Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([CH3:14])=[CH:12][C:11](=[O:15])[C:10]([C:16]([OH:18])=[O:17])=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26]1(O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>C1(C)C=CC=CC=1.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([CH3:14])=[CH:12][C:11](=[O:15])[C:10]([C:16]([O:18][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:17])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1cc(=O)c(C(=O)O)nn1-c1ccc(Cl)cc1
Reactant: Oc1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: Cc1cc(=O)c(C(=O)Oc2ccccc2)nn1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 19.1 %

Procedure:
To an ice cooled suspension of 5.29 g (0.02 mol) 1-(4-chlorophenyl)-1,4-dihydro-4-oxo-6-methyl pyridazine-3-carboxylic Acid (see Example 12) and 2.02 g (0.02 mol) of triethylamine in 125 ml of toluene there is added dropwise 3.13 g (0.02 mol) of phenyl chlorofomate. The suspension formed is stirred at room temperature for 15 minutes and to it there is added 1.88 g (0.02 mol) of phenol in 25 ml of toluene. The mixture is stirred at room temperature for 18 hrs. and to it there is added 100 ml of water. The suspension is stirred at room temperature for 2 hrs. and is poured into 800 ml of hexane. The suspension formed is stirred at room temperature for 3 hrs. and is vacuum filtered. The filter cake is slurried in 25 ml of toluene and is filtered. The filtrate is added to 150 ml of hexane and the suspension formed is stirred at room temperature for 2 hrs. The suspension is vacuum filtered and the filter cake air dried to afford 1.3 g (19% yield) of product, mp 140°-146° C.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[C:16]([O:19]C)[CH:17]=[CH:18][C:12]=3[N:11]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([N:30]4[CH2:34][CH:33]=[CH:32][CH2:31]4)=[O:29])=[CH:24][CH:23]=3)[C:10](=[O:35])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[Br-].[Br-].[Br-].B>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:12]=3[N:11]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([N:30]4[CH2:31][CH:32]=[CH:33][CH2:34]4)=[O:29])=[CH:24][CH:23]=3)[C:10](=[O:35])[CH2:9]2)=[O:7])=[CH:36][CH:37]=1
Reactant: COc1ccc2c(c1)CN(C(=O)c1ccc(Cl)cc1)CC(=O)N2Cc1ccc(C(=O)N2CC=CC2)cc1
Agent: B
Agent: [Br-]
Solvent: ClCCl
Product: O=C(c1ccc(CN2C(=O)CN(C(=O)c3ccc(Cl)cc3)Cc3cc(O)ccc32)cc1)N1CC=CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
35 mg (0.068 mmol) of 4-(4-chlorobenzoyl)-1-[4-(2,5-dihydro-1H-pyrrol-1-ylcarbonyl)benzyl]-7-methoxy-1,3,4,5-tetrahydrobenzo[e][1,4]-diazepin-2-on was dissolved in 10 ml of dichloromethane. 1.0 ml of borane tribromide was added to the obtained solution, and they were stirred at room temperature overnight. After the treatment with dichloromethane as the extracting solvent by an ordinary method, the obtained crude product was treated in the same manner as in step 3 in Example 1 to obtain the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([CH3:19])[C:9]=1[NH:10][C:11]1[C:16]([Cl:17])=[CH:15][N:14]=[C:13]([Cl:18])[N:12]=1)=[O:4].S(Cl)([Cl:23])(=O)=O>C(Cl)Cl>[CH3:1][NH:2][C:3]([C:5]1[S:6][C:7]([Cl:23])=[C:8]([CH3:19])[C:9]=1[NH:10][C:11]1[C:16]([Cl:17])=[CH:15][N:14]=[C:13]([Cl:18])[N:12]=1)=[O:4]
Reactant: CNC(=O)c1scc(C)c1Nc1nc(Cl)ncc1Cl
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CNC(=O)c1sc(Cl)c(C)c1Nc1nc(Cl)ncc1Cl
Temperature: 0 °C
Reaction time: 16 h
Yield: 9 %

Procedure:
An ice-cold solution of 3-(2,5-dichloro-pyrimidin-4-ylamino)-4-methyl-thiophene-2-carboxylic acid methylamide (0.105 g, 0.33 mmol) in methylene chloride (4 mL) was treated with sulfuryl chloride (33 μL). The mixture was stirred for 16 hours and concentrated. Chromatography on preparative TLC plate (hexanes/ethyl acetate/methanol (50:25:1)) gave 5-chloro-3-(2,5-dichloro-pyrimidin-4-ylamino)-4-methyl-thiophene-2-carboxylic acid methylamide (10.4 mg, 9%): 1H NMR (300 MHz, CDCl3) δ 9.9 (s, 1H), 8.33 (s, 1H), 5.82 (br, 1H), 3.05 (d, 3H), 2.22 (s, 3H); MS (m/e): 351.1 (M+1). 1770b) Following a procedure analogous to Example 1741e, 5-chloro-3-(2,5-dichloro-pyrimidin-4-ylamino)-4-methyl-thiophene-2-carboxylic acid methylamide and 2-amino-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one were converted to 5-chloro-3-[5-chloro-2-(5-methyl-6-oxo-5,6,8,9-tetrahydro-7-oxa-5-aza-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-4-methyl-thiophene-2-carboxylic acid methylamide: 1H NMR (300 MHz, CDCl3) δ 8.77 (s, 1H), 8.07 (br, 1H), 7.37 (d, 1H), 7.2 (dd, 1H), 7.15 (br, 1H), 7.0 (d, 1H), 5.85 (q, 1H), 4.43 (t, 2H), 3.33 (s, 3H), 2.92 (d, 3H), 2.85 (t, 2H), 2.0 (s, 3H); MS (m/e): 507.2 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[N:12]3[CH:13]=[CH:14][N:15]=[C:16]([CH3:17])[C:11]3=[CH:10][N:9]=2)[CH2:4][C:3]1=[O:18].[Br:19]N1C(=O)CCC1=O>CN(C)C=O>[Br:19][C:10]1[N:9]=[C:8]([CH:5]2[CH2:6][CH2:7][N:2]([CH3:1])[C:3](=[O:18])[CH2:4]2)[N:12]2[CH:13]=[CH:14][N:15]=[C:16]([CH3:17])[C:11]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nccn2c(C3CCN(C)C(=O)C3)ncc12
Solvent: CN(C)C=O
Product: Cc1nccn2c(C3CCN(C)C(=O)C3)nc(Br)c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69.4 %

Procedure:
To a solution of 1-methyl-4-(8-methylimidazo[1,5-a]pyrazin-3-yl)piperidin-2-one (0.205 mmol, 50 mg) in N,N-dimethylformamide (0.6 ml) was added N-bromosuccinimide (0.225 mmol, 40.1 mg) and the reaction mixture was stirred at room temperature for 15 minutes. Extraction dichloromethane/aqueous sodium hydrogen carbonate, drying (sodium sulfate) and concentrating in vacuo yielded the crude product. Purification by column chromatography (silica gel; dichloromethane with 10% methanol) yielded 4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)-1-methylpiperidin-2-one (46 mg).
Reaction SMILES: CN(C)C=O.[CH2:6]([C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[CH3:7].C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH2:29][CH2:30][OH:31]>C(OCC)(=O)C.O>[CH2:6]([C@H:8]1[CH2:9][CH2:10][C@H:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH:30]([OH:31])[CH2:29][CH3:28])=[CH:18][CH:19]=2)[CH2:12][CH2:13]1)[CH3:7]
Reactant: CC[C@H]1CC[C@H](c2ccc(O)cc2)CC1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC(O)Oc1ccc([C@H]2CC[C@H](CC)CC2)cc1
Temperature: 25 °C

Procedure:
In a 1-liter three-necked flask equipped with a condenser and a stirrer were placed 500 ml of dimethylformamide, 20.4 g (0.10 mol) of 4-(trans-4-ethyl-cyclohexyl)phenol and 41.4 g (0.30 mol) of potassium carbonate, followed by stirring at room temperature. Afterward, 18.1 g (0.13 mol) of 3-bromo-1-propanol was added thereto, and the solution was then vigorously stirred at 100° C. After reaction for 10 hours, this solution was poured into 2 liters of water, and extraction was then made with 1.5 liters of ethyl acetate. In succession, the resultant organic layer was washed with 3N hydrochloric acid three times, a 2N aqueous sodium hydroxide solution three times and water. The resultant ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent was then distilled off under reduced pressure. Next, the resultant crystal was recrystallized from n-heptane twice to obtain 17.6 g (0.067 mol) of 4-(trans-4-ethyl-cyclohexyl)phenoxypropanol. Its melting point was in the range of 68.5° to 69.9° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][NH:5][C:6]([NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[O:7].[H-].[Na+].C(OCC)(=O)C>CN(C=O)C.C1COCC1>[N:11]1[CH:12]=[CH:13][CH:14]=[C:9]([N:8]2[CH2:2][CH2:3][CH2:4][NH:5][C:6]2=[O:7])[CH:10]=1
Reactant: O=C(NCCCCl)Nc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1NCCCN1c1cccnc1
Temperature: 25 °C
Yield: 97.3 %

Procedure:
1-(3-Chloro-propyl)-3-pyridin-3-yl-urea (I-10a: 2.1 g, 9.859 mmol) in dry DMF (10 mL) was added to a solution of sodium hydride (487 mg, 10.154 mmol) in THF (2 mL) at 0° C. The reaction temperature was maintained at room temperature for 30 minutes. The reaction was monitored by TLC (100% ethyl acetate). The reaction mixture was quenched with MeOH (5 mL) at 0° C., concentrated under reduced pressure and partitioned between ice cold water and chloroform. The organic layer was dried over Na2SO4, and concentrated under reduced pressure to afford 1.7 g (97.14% yield) of 1-pyridin-3-yl-tetrahydro-pyrimidin-2-one.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:16]1[CH:25]=[N:24][C:23]2[C:18](=[CH:19][C:20]([F:27])=[C:21]([F:26])[CH:22]=2)[N:17]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:25]1[CH:16]=[N:17][C:18]2[C:23](=[CH:22][C:21]([F:26])=[C:20]([F:27])[CH:19]=2)[N:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CN
Reactant: Fc1cc2ncc(Cl)nc2cc1F
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1cnc2cc(F)c(F)cc2n1
Yield: 58.3 %

Procedure:
The title compound (0.53 g) was prepared from (S)-2-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.5 g) and 2-chloro-6,7-difluoroquinoxaline (0.5 g) according to the method of D30.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([F:13])[CH:4]=1)#[N:2].[N+:14]([O-])([OH:16])=[O:15].S(=O)(=O)(O)O>>[C:1]([C:3]1[C:12]([N+:14]([O-:16])=[O:15])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([F:13])[CH:4]=1)#[N:2]
Reactant: COC(=O)c1ccc(C#N)cc1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])c(C#N)cc1F
Temperature: 45 °C
Yield: 43 %

Procedure:
To a flask containing methyl 4-cyano-2-fluorobenzoate (1.61 g, 9.0 mmol) was added fuming nitric acid (15 mL) followed by concentrated sulfuric acid (4 mL). The mixture was heated to 45° C. for 15 h before cooling to room temperature. The solution was then poured into ice water and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with saturated sodium bicarbonate solution, dried over magnesium sulfate, filtered, and concentrated to provide methyl 4-cyano-2-fluoro-5-nitrobenzoate (859 mg, 3.83 mmol, 43% yield).
Reaction SMILES: [Br:1][C:2](=[CH2:6])[CH2:3][CH2:4][OH:5].Cl[Si:8]([C:21]([CH3:24])([CH3:23])[CH3:22])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N1C=CN=C1>CN(C)C1C=CN=CC=1>[Br:1][C:2](=[CH2:6])[CH2:3][CH2:4][O:5][Si:8]([C:21]([CH3:24])([CH3:23])[CH3:22])([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: C=C(Br)CCO
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Product: C=C(Br)CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C

Procedure:
The title compound was prepared in 8.7 g yield as a colourless oil, following an analogous procedure to that reported in WO2005058884, starting from 3-bromo-3-buten-1-ol (4 g), chloro(1,1-dimethylethyl)diphenylsilane (8.27 ml), imidazole (2.34 g) and N,N-dimethyl-4-pyridineamine (0.025 g).
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:14]([S:16][CH3:17])[C:13]2[C:4](=[C:5]3[C:10](=[CH:11][CH:12]=2)[CH:9]=[CH:8][CH:7]=[N:6]3)[N:3]=1.C.[O:19]1CCOCC1>O>[CH3:17][S:16][C:14]1[C:13]2[C:4](=[C:5]3[C:10](=[CH:11][CH:12]=2)[CH:9]=[CH:8][CH:7]=[N:6]3)[N:3]=[C:2]([CH:1]=[O:19])[CH:15]=1
Reactant: CSc1cc(C)nc2c1ccc1cccnc12
Reactant: C1COCCO1
Solvent: O
Product: CSc1cc(C=O)nc2c1ccc1cccnc12
Yield: 41 %

Procedure:
A solution of SeO2 (2.18 g, 19.6 mmol) in a mixture of dioxane (100 mL) and water (4 mL) was heated to reflux in a two-neck 250 mL round-bottomed flask. A solution of 2-methyl-4-methylsulfanyl-[1,10]phenanthroline (1.89 g, 7.90 mmol) in hot dioxane (100 mL) was added through an addition funnel over a period of 1 hour and the reaction mixture was refluxed for additional 45 minutes. The reaction mixture was filtered while hot and the residue rinsed with more hot dioxane (20 mL) and filtered. The filtrate was concentrated in vacuo and the residue obtained was redissolved in hot water, stirred with decolorizing charcoal and filtered. The filtrate was allowed to reach room temperature and basified with saturated NaHCO3 until precipitation of a white solid, which was filtered, washed with cold water and dried in vacuo. A white solid (0.80 g, 41% yield) was obtained.
Reaction SMILES: [N+](C1C=CC(C(CC(C)(C)C)(C)C)=CC=1N=NC1C=CC=CC=1O)([O-])=O.[C:27]1(=[O:40])[C:39]2[C:31]([C:32]3[C:37]([CH:38]=2)=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:30][CH:29]=[CH:28]1.[OH-].[Na+].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.Cl>O.CO>[C:27]1([OH:40])[C:39]2[CH2:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]=2[CH:30]=[CH:29][CH:28]=1
Reactant: O=C1C=CC=C2C1=Cc1ccccc12
Agent: CC(C)(C)CC(C)(C)c1ccc([N+](=O)[O-])c(N=Nc2ccccc2O)c1
Agent: Cl
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CO
Solvent: O
Product: Oc1cccc2c1Cc1ccccc1-2
Temperature: 25 °C

Procedure:
35.5g (0.1 mole) of 2-nitro-2'-hydroxy-5-t-octylazobenzene are added to the mixture of 60 ml of methanol, 2.3 g of fluorenone and 64 g of 50% aqueous solution of sodium hydroxide. The mixture is stirred at 70°-75° C. and to the mixture is slowly added 55.4 g (0.3 mol) of glucose in 55 ml of water over 2 hours. The reaction mixture is heated for an additional three hours, then 160 ml of methanol is added at 55°-60° C. and 14.2 g of 35% hydrochloric acid slowly added and stirred at 40°-50° C. for 20 minutes. During this time crystals should appear. Then more hydrochloric acid is added to attain pH 4-5. The reaction is cooled to 25° C. to yield 26.5 g (82%). Compared to Example 1, above, more than three times the amount of fluorenone is needed, more than double the reaction time is required, and a lower yield is obtained than when fluorenol is used.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].C(O)=O.C([O-])(=O)C.[Cu+2:16].C([O-])(=O)C>CO>[Cu:16].[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5]
Reactant: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Solvent: O=CO
Product: [Cu]

Procedure:
0.58 g of fumaric acid was dissolved in a mixture solvent having 40 cm3 of methanol and 12 cm3 of formic acid. Then, under stirring at the normal temperature, into the above solution, a further solution in which 1.0 g of copper acetate was dissolved in 80 cm3 of methanol was dripped. After this solution was left still for a few days, the precipitation product was suction-filtered and dried for 110° C./4 hours, whereby 0.3 g of fumaric acid copper was obtained.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:26])[NH:12][C:13]2[CH:18]=[C:17]([C:19]3[CH2:23][CH2:22][C:21](=[O:24])[CH:20]=3)[CH:16]=[CH:15][C:14]=2[NH2:25])=[CH:7][CH:6]=1)(=O)C.O.O.O.O.O.O.O.[Cl-].[Ce+3].[Cl-].[Cl-].[BH4-].[Na+]>C(Cl)Cl.CO>[NH2:25][C:14]1[CH:15]=[CH:16][C:17]([C:19]2[CH2:23][CH2:22][CH:21]([OH:24])[CH:20]=2)=[CH:18][C:13]=1[NH:12][C:11](=[O:26])[C:8]1[CH:7]=[CH:6][C:5]([OH:4])=[CH:10][CH:9]=1
Reactant: CC(=O)Oc1ccc(C(=O)Nc2cc(C3=CC(=O)CC3)ccc2N)cc1
Agent: [BH4-]
Agent: [Ce+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: Nc1ccc(C2=CC(O)CC2)cc1NC(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 0.8 %

Procedure:
To a stirring solution of amine 260 (0.11 g, 6.31 mmol) in DCM (9 mL) and cerium (III) chloride heptahydrate (0.37 g, 0.93 mmol) in MeOH (6 mL) at −78° C. was added sodium borohydride (60 mg, 0.93 mmol) in one portion. The reaction mixture was allowed to warm to room temperature and stirred for 15 min then concentrated. Purifications by flash chromatography (eluent: 5% MeOH in DCM) followed by chromatotron (same eluent) provided the title compounds 261 (15 mg, 14% yield) and 262 (15 mg, 16% yield).
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][CH2:8][NH:9][C:10]2[CH:20]=[CH:19][C:13]([C:14]([O:16]CC)=[O:15])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[OH-].[K+].C(O)C.O.Cl>O>[Br:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][CH2:8][NH:9][C:10]2[CH:20]=[CH:19][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(NCCOc2ccc(Br)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(NCCOc2ccc(Br)cc2)cc1

Procedure:
A mixture of 10.0 g of ethyl p-{[2-(p-bromophenoxy)-ethyl]amino}benzoate, 10 g of potassium hydroxide and 100 ml of ethanol-water (9:1) is refluxed for 3.5 hours. The mixture is acidified while hot with concentrated hydrochloric acid, diluted with water, chilled and filtered. The solid is washed with water to give crystals, mp 190°-192° C. Recrystallization from ethanol (500 ml) gives white crystals, mp 194°-196° C.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C@H:7]2[CH2:13][C@H:12]3[N:14]([CH2:15][CH2:16][C@H:17]([NH:24][C:25]([CH:27]4[CH2:32][CH2:31][C:30]([F:34])([F:33])[CH2:29][CH2:28]4)=[O:26])[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C@H:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:5]([CH:35]([CH3:37])[CH3:36])=[N:4][N:3]=1.[P:38](=[O:42])([OH:41])([OH:40])[OH:39]>C(O)C>[CH3:1][C:2]1[N:6]([C@H:7]2[CH2:13][C@H:12]3[N:14]([CH2:15][CH2:16][C@H:17]([NH:24][C:25]([CH:27]4[CH2:28][CH2:29][C:30]([F:34])([F:33])[CH2:31][CH2:32]4)=[O:26])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C@H:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:5]([CH:35]([CH3:37])[CH3:36])=[N:4][N:3]=1.[P:38]([O-:42])([O-:41])([O-:40])=[O:39]
Reactant: O=P(O)(O)O
Agent: Cc1nnc(C(C)C)n1[C@@H]1C[C@H]2CC[C@@H](C1)N2CC[C@H](NC(=O)C1CCC(F)(F)CC1)c1ccccc1
Solvent: CCO
Product: O=P([O-])([O-])[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Maraviroc (100 gm) was dissolved in ethanol (100 ml) and stirred for 30 minutes at room temperature. To the solution was added phosphoric acid (2 gm) and then cooled to 0 to 5° C. The reaction mass was stirred for 12 hours at 0 to 5° C. and filtered. The solid obtained was dried to obtain 98 gm of crystalline form 4 of maraviroc phosphate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[C:11]=1[NH:12][CH3:13])[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:50]1[CH2:55][CH2:54][CH2:53][C@@H:52]([NH:56][C:57](=[O:63])[O:58][C:59]([CH3:62])([CH3:61])[CH3:60])[CH2:51]1>CN(C)C=O.C(Cl)Cl>[C:59]([O:58][C:57](=[O:63])[NH:56][C@@H:52]1[CH2:53][CH2:54][CH2:55][N:50]([C:6](=[O:8])[C:5]2[CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[C:11]([NH:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:51]1)([CH3:62])([CH3:60])[CH3:61]
Reactant: CNc1c(OC)cc(C(=O)O)cc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNc1c(OC)cc(C(=O)N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
To a solution of 3-methoxy-4-(methylamino)-5-nitrobenzoic acid (11.09 g, 49.0 mmol) and HATU (18.64 g, 49.0 mmol) in N,N-dimethylformamide (DMF) (300 mL) was added DIPEA (17.13 mL, 98 mmol) and the mixture stirred for 30 mins. Upon addition of the DIPEA the mixture went cloudy after ˜1 min with stirring. (R)-tert-Butyl piperidin-3-ylcarbamate (9.82 g, 49.0 mmol) was then added and stirred for 1.5 hr, after which time LCMS showed the reaction was complete. To 5 mL of the reaction mixture was added sat.aq. LiCl solution (5 mL) and Et2O (10 mL) and the layers separated. The aqueous layer was re-extracted with Et2O (2×10 mL), the combined organics were backwashed with water (10 mL), dried with Na2SO4, filtered and concentrated in vacuo to give the crude product as an orange gum. The gum was dissolved in the minimum amount of DCM and purified by Si SNAP 25 g column using a 50-100% ethyl acetate/cyclohexane. The appropriate fractions were combined and evaporated in vacuo before being azeotroped with cyclohexane and dried under vacuum to give the required product, 281 mg as an orange solid. The remaining reaction mixture was concentrated in vacuo to remove some of the DMF. Saturated aq.LiCl solution (300 mL) and Et2O (700 mL) were added and the mixture separated. The aqueous layer was re-extracted with Et2O (2×700 mL), the combined organic layers were backwashed with water (1 L), dried with Na2SO4, filtered and concentrated in vacuo to give the crude product as an orange gum. This was purified on a 340 g SNAP silica cartridge eluting with 30%-60% ethyl acetate in cyclohexane. Appropriate fractions were combined and concentrated in vacuo to yield the title compound as an orange solid (19.4 g).
Reaction SMILES: [F:1][C:2]([F:56])([F:55])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:54])[C:16]([N:18]2[CH2:23][CH2:22][C@:21]([CH2:31][CH:32]=[C:33]([O:38][Si](C(C)(C)C)(C)C)[C:34]([O:36][CH3:37])=[O:35])([NH:24][S:25]([C:27]([CH3:30])([CH3:29])[CH3:28])=[O:26])[CH2:20][C@@H:19]2[C:46]2[CH:51]=[CH:50][C:49]([F:52])=[CH:48][C:47]=2[CH3:53])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(O)(=O)C.[F-].[Cs+].C([O-])(O)=O.[Na+]>C(#N)C>[CH3:37][O:36][C:34](=[O:35])[C:33](=[O:38])[CH2:32][CH2:31][C@:21]1([NH:24][S:25]([C:27]([CH3:29])([CH3:28])[CH3:30])=[O:26])[CH2:22][CH2:23][N:18]([C:16]([N:15]([C@@H:13]([C:5]2[CH:4]=[C:3]([C:2]([F:55])([F:56])[F:1])[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=2)[CH3:14])[CH3:54])=[O:17])[C@@H:19]([C:46]2[CH:51]=[CH:50][C:49]([F:52])=[CH:48][C:47]=2[CH3:53])[CH2:20]1
Reactant: COC(=O)C(=CC[C@]1(NS(=O)C(C)(C)C)CCN(C(=O)N(C)[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H](c2ccc(F)cc2C)C1)O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])O
Agent: [Cs+]
Agent: [F-]
Solvent: CC(=O)O
Solvent: CC#N
Product: COC(=O)C(=O)CC[C@]1(NS(=O)C(C)(C)C)CCN(C(=O)N(C)[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H](c2ccc(F)cc2C)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.7 %

Procedure:
To a solution of Methyl 4-[(2R,4S)-1-{[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-4-{[(1,1-dimethylethyl)sulfinyl]amino}-2-(4-fluoro-2-methylphenyl)-4-piperidinyl]-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2-butenoate (Intermediate 10, 184 mg, 0.220 mmol) and Acetic acid (0.025 mL, 0.439 mmol) in Acetonitrile (4 mL) was added Cesium Fluoride (107 mg, 0.703 mmol, Aldrich) and the reaction mixture was stirred at 25° C. for 5 hrs. NaHCO3 saturated solution was added very carefully and the mixture was extracted with EtOAc (3×). The combined organic phases were dried (Na2SO4) and evaporated to dryness. The crude was purified by flash chromatography on silica with SP1 (Biotage) system (from 1:0 to 0:1 Cyclohexane/EtOAc) to give the title compound (108 mg, 0.149 mmol, 68% yield) as a colourless oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.92-8.03 (m, 1H) 7.62-7.75 (m, 2H) 6.68-7.30 (m, 3H) 5.20-5.37 (m, 1H) 4.94-5.07 (m, 1H) 4.30-4.46 (m, 1H) 3.67-3.81 (m, 3H) 2.86-3.07 (m, 2H) 1.58-2.77 (m, 14H) 1.45-1.53 (m, 3H) 1.03-1.12 (m, 9H). Mixture of two species (see the signals of OMe at 3.77 ppm, 3.70 ppm). UPLC: 2 peaks Rt 0.87 and 0.93 mins, m/z=724 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([O:17]C)=[O:16])=[C:13]([CH3:19])[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[C:11]([S:30][CH3:31])=[N:10]2)=[CH:5][CH:4]=1)#[N:2].[OH-].[K+]>C1COCC1.C(O)C.O.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:14]([C:15]([OH:17])=[O:16])=[C:13]([CH3:19])[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[C:11]([S:30][CH3:31])=[N:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(SC)=NC1c1ccc(C#N)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CSC1=NC(c2ccc(C#N)cc2)C(C(=O)O)=C(C)N1c1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
Methyl 4-(4-cyanophenyl)-6-methyl-2-(methylsulfanyl)-1-[3-(trifluoromethyl)-phenyl]-1,4-dihydro-5-pyrimidinecarboxylate (Example 8; 9.51 g, 21.4 mmol) is dissolved in 175 ml THF/ethanol/water (10:5:1). Potassium hydroxide (3.59 g, 64.1 mmol) is added, and the reaction mixture is stirred overnight. The reaction mixture is diluted with 100 ml of water, and the aqueous phase is washed with diethyl ether. The resulting aqueous phase is acidified to pH 1 with hydrochloric acid, and the resulting precipitate is filtered off, dissolved in ethyl acetate and washed with water. After drying with sodium sulfate, the solvent is removed in vacuo to give the product.