Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][C:12]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:11][CH:10]=2)([O:3][CH2:4]C)=[O:2].[Na].O.[CH2:25](Cl)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CO>[CH2:25]([N:8]1[C:9]2[C:14](=[CH:13][C:12]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:11][CH:10]=2)[C:15](=[O:16])[C:6]([C:1]([O:3][CH3:4])=[O:2])=[CH:7]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)c1cnc2ccc(C3CCCCC3)cc2c1O
Reactant: ClCc1ccccc1
Agent: [Na]
Solvent: O
Solvent: CO
Product: COC(=O)c1cn(Cc2ccccc2)c2ccc(C3CCCCC3)cc2c1=O
Reaction time: 5 h

Procedure:
14 g of 3-carboethoxy-4-hydroxy-6-cyclohexyl-quinoline are added to a solution of 1.45 g of sodium in 150 ml of absolute methanol, whilst stirring, and the mixture is heated to the boil for 1 hour, with exclusion of water. 7.15 g of benzyl chloride are then added dropwise to the reaction mixture, which is boiled for a further 5 hours under reflux. It is then evaporated to dryness in vacuo and the residue is partitioned between 4 times 500 ml of chloroform and 500 ml of 1 N potassium hydroxide solution at 0°C. The organic phases are washed with twice 500 ml of water, dried over sodium sulphate and evaporated to dryness in vacuo. Repeated crystallisation of the evaporation residue from ethanol gives 1-benzyl-3-carbomethoxy-4-oxo-6-cyclohexyl-1,4-dihydroquinoline of melting point 211°-213°C.
Reaction SMILES: C([Li])CCC.BrN1C=CC=NC1.Br[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=1>O1CCCC1.C(OCC)C>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH:26]([C:25]2[CH:28]=[CH:29][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)[OH:27])[CH:15]=1
Reactant: Brc1cccnc1
Reactant: COc1ccc(C=O)cc1
Agent: BrN1C=CC=NC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(C(O)c2cccnc2)cc1
Temperature: -120 °C
Reaction time: 5 h

Procedure:
To a 500-ml 3-neck round bottom flask equipped with an addition funnel, septum, thermometer and an argon inlet is added 150 ml of anhydrous diethylether and 94 ml of 1.6 molar butyllithium solution (in hexane). The system is cooled to -120° C. and 23.8 gm of 3-bromopyrimidine in 75 ml of anhydrous tetrahydrofuran is added over 2 hours. After addition of the 3-bromopyridine, the system is stirred for an additional 45 minutes at this time, 18.3 ml of 4-methoxybenzaldehyde in 75 ml of tetrahydrofuran is added to the system while maintaining a temperature of -120° C. The system is kept at -120° C. for an additional 5 hours after addition of the 4-methoxy-benzaldehyde and afterwards the system is allowed to come to room temperature. After 10 hours at room temperature, the system is quenched with saturated ammonium chloride (in water). The system is adjusted to pH 2 with concentrated HCl solution. The solution is extracted with ether. The aqueous solution is then made basic with a 50% NaOH solution. The product is extracted with methylene chloride which then dried over sodium sulfate. The methylene chloride is removed by stripping and the residue triturated with hexane to give the 3-pyridyl-4-methoxyphenylcarbinol, which is converted to the compounds of this invention as described in Examples 1-7.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]([CH3:21])([CH3:20])[CH2:8][C:9]1[N:10]=[CH:11][N:12]([S:14]([N:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])[CH:13]=1.[F:22][C:23]([F:43])([C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][N:37]=2)=[CH:32][CH:31]=1)[C:24](N(OC)C)=[O:25]>O1CCCC1>[F:43][C:23]([F:22])([C:30]1[CH:31]=[CH:32][C:33]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][N:37]=2)=[CH:34][CH:35]=1)[C:24]([C:11]1[N:12]([S:14]([N:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])[CH:13]=[C:9]([CH2:8][C:7]([CH3:21])([CH3:20])[CH3:6])[N:10]=1)=[O:25]
Reactant: CN(C)S(=O)(=O)n1cnc(CC(C)(C)C)c1
Reactant: CON(C)C(=O)C(F)(F)c1ccc(-c2ccc(F)cn2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(=O)C(F)(F)c1ccc(-c2ccc(F)cn2)cc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
n-Butyllithium (1.6 M in hexane) (0.60 mL, 0.96 mmol) was added to a −78° C. solution of 4-(2,2-dimethylpropyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (234 mg, 0.96 mmol) in tetrahydrofuran (10 mL). After stirring at −78° C. for 10 min, 2,2-difluoro-2-[4-(5-fluoropyridin-2-yl)phenyl]-N-methoxy-N-methylacetamide (296 mg, 0.96 mmol) was added and the reaction allowed to warm to ambient temperature, quenched with water and extracted with methylene chloride and ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-50% ethyl acetate/hexane afforded 2-{difluoro[4-(5-fluoropyridin-2-yl)phenyl]acetyl}-4-(2,2-dimethylpropyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide.
Reaction SMILES: [CH2:1]([C:4]1[C:9]([OH:10])=[C:8]([Cl:11])[C:7]([Cl:12])=[C:6]([C:13]([C:15]2[N:19]([CH3:20])[N:18]=[CH:17][CH:16]=2)=[O:14])[CH:5]=1)[CH:2]=[CH2:3].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[CH2:1]([C:4]1[C:9]([O:10][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:8]([Cl:11])[C:7]([Cl:12])=[C:6]([C:13]([C:15]2[N:19]([CH3:20])[N:18]=[CH:17][CH:16]=2)=[O:14])[CH:5]=1)[CH:2]=[CH2:3]
Reactant: CCOC(=O)CBr
Reactant: C=CCc1cc(C(=O)c2ccnn2C)c(Cl)c(Cl)c1O
Product: C=CCc1cc(C(=O)c2ccnn2C)c(Cl)c(Cl)c1OCC(=O)OCC
Yield: 99.8 %

Procedure:
1.13 g of 6-allyl-2,3-dichloro-4-(1-methyl-5-pyrazolylcarbonyl)phenol and 0.67 g of ethyl bromoacetate are treated in the same manner as described in Example 1 to give 1.44 g of ethyl [6-allyl-2,3-dichloro-4-(1-methyl-5-pyrazolylcarbonyl)phenoxy]acetate. IRνmaxliquid (cm-1): 1755, 1735, 1665, 1640, 1585, 1550.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:18]=[CH:17][O:16][C:15]=2[CH2:19][OH:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N2CCN(CC2)C1.[S:29](Cl)([C:32]1[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=1)(=[O:31])=[O:30]>C(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:18]=[CH:17][O:16][C:15]=2[CH2:19][O:20][S:29]([C:32]2[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccoc2CO)CC1
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OCc2occc2C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 71 %

Procedure:
4-(2-Hydroxymethylfuran-3-yl)piperidine-1-carboxylic acid t-butyl ester (0.3 g, 1.1 mmol, 1.0 eq.) was dissolved in DCM (5.7 mL). The mixture was cooled to 0° C. and DABCO (132 mg, 1.2 mmol, 1.1 eq.) was added, followed by TsCl (224 mg, 1.2 mmol, 1.1 eq.). The mixture was stirred at 0° C. for 90 minutes, then diluted with EtOAc (500 ml) and washed with water (2×250 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation to yield the title compound (340 mg), which was used without further purification.
Reaction SMILES: [CH3:1][N:2]=[C:3]1[C:8]2[N:9]=[CH:10][S:11][C:7]=2[CH2:6][CH2:5][CH2:4]1.[H][H]>C(O)C.[Pt]=O>[CH3:1][NH:2][CH:3]1[C:8]2[N:9]=[CH:10][S:11][C:7]=2[CH2:6][CH2:5][CH2:4]1
Reactant: CN=C1CCCc2scnc21
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: CNC1CCCc2scnc21
Yield: 80 %

Procedure:
Catalytic hydrogenation of the 4-methylimino derivative obtained in step (e) in ethanol containing excess methylamine, in the presence of platinum oxide, proceeds slowly at 50° C. under ordinary pressure. After the theoretical amount of hydrogen has been taken up, the solution is filtered, evaporated, and the residue is distilled: B.p.0.4 =86°-88° C.; Yield; 80%.
Reaction SMILES: CN(C)C=O.[CH2:6]([O:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]=1)[CH2:7][CH2:8][CH3:9].CS(O[CH2:25][CH2:26][C:27]([CH3:31])=[C:28]([F:30])[F:29])(=O)=O.C(=O)([O-])O.[Na+]>O>[CH2:6]([O:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([O:17][CH2:25][CH2:26][C:27]([CH3:31])=[C:28]([F:30])[F:29])=[O:16])=[CH:13][N:12]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CC(CCOS(C)(=O)=O)=C(F)F
Reactant: CCCCOc1ccc(C(=O)O)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOc1ccc(C(=O)OCCC(C)=C(F)F)cn1
Temperature: 100 °C
Reaction time: 3 h
Yield: 75.2 %

Procedure:
To 5 ml of N,N-dimethylformamide were dissolved 0.39 g (2.0 mmol) of 6-butoxynicotinic acid, synthesized by a method in accordance with one used in Intermediate Production Example 1, and 0.40 g (2.0 mmol) of 4,4-difluoro-3-methyl-3-butenyl methanesulfonate, followed by the addition of 0.34 g (4.0 mmol) of sodium hydrogencarbonate and stirring at 100° C. for 3 hours. The reaction liquid was then poured in water and extracted with diethyl ether. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (diisopropyl ether:hexane=1:7) to obtain 0.45 g (yield: 75%) of 4,4-difluoro-3-methyl-3-butenyl 6-butoxynicotinate.
Reaction SMILES: CN(C=O)C.[H-].[Na+].[N+:8]([C:11]1[N:16]=[CH:15][C:14]2[CH:17]=[CH:18][O:19][C:13]=2[C:12]=1[OH:20])([O-:10])=[O:9].Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([C:32]2[C:33](=[O:45])[N:34]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[CH:35]=[CH:36][CH:37]=2)=[O:31])=[CH:25][CH:24]=1>O>[N+:8]([C:11]1[N:16]=[CH:15][C:14]2[CH:17]=[CH:18][O:19][C:13]=2[C:12]=1[O:20][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([C:32]2[C:33](=[O:45])[N:34]([C:38]3[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=3)[CH:35]=[CH:36][CH:37]=2)=[O:31])=[CH:25][CH:24]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ncc2ccoc2c1O
Reactant: O=C(Nc1ccc(CBr)cc1)c1cccn(-c2ccc(F)cc2)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(COc2c([N+](=O)[O-])ncc3ccoc23)cc1)c1cccn(-c2ccc(F)cc2)c1=O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Into a DMF (1.5 ml) suspension of NaH (11.0 mg, 60% suspension in oil, 0.275 mmol), which was cooled at 0° C. under an atmosphere of nitrogen, was added the DMF (1.5 ml) solution of 6-nitrofuro[3,2-c]pyridin-7-ol (Intermediate 7) (45.1 mg, 0.248 mmol) dropwise. The mixture was stirred at 0° C. for 5 min and was then raised to rt and stirred at rt for 30 min. Then this reaction mixture was added dropwise into the DMF (4 ml) suspension of 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (4-bromomethylphenyl)-amide (0.248 mmol) at rt under an atmosphere of nitrogen. The combined mixture was stirred at rt for 1 h. After that time, the reaction mixture was poured into water. The solid was filtered off and washed with water to give a beige solid. It was triturated with EtOAc (4 ml). The solid was filtered off and the mother liquor was purified by TLC eluting with 2.5% MeOH/DCM 2 times to give the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3): δ=5.58 (s, 2H), 6.59 (dd, J=6.8 & 7.2 Hz, 1H), 6.96 (d, J=2.4 Hz, 1H), 7.23-7.29 (m, 2H), 7.38-7.45 (m, 4H), 7.60 (dd, J=2.0 & 4.8 Hz, 1H), 7.73 (dd, J=2.4 & 6.8 Hz, 2H), 7.88 (d, J=2.0, 1H), 8.44 (s, 1H), 8.73 (dd, J=2.4 & 6.8 Hz, 1H), 11.84 (brs, 1H). MS (ES+): m/z 500.99 [MH+]. HPLC: tR=3.58 min (polar—5 min, ZQ3).
Reaction SMILES: O=[CH:2][C@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH2:27])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[CH2:13]([NH:27][CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@@H:3]1[OH:4])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCCCN
Reactant: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: CCCCCCCCCCCCCCNC1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O

Procedure:
20 g of D-mannose and 35 g of tetradecylamine were reacted as described in Example 44 to give N-tetradecylmannopyranosylamine. In a second reaction step, the glycosylamine (7.5 g) was reacted with 6.0 g of oleoyl chloride as described in Example 11 to give the glycosylamide.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[S:11][C:12]1[S:16][C:15]([C:17]([O:19]CC)=[O:18])=[CH:14][C:13]=1[N+:22]([O-:24])=[O:23]>O>[Cl:3][C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[S:11][C:12]1[S:16][C:15]([C:17]([OH:19])=[O:18])=[CH:14][C:13]=1[N+:22]([O-:24])=[O:23]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(Sc2cccc(Cl)c2Cl)s1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc([N+](=O)[O-])c(Sc2cccc(Cl)c2Cl)s1
Temperature: 25 °C
Reaction time: 72 h
Yield: 26.3 %

Procedure:
A solution of potassium hydroxide (72 mg, 1.27 mmol) in water (3.5 mL) was added to a suspension of ethyl 5-(2,3-dichlorophenylsulfanyl)-4-nitrothiophene-2-carboxylate (0.24 g, 0.63 mmol) in IMS (2 mL) and the resulting mixture was stirred at ambient temperature for 72 hours. After this time the mixture was diluted with water (4.5 mL) and washed the diethyl ether (2×5 mL). The aqueous phase was then acidified to pH 1 by the addition of 20% hydrochloric acid. The oil formed which solidified after stirring for 2 minutes. The mixture was left to stir for 1 hour then the solid was collected by filtration, washed with water (3×2 mL) and dried in vacuo at 40° C. overnight. The crude solid was absorbed onto silica and purified by chromatography over silica using ethyl acetate as eluent. The fractions containing the product were collected and the solvent removed under reduced pressure. The resulting solid was triturated with a small volume of diethyl ether, collected by filtration and dried in vacuo at 40° C. overnight to afford the title product as a yellow solid (58 mg, 26% yield). 1H NMR (d6-DMSO) δ: 8.08 (1H, s), 8.00 (2H, m), 7.64 (1H, m).
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]([CH3:13])=[C:8]([CH2:10][C:11]#N)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-:14].[Na+].CCO.[OH2:19]>>[C:1]([C:5]1[O:6][C:7]([CH3:13])=[C:8]([CH2:10][C:11]([OH:19])=[O:14])[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O
Reactant: Cc1oc(C(C)(C)C)nc1CC#N
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: Cc1oc(C(C)(C)C)nc1CC(=O)O

Procedure:
13.19 g of the above prepared (2-tert-butyl-5-methyl-oxazol-4-yl)-acetonitrile (74.0 mmol) was dissolved in 170 ml EtOH/water=1/1 and treated with 5 eq. of NaOH-pellets (14.8 g). Hydrolysis was allowed to proceed over night at 65° C. Pouring onto crashed ice/HCl, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, followed by evaporation of the solvents, yielded 13.77 g of the title acid as waxy solid.
Reaction SMILES: [C:1]1([C:7]2([CH2:20][O:21][CH2:22][C:23]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]4[C:24]=3[CH:25]=[CH:26][NH:27]4)[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:36]C(C)([O-])C.[K+].S(OC)(OC)(=O)=O>O1CCCC1>[CH3:36][N:27]1[C:28]2[C:24](=[C:23]([CH2:22][O:21][CH2:20][C:7]3([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[CH2:11][CH2:12]3)[CH:31]=[C:30]([C:32]([F:34])([F:35])[F:33])[CH:29]=2)[CH:25]=[CH:26]1
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(C(F)(F)F)cc3[nH]ccc23)(c2ccccc2)CC1
Agent: [K+]
Solvent: C1CCOC1
Solvent: COS(=O)(=O)OC
Product: Cn1ccc2c(COCC3(c4ccccc4)CCN(C(=O)OC(C)(C)C)CC3)cc(C(F)(F)F)cc21
Reaction time: 0.08 h

Procedure:
A solution of tert-butyl 4-phenyl-4-(((6-(trifluoromethyl)-1H-indol-4-yl)methoxy)methyl)piperidine-1-carboxylate (59 mg, 0.121 mmol) in tetrahydrofuran (5 ml) at 25° C. was treated with potassium tert-butoxide (13.6 mg, 0.121 mmol) and stirred for 5 minutes. Dimethyl sulfate (0.012 ml, 0.121 mmol) was added, the solution was stirred at 25° C. for 1 h, and then concentrated in vacuo. Column chromatography (ethyl acetate/hexanes gradient elution) afforded 45 mg (90%) as a colorless oil. Mass spec.: 503.17 (MH)+.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:11])[CH:6]=[CH:7][CH:8]=1.[C:23](=[S:25])=[S:24].[OH-].[K+].Cl[CH2:29][CH2:30][CH2:31]Cl>CS(C)=O.O.CCCCCC>[S:24]1[CH2:31][CH2:30][CH2:29][S:25][C:23]1=[C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:21])([F:22])[F:1])[CH:4]=1)[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:11]
Reactant: CCCCCCCCOC(=O)Cc1cccc(C(F)(F)F)c1
Reactant: ClCCCCl
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCCCOC(=O)C(=C1SCCCS1)c1cccc(C(F)(F)F)c1
Reaction time: 2 h

Procedure:
To a solution of n-octyl 3-trifluoromethylphenylacetate (112.2 g) in dimethyl sulphoxide (850 ml) there are added carbon disulphide (30.4 g) and, slowly, a solution of potassium hydroxide (60.0 g) in water (100 ml). The mixture is stirred for 2 hours at 40°. 1,3-dichloropropane (40.1 g) is then added and the mixture is stirred at 50° for 3 hours. Water (800 ml) and hexane (800 ml) are added, the two phases are separated and the aqueous solution is extracted with hexane (2×500 ml). The combined organic phases are washed with water (400 ml), dried over magnesium sulphate and evaporated. The residue is crystallized from pentane. The product is dried in vacuo to constant weight to yield n-octyl (1,3-dithian-2-ylidene)-(3-trifluoromethylphenyl)-acetate, m.p. 49° (as Example 11).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.[NH2:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([NH:28][CH:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:27])=[CH:24][C:23]=1[O:38][CH3:39].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)(C)C>ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>[CH:15]1([N:7]2[CH2:8][C:9]([F:14])([F:13])[C:10](=[O:12])[NH:11][C:5]3[CH:4]=[N:3][C:2]([NH:21][C:22]4[CH:37]=[CH:36][C:25]([C:26]([NH:28][CH:29]5[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]5)=[O:27])=[CH:24][C:23]=4[O:38][CH3:39])=[N:20][C:6]2=3)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C1Nc2cnc(Cl)nc2N(C2CCCC2)CC1(F)F
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Solvent: ClCCl
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2
Reaction time: 8 h
Yield: 62.3 %

Procedure:
A mixture of 0.040 g (0.1 mmole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-20), 0.029 g (0.11 mmole) of 4-amino-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide, 0.030 g (0.15 mmole) of p-toluenesulfonic acid monohydrate and 2 mL of isopropanol was stirred in a pressure tube at 140 degrees overnight. The mixture was cooled, diluted with dichloromethane and saturated sodium carbonate and extracted twice with dichloromethane. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (100:0-50:50) gave 0.033 g of give 4-(9-cyclopentyl-7,7-difluoro-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-137) as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[C:5](I)=[CH:4][N:3]=1.[F:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[C:18]([F:20])[CH:19]=1.[NH2:24][C:25]1[S:26][CH:27]=[C:28]([CH3:30])[N:29]=1>>[F:13][C:14]1[CH:15]=[C:16]([C:5]2[C:6]3[S:10][C:9]([CH3:11])=[N:8][C:7]=3[C:2]([NH:24][C:25]3[S:26][CH:27]=[C:28]([CH3:30])[N:29]=3)=[N:3][CH:4]=2)[CH:17]=[C:18]([F:20])[CH:19]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: Cc1csc(N)n1
Reactant: Cc1nc2c(Cl)ncc(I)c2s1
Product: Cc1csc(Nc2ncc(-c3cc(F)cc(F)c3)c3sc(C)nc23)n1

Procedure:
The title compound, MS: m/e=375.1 (M+H+), was prepared in accordance with the general method of example 2, step 1 and step 2 from 4-chloro-7-iodo-2-methyl-thiazolo[4,5-c]pyridine (Example B), 3,5-difluorophenylboronic acid and 2-amino-4-methylthiazole.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]=[C:6]([CH:12]([P:14](=[O:17])([OH:16])[OH:15])O)[C:5]2=[O:18].I>C(O)(=O)C>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]=[C:6]([CH2:12][P:14](=[O:15])([OH:16])[OH:17])[C:5]2=[O:18]
Reactant: O=c1c(C(O)P(=O)(O)O)coc2ccc(O)cc12
Agent: I
Solvent: CC(=O)O
Product: O=c1c(CP(=O)(O)O)coc2ccc(O)cc12
Temperature: 112.5 °C

Procedure:
[(6-Hydroxy-4-oxo-4H-chromen-3-yl)hydroxymethyl]phosphonic acid (10 mmol), prepared in accordance with Example 2d), hydroiodic acid (57%) (38 mmol) and red phosphorus (20 mmol) are added to acetic acid (100 ml). This mixture is heated at 110-115° C. until the reaction is complete. The hot reaction mixture is subsequently filtered, and the residue is washed twice with 10 ml of hot acetic acid. The filtrate is decolourised by addition of aqueous Na2SO3 solution. A solid precipitates at temperatures of 6 to 10° C. After filtration, the solid is washed with a little cold water and dried, giving [(6-hydroxy-4-oxo-4H-chromen-3-yl)methyl]phosphonic acid.
Reaction SMILES: [Br:1][C:2]1[C:8]([Cl:9])=[C:7]([F:10])[CH:6]=[C:5]([N+:11]([O-:13])=[O:12])[C:3]=1N.C(ON=O)(C)(C)C.[ClH:21]>C(#N)C>[Br:1][C:2]1[C:3]([Cl:21])=[C:5]([N+:11]([O-:13])=[O:12])[CH:6]=[C:7]([F:10])[C:8]=1[Cl:9]
Reactant: Cl
Reactant: Nc1c([N+](=O)[O-])cc(F)c(Cl)c1Br
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: O=[N+]([O-])c1cc(F)c(Cl)c(Br)c1Cl

Procedure:
To a mixture of anhydrous cupric chloride (147 g) and 2-bromo-3-chloro-4-fluoro-6-nitroaniline (235.6 g) in anhydrous acetonitrile (1.5 litter) was added tert-butylnitrite (135.2 g) at 60° C. during 70 minutes. The reaction mixture was poured into ice-chilled diluted hydrochloric acid (1.5 litter) and extracted with benzene. The organic layer was successively washed with ice-chilled diluted hydrochloric acid and water saturated with sodium chloride, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by distillation to give the title compound (218.8 g), bp 78°-117° C./2 mmHg. The oil was crystallized from methanol to give yellow prisms, mp 65.5°-67.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:22]2([OH:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:9]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:13][CH2:12]2)=O)[CH:5]=[CH:6][CH:7]=1.[ClH:29]>>[ClH:1].[ClH:29].[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:22]2([OH:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:9][N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[CH2:18][CH2:19][CH2:20][CH2:21]3)[CH2:13][CH2:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(C(c1cccc(Cl)c1)C1(O)CCCCC1)N1CCC(N2CCCC2)CC1
Agent: Cl
Product: OC1(C(CN2CCC(N3CCCC3)CC2)c2cccc(Cl)c2)CCCCC1

Procedure:
In an analogous manner to Example 1, step 21-[1-(3-chlorophenyl)-2-(4-pyrrolidin-1-ylpiperidin-1-yl)ethyl]cyclohexanoldihydrochloride was prepared from 1-[1-(3-chlorophenyl)-2-(4-pyrrolidin-1-ylpiperidin-1-yl)-2-oxoethyl]cyclohexanol. MS (ESI) m/z 391/393 ([M+H]+); HRMS: calcd for C23H35ClN2O.2.00 HCl, 462.1971; found (ESI), 391.2497.