Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Mg]Cl)(C)C.I[C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1.[O:15]=[C:16]1[CH2:19][O:18][CH2:17]1.[Cl-].[NH4+]>C(OCC)C.C1COCC1.O>[OH:15][C:16]1([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[CH2:19][O:18][CH2:17]1
Reactant: N#Cc1ccc(I)cc1
Reactant: O=C1COC1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: N#Cc1ccc(C2(O)COC2)cc1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
Under inert conditions, 11 ml (21.8 mmol) of a 2 M solution of isopropylmagnesium chloride in diethyl ether were added dropwise at −40° C. to a solution of 5.0 g (21.8 mmol) of 4-iodobenzonitrile in 100 ml of anhydrous THF. After the mixture had been stirred at the same temperature for 1.5 h, it was cooled down to −78° C. and, with the aid of a cannula, was slowly added to a solution, likewise cooled to −78° C., of 2.95 g (32.7 mmol, 80% in dichloromethane) of 3-oxooxetane [G. Wuitschik et al., Angew. Chem. Int. Ed. Engl. 2006, 45 (46), 7736-7739] in 100 ml of anhydrous THF. After the addition had ended, the reaction mixture was stirred first at −78° C. for 10 min, then at 0° C. for 2 h and finally at RT for 30 min. Then a few ml of saturated aqueous ammonium chloride solution were added. Subsequently, the solvent was substantially removed on a rotary evaporator. The residue obtained was diluted with 200 ml of water and extracted three times with approx. 200 ml each time of ethyl acetate. The combined organic extracts were washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulphate, the mixture was filtered and the solvent was removed on a rotary evaporator. The resulting crude product was purified by crystallization from 10:1 cyclohexane/ethyl acetate. 2.42 g (63% of theory) of the title compound were obtained.
Reaction SMILES: COCC1C=C([NH2:10])C=CC=1N.N.[N+:13]([C:16]1[CH:21]=[CH:20][C:19](Cl)=[CH:18][C:17]=1[CH2:23][O:24][CH3:25])([O-:15])=[O:14]>>[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([NH2:10])=[CH:18][C:17]=1[CH2:23][O:24][CH3:25])([O-:15])=[O:14]
Reactant: COCc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: COCc1cc(N)ccc1N
Agent: N
Product: COCc1cc(N)ccc1[N+](=O)[O-]

Procedure:
Another embodiment of the present application relates to a method of making 2-methoxymethyl-1,4-benzenediamine comprising the steps: (a) introducing ammonia to a 4-nitro-3-methoxymethyl-chlorobenzene to obtain 4-nitro-3-methoxymethyl-aminobenzene; and (b) hydrogenating the 4-nitro-3-methoxymethyl-aminobenzene in the presence of a hydrogenation catalyst to obtain the 2-methoxymethyl-1,4-benzenediamine.
Reaction SMILES: [C:1]1([CH:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[N:19]=[C:18]3[NH2:26])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>CC1C=CC=CC=1>[C:27]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[NH:19][C:18]3=[N:26][C:33](=[O:35])[CH3:34])[CH2:10][CH2:9]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc2ccccc2n1CCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Solvent: Cc1ccccc1
Product: CC(=O)N=c1[nH]c2ccccc2n1CCCN1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
A mixture of 10.7 parts of 1-{3-[4-(diphenylmethyl)piperazinyl]propyl}-1H-benzimidazol-2-amine, 5.1 parts of acetic acid anhydride and 90 parts of methylbenzene is stirred and refluxed for 5 hours. The reaction mixture is evaporated and the residue is stirred in water. The whole is alkalized with ammonium hydroxide and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from ethanol. The product is filtered off and dried, yielding N-[1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-ylidene]acetamide; mp. 143.3° C.
Reaction SMILES: C([O:5][C:6]([C@H:8]([C@@H:18]([CH2:54][CH:55]([CH3:57])[CH3:56])[C:19]([NH:21][N:22]([CH2:50][CH:51]([CH3:53])[CH3:52])[C:23](=[O:49])[C@@H:24]([CH2:43][O:44]C(C)(C)C)[NH:25][C:26]([O:28][CH2:29][CH:30]1[C:42]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[C:36]2[C:31]1=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:27])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:6]([C@H:8]([C@@H:18]([CH2:54][CH:55]([CH3:57])[CH3:56])[C:19]([NH:21][N:22]([CH2:50][CH:51]([CH3:52])[CH3:53])[C:23](=[O:49])[C@@H:24]([CH2:43][OH:44])[NH:25][C:26]([O:28][CH2:29][CH:30]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:36]=2[C:37]2[C:42]1=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:27])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([OH:7])=[O:5]
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)[C@@H](COC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)[C@@H](CO)NC(=O)OCC1c2ccccc2-c2ccccc21)[C@H](C/C=C/c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 86.7 %

Procedure:
A solution of 1.05 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-2′-isobutyl-2′-[N-(9-fluorenylmethyloxycarbonyl)-O-tert.butyl-D-seryl]-4-methylvalerohydrazide in 5 ml of dichloromethane was treated at room temperature under nitrogen with 5 ml of trifluoroacetic acid. The mixture was stirred at room temperature for 2.5 hours and evaporated. Final traces of trifluoroacetic acid were removed by the addition and evaporation of three 10 ml portions of toluene. The residue in diethyl ether was treated with hexane to yield 0.78 g of (E)-2(R)-[1(S)-(carboxy)-4-phenyl-3-butenyl]-2′-isobutyl-2′[N-(9-fluorenylmethyloxycarbonyl)-D-seryl]-4-methylvalerohydrazide as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([N:18]([CH2:38][CH:39]([CH3:41])[CH3:40])[C@H:19]1[CH2:24][C@@H:23]([C:25](=[O:30])N(OC)C)[CH2:22][N:21]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:20]1)=[O:17].[Cl-].[NH4+].[CH2:44]1COC[CH2:45]1>>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([N:18]([CH2:38][CH:39]([CH3:40])[CH3:41])[C@H:19]1[CH2:24][C@@H:23]([C:25](=[O:30])[CH2:44][CH3:45])[CH2:22][N:21]([C:31]([O:33][C:34]([CH3:37])([CH3:35])[CH3:36])=[O:32])[CH2:20]1)=[O:17]
Reactant: C1CCOC1
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N(C)OC)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Product: CCC(=O)[C@@H]1C[C@H](N(CC(C)C)C(=O)c2nc3ccccc3n2CCCCOC)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of tert-butyl (3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate (22.7 g) in THF (20 ml) was added 1Methylmagnesium bromide-THF solution (119 ml) at room temperature, and the mixture was stirred at room temperature for 5 hr. The reaction mixture was poured into saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:9-3:2) was concentrated under reduced pressure to give the object product (14.96 g).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([O:27][CH2:28][P:29]([O:34][CH2:35][CH3:36])([O:31][CH2:32][CH3:33])=[O:30])[CH2:11][O:12][NH:13][C:14]1[N:19]=[C:18]([NH:20][CH:21]=[O:22])[N:17]=[C:16]([Cl:23])[C:15]=1[NH:24][CH:25]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OC(OCC)OCC)(=O)C>[CH2:1]([O:8][CH2:9][CH:10]([O:27][CH2:28][P:29]([O:34][CH2:35][CH3:36])([O:31][CH2:32][CH3:33])=[O:30])[CH2:11][O:12][N:13]1[CH:25]=[N:24][C:15]2[C:14]1=[N:19][C:18]([NH:20][CH:21]=[O:22])=[N:17][C:16]=2[Cl:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOP(=O)(COC(COCc1ccccc1)CONc1nc(NC=O)nc(Cl)c1NC=O)OCC
Agent: CCOC(OCC)OC(C)=O
Product: CCOP(=O)(COC(COCc1ccccc1)COn1cnc2c(Cl)nc(NC=O)nc21)OCC
Temperature: 120 °C
Yield: 74.4 %

Procedure:
A solution of 6-[3-benzyloxy-2-(diethoxyphosphorylmethoxy)propoxyamino]-4-chloro-2,5-diformamidopyrimidine (760 mg, 1.4 mmol) in diethoxymethyl acetate (2 ml) was stirred and heated in an oil bath at 120° C. for 2 hours. After cooling to ambient temperature, the solvent was evaporated and the residue dissolved in methanol (10 ml) and 0.880 ammonia (1 ml). After 15 minutes at ambient temperature the solution was evaporated to dryness. The residue obtained was chromatographed on silica gel (dichloromethane/methanol, 98:2 as eluant) to give the title compound as a colourless oil (550 mg, 75%). IR: νmax (film), 3400, 3220, 3110, 2980, 2900, 1710, 1610, 1580, 1510, 1475, 1440, 1385, 1330, 1240, 1160, 1140, 1095, 1050, 1020, 980, 920, 820, 780, 740, 700 cm-1. 1H NMR: δH [(CD3)2SO] 1.20, 1.21 (6H, 2×t, P-(OCH2CH3)2), 3.6-3.75 (2 H, m, CHCH2), 3.8-4.15 (7H, m, CH2CHCH2, OCH2P, P-(OCH2CH3)2), 4.52 (2H, s, OCH2Ph), 4.45-4.65 (2H, m, N-OCH2), 7.25-7.40 (5H, m, Ph), 8.81 (1H, s, H-8), 9.37 (1H, br.s, NHCHO), 11.31 (1H, br.s, D2O exchangeable NHCHO). Found: C, 48.11; H, 5 37; N, 12.50%. C21H27N5O7PCl requires: C, 47.77; H, 5.16; N, 13.27%. m/z: C21H28N5O7PCl requires 528.1415; observed 528.1363 (M +H+).
Reaction SMILES: C([Li])CCC.[CH2:6]([OH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:14]1([NH:20][C:21]2[CH:30]=[C:29]3[C:24]([C:25](=[O:39])[C:26]([C:36]([OH:38])=[O:37])=[CH:27][N:28]3[CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[C:23](F)[C:22]=2[F:41])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.Cl>C1(C)C=CC=CC=1.C1COCC1>[CH2:6]([O:13][C:23]1[C:22]([F:41])=[C:21]([NH:20][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)[CH:30]=[C:29]2[C:24]=1[C:25](=[O:39])[C:26]([C:36]([OH:38])=[O:37])=[CH:27][N:28]2[CH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)c1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)c(F)c2c1=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(O)c1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)c(OCc3ccccc3)c2c1=O
Reaction time: 1 h

Procedure:
Under ice-cooling, 3.2 ml of n-butyl lithium (1.60 M hexane solution) was added to a 2.4 ml THF solution of 0.58 ml benzyl alcohol, followed by stirring for 1 hour. The solvent was evaporated under a reduced pressure, followed by the addition of 8.0 ml of toluene for suspension. The suspension prepared was added to a toluene suspension of 400 mg of 7-(cyclohexylamino)-1-cyclopentyl-5,6-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, which was prepared in a separate container, followed by stirring at room temperature for 6 hours. Then, 1 M hydrochloric acid was added to the reaction mixture, followed by extraction with chloroform and washing with aqueous saturated sodium chloride. After drying over anhydrous sodium sulfate and subsequent filtration, the solvent was evaporated under a reduced pressure. By recrystallizing the resulting residue using ethyl acetate, 400 mg of 5-(benzyloxy)-7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid was obtained.
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[C:11]([OH:22])[CH:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].C1([O-])C=CC=CC=1.[Na+].[C:34](Cl)(=[O:39])[CH2:35][CH:36]([CH3:38])[CH3:37]>>[C:1]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[C:11]([O:22][C:34](=[O:39])[CH2:35][CH:36]([CH3:38])[CH3:37])[CH:10]=1)=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NCC(=O)c1ccc(OC(=O)C(C)(C)C)c(O)c1
Reactant: CC(C)CC(=O)Cl
Agent: C[O-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Product: CC(C)CC(=O)Oc1cc(C(=O)CNC(C)(C)C)ccc1OC(=O)C(C)(C)C

Procedure:
Following a procedure similar to that described in Example 2A above, when 3-hydroxy-4-(pivalyloxy)phenyl tert-butylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted with isovaleryl chloride there is obtained 3-(isovaleryloxy)-4-(pivalyloxy)phenyl tert-butylaminomethyl ketone, which reacts with hydrochloric acid to yield the hydrochloride salt as a white crystalline solid, m.p. 216-220° C. (uncorr.).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]([NH:15][C:16](=[O:38])[CH2:17][CH:18]([NH:26][S:27]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=1)(=[O:29])=[O:28])[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[CH2:10][CH2:9][CH2:8]2.[CH:39](=O)[CH:40]([CH3:42])[CH3:41].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CC(O)=O>[Cl:37][C:32]1[CH:31]=[C:30]([S:27]([NH:26][CH:18]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH2:17][C:16]([NH:15][CH:11]2[C:12]3[C:7](=[CH:6][C:5]([CH2:4][CH2:3][CH2:2][NH:1][CH2:39][CH:40]([CH3:42])[CH3:41])=[CH:14][CH:13]=3)[CH2:8][CH2:9][CH2:10]2)=[O:38])(=[O:29])=[O:28])[CH:35]=[CH:34][C:33]=1[Cl:36]
Reactant: CC(C)C=O
Reactant: NCCCc1ccc2c(c1)CCCC2NC(=O)CC(NS(=O)(=O)c1ccc(Cl)c(Cl)c1)c1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)CNCCCc1ccc2c(c1)CCCC2NC(=O)CC(NS(=O)(=O)c1ccc(Cl)c(Cl)c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-[6-(3-aminopropyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-3-(3,4-dichloro-benzenesulfonylamino)-3-(4-fluoro-phenyl)-propionamide(63 mg, 0.109 mmol) in dry CH2Cl2 (5 mL) was added isobutyraldehyde (10 μL, 0.109 mmol) and HOAc (1 drop). The resulting mixture was stirred at RT under N2 After 1 h, MS showed the formation of imine; NaBH(OAc)3 (46 mg, 0.218 mmol) was then added. The resulting mixture was stirred for 10 min. The reaction mixture was quenched with sat. NaHCO3. The organic layer was dried over MgSO4 and evaporated in vacuo. The crude solid was purified by chromatography on silica gel. Elution with CH2Cl2:MeOH(2M NH3) mixture (95:5) gave final compound. MS m/z: 635.11 (M+H). Calc'd. for C32H38Cl2FN3O3S-634.63.
Reaction SMILES: ClC(OCC(C)C)=O.CN1CCOCC1.[CH3:16][O:17][C:18](=[O:28])[C@H:19]([CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:20][C:21]([OH:23])=O.[CH2:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31][NH:30]1.[Cl-].[Na+]>ClCCl>[CH3:16][O:17][C:18](=[O:28])[CH:19]([CH2:20][C:21]([N:30]1[CH2:31][CH2:32][C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:29]1)=[O:23])[CH2:24][CH:25]([CH3:27])[CH3:26]
Reactant: c1ccc2c(c1)CCNC2
Reactant: COC(=O)[C@@H](CC(=O)O)CC(C)C
Agent: CC(C)COC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)C(CC(=O)N1CCc2ccccc2C1)CC(C)C
Temperature: -15 °C
Reaction time: 0.25 h

Procedure:
iso-Butyl chloroformate (33.64 mg, 0.2463 mmol) in dichloromethane (2 ml) and N-methyl morpholine (49.83 mg, 0.4927 mmol) in dichloromethane (2 ml) were simultaneously added to a stirred solution of (R)-2-isobutyl succinic acid 1-methyl ester (42.15 mg, 0.2239 mmol) in dichloromethane (2 ml) at −15° C. under argon over 5 minutes. The mixture was stirred at −15° C. for 15 minutes. A freshly prepared solution of 1,2,3,4-tetrahydro-isoquinoline (29.83 mg, 0.2239 mmol) in dichloromethane (2 ml) and N-methylmorpholine (24.92 mg, 0.2463 mmol) was then added dropwise. The mixture was then stirred at ambient temperature for 16 hours. The reaction mixture was poured into saturated aqueous sodium chloride solution (1 ml). The aqueous layer was extracted with diethyl ether (2×5 ml) which was discarded. The aqueous layer was acidified with 1M hydrochloric acid to pH (12), then the product was extracted into dichloromethane (3×5 ml). The combined dichloromethane layers were washed with water (2×5 ml), saturated aqueous sodium chloride solution (2×5 ml) then dried (Na2SO4). The solvent was removed in vacuo to give a residue which was purified over silica gel eluting with a gradient of n-heptane:ethyl acetate 4:1. Desired fractions were combined and reduced in vacuo to leave 2-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]-4-methyl-pentanoic acid methyl ester as a colourless oil (35 mg, 51.5% from starting acid). TLC (single UV spot, Rf=0.6, n-heptane:ethyl acetate 1:1), HPLC-MS (single UV peak with Rt=9.544 mins, 304.2 [M+H]+, 305.2 [M+2]+, 306.2 [M+3]+, 629.3 [2M+Na]+.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[F:16])[C:10]([OH:12])=[O:11].[CH3:17][S:18]SC>O1CCCC1.CCOCC>[F:6][C:7]1[C:8]([S:18][CH3:17])=[C:9]([CH:13]=[CH:14][C:15]=1[F:16])[C:10]([OH:12])=[O:11]
Reactant: O=C(O)c1ccc(F)c(F)c1
Reactant: CSSC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CSc1c(C(=O)O)ccc(F)c1F
Temperature: -70 °C
Reaction time: 2 h
Yield: 83.1 %

Procedure:
n-Butyllithium (2.5 m in hexane, 35 ml) was added with cooling to a solution of 3,4-difluorobenzoic acid (5.5 g) in dry tetrahydrofuran while maintaining the temperature below -70° C. The mixture was stirred for 2 hours at -70° C. A solution of dimethyl disulphide (19.8 g) in tetrahydrofuran was added and the mixture was stirred at -70° C. for 1.5 hours. It was allowed to warm to room temperature, diluted with ether and washed with water. The aqueous layer was acidified to pH 1 and extracted with ether, washed with water, dried (anhydrous MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was recrystallised from a mixture of cyclohexane and ether to give 3,4-difluoro-2-(methylsulphenyl)benzoic acid (5.9 g) as a white solid, m.p. 149.2°-149.6° C.
Reaction SMILES: [OH:1][C@@H:2]([CH3:15])[CH2:3][NH:4][C:5]1[C:10]([CH:11]=O)=[CH:9][N:8]=[C:7]([S:13][CH3:14])[N:6]=1.C[O:17][C:18](=O)[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:28][C:22]1[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=1[O:20][C:19]1[C:18](=[O:17])[N:4]([CH2:3][C@@H:2]([OH:1])[CH3:15])[C:5]2[N:6]=[C:7]([S:13][CH3:14])[N:8]=[CH:9][C:10]=2[CH:11]=1
Reactant: COC(=O)COc1ccc(F)cc1F
Reactant: CSc1ncc(C=O)c(NC[C@H](C)O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1ncc2cc(Oc3ccc(F)cc3F)c(=O)n(C[C@H](C)O)c2n1
Temperature: 60 °C
Yield: 108.3 %

Procedure:
To a mixture of 4-((S)-2-hydroxy-propylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde (16.5 g, 73 mmol) and (2,4-difluorophenoxy)acetic acid methyl ester (29.4 g, 145 mmol) in anhydrous dimethyl formamide (300 mL) was added potassium carbonate (30 g, 218 mmol). The reaction mixture was heated to 60° C. and after 18 hours, the reaction mixture was cooled and the dimethylformamide was distilled off under vacuum. Crude residue suspended in water (300 mL) and extracted with dichloromethane, washed with brine and dried over magnesium sulfate. Filtered and concentrated under vacuum to give 41 g crude material which was chromatographed on silica gel column eluding with 1% methanol in dichloromethane to give 30 g 6-(2,4-difluorophenoxy)-8-((S)-2-hydroxypropyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (mass spec M+1=274).
Reaction SMILES: [CH:1]([C:3]1[C:4]([CH3:14])=[CH:5][C:6]([CH3:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])=[O:2].[CH:15]1(C2C(I)=CC(C(O)=O)=C(C)C=2)C[CH2:16]1.IC1C(C)=CC(C)=C(C=1)C(O)=O>>[CH:14]1([C:4]2[C:3]([CH:1]=[O:2])=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:13])[CH:5]=2)[CH2:16][CH2:15]1
Reactant: Cc1cc(C2CC2)c(I)cc1C(=O)O
Reactant: COC(=O)c1cc(C=O)c(C)cc1C
Agent: Cc1cc(C)c(C(=O)O)cc1I
Product: COC(=O)c1cc(C=O)c(C2CC2)cc1C

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 83.2, except 4-cyclopropyl-5-iodo-2-methylbenzoic acid (compound 86.3) was used in place of 5-iodo-2,4-dimethylbenzoic acid (compound 1.3).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][S:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:4]1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.C(N(CC)CC)C>ClCCl>[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22]([O:1][CH2:2][CH:3]2[CH2:7][S:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[N:4]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)NC1=NC(CO)CS1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CSC(NC(=O)OC(C)(C)C)=N2)cc1
Yield: 60.1 %

Procedure:
A solution of 0.8 g of tert-butyl N-[(4RS)-4-hydroxymethyl-4,5-dihydro-2-thiazolyl]carbamate, 0.76 g of p-toluenesulphonyl chloride and 0.56 cm3 of triethylamine in 25 cm3 of dichloromethane is stirred for 16 hours at a temperature in the region of 20° C. The solution obtained is concentrated under reduced pressure (1 kPa) at a temperature in the region of 40° C. The evaporation residue obtained is purified by chromatography at atmospheric pressure on a column of silica gel (particle size 60-200μ; diameter 2 cm; height 25 cm), eluting with a mixture of cyclohexane/ethyl acetate (70/30 by volume) and collecting 30 cm3 fractions. The fractions containing the expected product are combined and then concentrated under the above conditions. 0.8 g of tert-butyl N-[(4RS)-4-(p-toluenesulphonyloxymethyl)-4,5-dihydro-2-thiazolyl]carbamate is obtained in the form of a white solid [1H NMR spectrum (300 MHz, CD3l2, δ in ppm): 1.48 (s: 9H); 2.46 (s: 3H); 3.10 (dd, J=11.5 and 5.5 Hz: 1H); 3.33 (dd, J=11.5 and 8.5 Hz: 1H); 3.97 (dd, J=9.5 and 8 Hz: 1H); 4.06 (dd, J=9.5 and 4.5 Hz: 1H); 4.43 (mt: 1H); 7.36 (d, J=8 Hz: 2H); 7.80 (d, J=8 Hz: 2H); from 8.50 to 9.40 (very broad unresolved complex: 1H)].
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][C:17](=[O:24])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:11][C:10]=1[O:25][CH3:26])C1C=CC=CC=1.OC1C=C(CCC(=O)CCCCCCC)C=CC=1O>>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]([OH:24])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:11][C:10]=1[O:25][CH3:26]
Reactant: CCCCCCC(=O)C=Cc1ccc(OCc2ccccc2)c(OC)c1
Agent: CCCCCCCC(=O)CCc1ccc(O)c(O)c1
Product: CCCCCCC(O)CCc1ccc(O)c(OC)c1
Yield: 13.2 %

Procedure:
By following the same procedure as in Example 4 using 1.2 g of 1-(4-benzyloxy-3-methoxyphenyl)-1-nonen-3-one as a raw material, 660 mg of 1-(4-hydroxy-3-methoxyphenyl)-3-nonanone (a) as an oil and 120 mg of 1-(4-hydroxy-3-methoxyphenyl)-3-nonanol (b) as an oil were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4](Cl)=[O:5].[F:12][C:13]([F:40])([F:39])[C:14]([CH2:34][NH:35][CH2:36][CH2:37]C)([OH:33])[CH2:15][NH:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH:19]=[N:20][N:21]2[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([N:35]([CH2:36][CH3:37])[CH2:34][C:14]([CH2:15][NH:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH:19]=[N:20][N:21]2[C:26]1[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=1)([OH:33])[C:13]([F:12])([F:40])[F:39])=[O:5]
Reactant: Cc1cccc(Cl)c1C(=O)Cl
Reactant: CCCNCC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCN(CC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1c(C)cccc1Cl

Procedure:
Prepared similarly to Example 48 by reaction of 2-chloro-6-methylbenzoylchloride and 1,1,1-trifluoro-3-{[1-(4-fluorophenyl)-1H-indazol-4-yl]amino}-2-[(propylamino)methyl]-2-propanol in chloroform over 42 hours. Purification by mass directed autopreparation (System B) resulted in separation of atropisomers of the title compound: