30 min, after which 1H-NMR analysis showed the reaction to be complete. The reaction mixture was washed with water (2×2 L) and brine (1 L) and dried over sodium sulfate. Evaporation of the solvent afforded the title compound (9) as an orange oil (670 g, 98% yield). 1HNMR (CDCl3, 400 MHz): 1.33–1.53 (m, 10H), 1.75 (d, 3H), 2.33 (s, 2H), 3.18 (d, 2H), 5.09 (s, 2H), 5.58 (t, 1H), 6.53 (q, 1H), 7.29–7.33 (m, 5H).
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH3:6])=[O:4].[S:7]([O-:10])([O-:9])=[O:8].[Na+:11].[Na+]>O>[CH3:6][O:5][C:3]([CH2:2][S:7]([O-:10])(=[O:9])=[O:8])=[O:4].[Na+:11]
Reactant: O=S([O-])[O-]
Reactant: COC(=O)CCl
Agent: [Na+]
Solvent: O
Product: COC(=O)CS(=O)(=O)[O-]
Reaction time: 56 h

Procedure:
A slurry of 217 g (2 mols) methyl chloroactate and 252 g (2 mols) sodium sulfite in 500 ml water was stirred and heated under reflux for about 2 hours. The resulting solution was allowed to stand at about 25° C. for 56 hours and then evaporated under reduced pressure to give solid residue. The residue was washed with acetone and dried under vacuum at 80°-90° C. to give crude sodium methoxycarbonylmethylsulfonate salt.
Reaction SMILES: [F:1][C:2]1[C:23]([O:24][CH3:25])=[C:22]([F:26])[C:5]2[N:6]=[C:7]([NH:9][C:10]([C:12]3[N:13]=[CH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][CH:18]=[CH:17][CH:16]=4)=[O:11])[NH:8][C:4]=2[C:3]=1[C:27](O)=[O:28].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.S(O)(O)(=O)=O.[NH2:68][C:69]1[NH:70][CH:71]=[CH:72][N:73]=1>CN(C=O)C.[Cl-].[Na+].O>[F:26][C:22]1[C:5]2[N:6]=[C:7]([NH:9][C:10]([C:12]3[N:13]=[CH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][CH:18]=[CH:17][CH:16]=4)=[O:11])[NH:8][C:4]=2[C:3]([C:27](=[O:28])[NH:68][C:69]2[NH:70][CH:71]=[CH:72][N:73]=2)=[C:2]([F:1])[C:23]=1[O:24][CH3:25]
Reactant: Nc1ncc[nH]1
Reactant: COc1c(F)c(C(=O)O)c2[nH]c(NC(=O)c3cc4ccccc4cn3)nc2c1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(F)c(C(=O)Nc2ncc[nH]2)c2[nH]c(NC(=O)c3cc4ccccc4cn3)nc2c1F
Yield: 34.5 %

Procedure:
60 mg (0.15 mmol) of the above 5,7-difluoro-2-[(isoquinoline-3-carbonyl)-amino]-6-methoxy-3H-benzoimidazole-4-carboxylic acid and 100 mg (0.25 mmol) of HBTU were dissolved in 1.0 mL of DMF and 0.5 mL of DIEA and treated with 68 mg (0.5 mmol) of 2-aminoimidazole sulfate as described in general procedure A. Upon completion, the reaction was diluted with brine. The resulting solid was filtered, washed with water and EtOAc, and dried under vacuum to produce 24 mg (35%) of isoquinoline-3-carboxylic acid [4,6-difluoro-7-(1H-imidazol-2-ylcarbamoyl)-5-methoxy-1H-benzoimidazol-2-yl]-amide. LCMS: 464 (M+1)+.