Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=[C:9]([N:18]3[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])[CH2:20][CH2:19]3)[C:8]=2[CH:31]=1>CO>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=[C:9]([N:18]3[CH2:19][CH2:20][N:21]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])[CH2:22][CH2:23]3)[C:8]=2[CH:31]=1
Reactant: CCOC(=O)CCN1CCN(C2=Nc3ccccc3Sc3ccc(Cl)cc32)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCN1CCN(C2=Nc3ccccc3Sc3ccc(Cl)cc32)CC1
Yield: 91.6 %

Procedure:
2N Aqueous sodium hydroxide solution (5 ml) was added to a solution of 2.15 g of ethyl 4-(2-chlorodibenzo[b,f][1,4]thiazepin-11-yl)-1-piperazinepropionate in 22 ml of methanol. The solution was refluxed for 30 min and then concentrated. The residue was dissolved in hot water and the solution was neutralized with 0.5N hydrochloric acid. The precipitates were collected by filtration to give 1.84 g of pale yellow crystals, which were recrystallized from aqueous ethanol to give pale yellow crystals, mp 120°-121° C.
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15](I)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:33]1(B(O)O)[CH2:35][CH2:34]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH:33]1([C:15]2[N:14]=[C:13]([C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:8]=3)[N:17]([CH3:18])[C:16]=2[C:19]([N:21]2[CH2:22][CH2:23][CH:24]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:25][CH2:26]2)=[O:20])[CH2:35][CH2:34]1
Reactant: OB(O)C1CC1
Reactant: CCCCCCc1cccc(-c2nc(I)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCc1cccc(-c2nc(C3CC3)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 33.3 %

Procedure:
A suspension of 0.275 g (0.50 mmol) of [2-(3-hexyl-phenyl)-5-iodo-3-methyl-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 2), 0.086 g (1.0 mmol) of cyclopropyl boronic acid and 0.573 g (2.7 mmol) of tribasic potassium phosphate in 10 ml of toluene was treated with 0.30 ml of water, followed by 0.031 g (0.11 mmol) of tricyclohexylphosphine and 0.012 g (0.055 mmol) of palladium(II)acetate. This reaction mixture was heated up to 100° C., stirred for 18 hours at this temperature and subsequently cooled down to RT. The reaction mixture was then poured into crashed ice and extracted twice with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 4:1) to give 0.077 g (33%) of the title compound as light yellow oil. MS: 463.4 (MH+).
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9]C)=O.Cl.[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[NH:18])=[CH:15][CH:14]=1.CC(C)([O-])C.[K+]>CO>[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]2[N:18]=[C:7]([OH:9])[C:3]3[CH2:4][CH2:5][CH2:6][C:2]=3[N:19]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)C1CCCC1=O
Reactant: N=C(N)c1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: Oc1nc(-c2ccc(Cl)cc2)nc2c1CCC2

Procedure:
7.1 g of methyl 2-oxocyclopentane-1-carboxylate and 9.6 g of 4-chlorobenz-amidine hydrochloride were introduced into 50 ml of methanol. 5.6 g of potassium tert-butoxide were added with stirring. The reaction mixture was stirred under reflux for 4 hours and then poured onto ice water. The crystalline product was filtered off with suction, washed with water and recrystallized from dimethylformamide. Yield: 8.8 g. M.p.: 282° C.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:21]([C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)#[N:22]>>[C:21]([C:23]1[CH:31]=[CH:30][C:26]([C:27]([N:20]=[C:16]([N:7]2[CH2:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8]2)[O:17][CH2:18][CH3:19])=[O:28])=[CH:25][CH:24]=1)#[N:22]
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Product: CCOC(=NC(=O)c1ccc(C#N)cc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and p-cyanobenzoyl chloride, there is obtained ethyl N-(p-cyanobenzoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a solid, mass spectrum m/e: M+ 395 (5), 366 (24), 194 (100), 165 (18), 130 (20), 102 (14);
Reaction SMILES: [C:1]([OH:22])(=[O:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=C\C/C=C\C/C=C\CCCCC>O>[C:1]([OH:22])(=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O
Solvent: O
Product: CCCCCCCC(=O)O

Procedure:
Next, 80 g of the triglycerides containing 40 wt % arachidonic acid (TGA40S) obtained in Example 1, 160 g of caprylic acid, 12 g of the aforementioned immobilized lipase and 4.8 ml of water were reacted for 48 hours at 30° C. while stirring (130 rpm). Upon completion of the reaction, the reaction solution was removed to obtain the activated immobilized enzyme.
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1.O.[NH:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1>CO>[F:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:17]3[CH2:18][CH2:19][NH:14][CH2:15][CH:16]=3)=[CH:9][NH:10]2)=[CH:6][CH:5]=1
Reactant: O=C1CCNCC1
Reactant: Fc1ccc2cc[nH]c2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Fc1ccc2c(C3=CCNCC3)c[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Powdered potassium hydroxide (144.4 g) was added carefully to a mechanically stirred mixture of 6-fluoroindole (49.23 g, 0.364 mol) and 4-piperidone monohydrate (111.93 g, 0.728 mol) in methanol (1500 ml). The mixture was then heated under reflux under nitrogen for 18 hr and then more potassium hydroxide (40 g) was added and the reaction mixture heated under reflux for a further 4 hr. The reaction mixture was allowed to cool to room temperature and poured onto ice-water (3 l) and stirred for 1 hr and the precipitated solid isolated by filtration and dried at 50° C. in vacuo to give a solid. (WO 9747302).
Reaction SMILES: [CH3:1][C:2]([O:4][CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=[O:3].C(N(CC)P1OCCO1)C.C[Si](C)(C)Cl.[C:34]([CH2:36][C:37](Cl)=[O:38])#[N:35]>C(Cl)Cl>[CH3:1][C:2]([O:4][CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH:13][C:37]([CH2:36][C:34]#[N:35])=[O:38])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=[O:3]
Reactant: N#CCC(=O)Cl
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: CCN(CC)P1OCCO1
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)CC#N)[C@H]2SC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2.72 g (10 mmol) of 7-aminocephalosporanic acid are suspended in 50 ml of dry methylene chloride. 1.5 ml (10 mmol) of 2-diethylamino-1,3,2-dioxaphospholane and 1.33 ml (10.5 mmol) of trimethylchlorosilane are added under nitrogen at room temperature. The reaction mixture is stirred for 16 hours at room temperature. After cooling to 0° C, a solution of 10 mmol of cyanoacetyl chloride in 6 ml of methylene chloride is added over 5 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[N:21]=[CH:20][C:19]([C:22]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:23]=2[CH2:24][CH2:25][NH:26][CH:27]3[CH3:32])=[CH:18][CH:17]=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:26]3[CH2:25][CH2:24][C:23]4[C:28](=[CH:29][CH:30]=[CH:31][C:22]=4[C:19]4[CH:20]=[N:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=4)[CH:27]3[CH3:32])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: COc1ccc(-c2cccc3c2CCNC3C)cn1
Product: COc1ccc(-c2cccc3c2CCN(C(=O)c2cc4ncc(Cl)cn4n2)C3C)cn1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-(6-Methoxy-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:16])[C:9]#[C:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1.[N+:20](=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N-:21]>C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:16])[C:9]2[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:20][NH:21][C:10]=2[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1
Reactant: CCOC(=O)C#CC(O)c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: CCOCC
Product: CCOC(=O)c1n[nH]c(C(=O)OCC)c1C(O)c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 58.9 %

Procedure:
A solution of ethyl 4-(4-chloro-2-nitrophenyl)-4-hydroxy-2-butynoate (5.00 g, 17.7 mmol) and ethyl diazoacetate (2.75 g, 26.5 mmol) in diethyl ether (43.3 mL) was refluxed for 5 days. After cooling to room temperature the reaction mixture was chromatographed eluting with ethyl acetate:hexanes (20:80, 30:70, 40:60, and 50:50). All of the fractions containing the desired compound were combined, concentrated on the rotary evaporator, and the product was recrystallized twice from toluene (total volume 225 mL) to give the title compound as a white solid (4.15 g, 59%, mp 60° C.).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:7]=[CH:6][C:5]=1[OH:16])([O-])=O.O.NN>C(O)C>[NH2:1][C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:7]=[CH:6][C:5]=1[OH:16]
Reactant: CCCCCCc1ccc(O)c([N+](=O)[O-])c1
Agent: NN
Solvent: CCO
Solvent: O
Product: CCCCCCc1ccc(O)c(N)c1
Temperature: 70 °C
Yield: 81.9 %

Procedure:
In a 50 ml-three-necked flask, 1.10 g (4.93 mM) of 2-nitro-4-hexylphenol, 0.30 g of activated carbon, 0.02 g of FeCl3.6H2O and 5 ml of ethanol were placed and heated to 55°-70° C. under stirring. To the mixture, 1.5 ml of 80% hydrazine hydrate was gradually added dropwise and heated to 70° C., followed by stirring for 30 min at 70°-75° C. After the reaction, the reaction mixture was filtered under heating to remove the activated carbon and the filtrate was poured into water to precipitate a crystal. The crystal was recovered by filtration, followed by drying under reduced pressure to obtain 0.78 g of 2-amino-4-hexylphenol (yield: 81.9%).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH2:31]([NH:33][CH2:34][CH3:35])[CH3:32]>>[CH2:31]([N:33]([CH2:34][CH3:35])[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:11]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][CH:18]=3)=[CH:15][C:16]=2[CH:12]=1)[CH3:32]
Reactant: CCNCC
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cc3)ccc2o1
Product: CCN(CC)CCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cc3)ccc2o1

Procedure:
The product from Example 23D and diethylamine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ 7.82 (m, 1H), 7.74 (d, J=8.1, 2H), 7.54 (m, 2H), 7.51 (d, J=8.1 Hz, 2H), 6.80 (s, 1H), 3.32-3.8 (m, 16H), 1.38 (t, J=7.5 Hz, 6H); MS (DCI) m/z 407 (M+H)+;
Reaction SMILES: [I:1][C:2]1[C:3]2[NH:16][CH:15]=[CH:14][C:4]=2[C:5]2[C:10]([CH:11]=1)=[N:9][C:8]([NH2:12])=[N:7][C:6]=2[NH2:13].[OH-].[Na+].I[CH3:20]>O1CCCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[I:1][C:2]1[C:3]2[N:16]([CH3:20])[CH:15]=[CH:14][C:4]=2[C:5]2[C:10]([CH:11]=1)=[N:9][C:8]([NH2:12])=[N:7][C:6]=2[NH2:13]
Reactant: CI
Reactant: Nc1nc(N)c2c(cc(I)c3[nH]ccc32)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1ccc2c3c(N)nc(N)nc3cc(I)c21
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.5 %

Procedure:
A solution 6-iodo-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine VI (2.68 g, 8.24 mmol) in tetrahydrofuran (100 mL) was treated with powdered sodium hydroxide (0.66 g, 16.5 mmol), iodomethane (0.62 mL, 9.96 mmol), and tetrabutylammonium bromide (0.8 g, 2.48 mmol) and the resulting mixture stirred at 25° C. for 18 h. The resulting mixture was concentrated in vacuo. The residue was partitioned between methylene chloride (70 mL) and water (70 mL) and this mixture was stirred at 25° C. for 30 min. The precipitate was isolated by filtration, washed with water, and dried in vacuo to afford 6-iodo-7-methyl-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine (2.67 g, 95.5%) as a yellow solid; 1H NMR (DMSO-d6, 300 MHz) δ 7.58 (s, 1H), 7.47 (d, J=2.93 Hz, 1H), 6.99 (d, J=2.93 Hz, 1H), 6.78 (broad s, 2H), 5.83 (broad s, 2H), 4.16 (s, 3H).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]([C:15]2([NH:18][C:19]([C:21]3[N:25]4[C@:26]([CH3:50])([CH2:38][C:39]5[CH:44]=[CH:43][C:42]([O:45][C:46]([F:49])([F:48])[F:47])=[CH:41][CH:40]=5)[C:27](=[O:37])[N:28]([C:29]5[CH:34]=[C:33]([Cl:35])[CH:32]=[C:31]([Cl:36])[CH:30]=5)[C:24]4=[N:23][CH:22]=3)=[O:20])[CH2:17][CH2:16]2)=[O:14])[CH2:9]1)=O)C.[NH2:52][NH2:53]>C(O)C>[Cl:35][C:33]1[CH:34]=[C:29]([N:28]2[C:27](=[O:37])[C@@:26]([CH3:50])([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][C:46]([F:48])([F:47])[F:49])=[CH:41][CH:40]=3)[N:25]3[C:21]([C:19]([NH:18][C:15]4([C:13]([N:10]5[CH2:11][CH2:12][C@@H:8]([C:6]6[NH:53][N:52]=[C:4]([OH:3])[CH:5]=6)[CH2:9]5)=[O:14])[CH2:16][CH2:17]4)=[O:20])=[CH:22][N:23]=[C:24]23)[CH:30]=[C:31]([Cl:36])[CH:32]=1
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)C2(NC(=O)c3cnc4n3[C@](C)(Cc3ccc(OC(F)(F)F)cc3)C(=O)N4c3cc(Cl)cc(Cl)c3)CC2)C1
Reactant: NN
Solvent: CCO
Product: C[C@@]1(Cc2ccc(OC(F)(F)F)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)N4CC[C@@H](c5cc(O)n[nH]5)C4)CC3)n21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 55.7 %

Procedure:
To a solution of 3-[(R)-1-(1-{[(R)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-5-(4-trifluoromethoxy-benzyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-cyclopropanecarbonyl)-pyrrolidin-3-yl]-3-oxo-propionic acid ethyl ester (35 mg, 0.05 mmol) in ethanol (2 mL) was added hydrazine (7.0 μL, 0.23 mmol). The reaction mixture was stirred at room temperature for 1.5 h. The solvent was evaporated in vacuo, and the residue was purified via reverse phase HPLC to afford the title compound (20 mg, 60%) as a white solid, m/z 718.1 [M+1]+.
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([O-])([O-])([O-])=O.N.C1CCCCC1>C(OCC)(=O)C.O>[CH:35]([C:5]1[N:6]([CH:7]2[CH2:13][CH: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)[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:2]([CH3:1])=[N:3][N:4]=1)([CH3:36])[CH3:37]
Reactant: Cc1nnc(C(C)C)n1[C@@H]1C[C@H]2CC[C@@H](C1)N2CC[C@H](NC(=O)C1CCC(F)(F)CC1)c1ccccc1
Agent: N
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Solvent: O
Product: Cc1nnc(C(C)C)n1C1CC2CCC(C1)N2CC[C@H](NC(=O)C1CCC(F)(F)CC1)c1ccccc1
Reaction time: 0.25 h
Yield: 82.9 %

Procedure:
Crystalline form 1 of maraviroc phosphate (5 gm) was dissolved in ethyl acetate (60 ml) and water (40 ml). The pH of the reaction mass was adjusted to 8.0 to 8.5 with ammonia solution (3 ml) and stirred for 15 minutes. The separated organic layer was dried with sodium sulfate and treated with carbon. The ethyl acetate was distilled off under vacuum at below 45° C. to obtain residual mass. To the residual mass was added cyclohexane (50 ml) and stirred for 15 minutes at room temperature, filtered. The solid obtained was dried to obtain 3.5 gm of maraviroc amorphous form.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][OH:16])[CH:10]=1.O[C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[CH:21]2.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.C(OCC)C>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][CH:22]=[CH:21]3)[CH:10]=1
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: Cc1cccc(C)c1-c1cccc(CO)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cccc(C)c1-c1cccc(COc2ccc3[nH]ccc3c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.6 %

Procedure:
A solution of (2′,6′-dimethylbiphenyl-3-yl)methanol (1.0 g, 4.71 mmol), 5-hydroxyindole (0.63 g, 4.73 mmol) and tributylphosphine (1.5 mL, 6.02 mmol) in tetrahydrofuran (30 mL) was stirred, and 1,1′-(azodicarbonyl)dipiperidine (1.6 g, 6.34 mmol) was added by portions, and the mixture was stirred at room temperature for 18 hr. Diethyl ether (30 mL) was added to the reaction mixture, and the precipitated insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:10-1:5) to give the title compound (0.95 g, yield 62%) as a pale-brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[NH:12][CH2:13][CH3:14])[N:8]=[CH:7][N:6]=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21](=[S:30])[NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:17][CH2:16]1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40].[Cl-].[Na+]>CN(C)C=O.O>[CH2:23]([NH:22][C:21]([N:18]1[CH2:19][CH2:20][N:15]([C:5]2[C:4]3[C:9](=[CH:10][C:11]([NH:12][CH2:13][CH3:14])=[C:2]([NH:1][S:39]([CH3:38])(=[O:41])=[O:40])[CH:3]=3)[N:8]=[CH:7][N:6]=2)[CH2:16][CH2:17]1)=[S:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCNc1cc2ncnc(N3CCN(C(=S)NCc4ccccc4)CC3)c2cc1N
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCNc1cc2ncnc(N3CCN(C(=S)NCc4ccccc4)CC3)c2cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 6 %

Procedure:
To a solution of 528 mg (1.25 mmol) of 4-(6-amino-7-ethylamino-4-quinazolinyl)-N-benzyl-1-piperazinethiocarboxamide obtained in Example 461 in 15 ml of dimethylformamide were added 0.57 ml (4.09 mmol) of triethylamine and 0.31 ml (1.55 mmol) of methanesulfonyl chloride, followed by overnight stirring at room temperature in an atmosphere of argon. To the resulting mixture was added 0.06 ml (0.31 mmol) of methanesulfonyl chloride, followed by overnight stirring at room temperature. The reaction mixture was poured into water, and sodium chloride was added thereto. The precipitated crystals were collected by filtration, washed with water, and dried, followed by purification by silica gel chromatography to give the desired compound as colorless crystals.
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:7]#[N:8])=[CH:5][N:6]=1.[C:9]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C([O-])([O-])=O.[K+].[K+].O>CN(C)C=O>[C:7]([C:4]1[S:3][C:2]([O:23][C:20]2[CH:19]=[CH:18][C:17]([NH:16][C:9](=[O:10])[O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[CH:22][CH:21]=2)=[N:6][CH:5]=1)#[N:8]
Reactant: N#Cc1cnc(Cl)s1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ncc(C#N)s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
2-chloro-thiazole-5-carbonitrile (900 mg 6.2 mmol; prepared according to procedure described in WO 01/17995, p. 103) and N-Boc-4-hydroxy-aniline (1.3 g, 6.2 mmol) were combined in N,N-dimethyl formamide (5 mL). To this solution, K2CO3 (2.6 g, 18.8 mmol) was added and the resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was then poured into water and extracted with ethyl acetate (2×). The combined organics were dried (Na2SO4), filtered and concentrated by rotary evaporation. The residue was purified by flash column chromatography (ethyl acetate:hexanes: 5%-50% ethyl acetate gradient) to give the title compound (2.0 g, 6.2 mmol, 100%) as a white solid. MS (ESI APCI) m/z 316.0 (M−H+); 1H NMR (300 MHz, DMSO-d6) δ 9.59 (s, 1H) 8.24 (s, 1H) 7.58 (d, J=9.0 Hz, 2H) 7.36 (d, J=9.0 Hz, 2H) 1.48 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH:10]2[CH:14]([OH:16])[CH3:15])=[CH:6][CH:5]=1)([O-])=O.C.O.NN>CO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH:10]2[CH:14]([OH:16])[CH3:15])=[CH:17][CH:18]=1
Reactant: CC(O)C1CCCN1Cc1ccc([N+](=O)[O-])cc1
Agent: NN
Solvent: O
Solvent: CO
Product: CC(O)C1CCCN1Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-[1-(4-Nitro-benzyl)-pyrrolidin-2-yl]-ethanol (370 mg, 1.48 mmol) is dissolved in MeOH (15 mL), to this solution is added FeCl3.6H2O (30 mg, 0.11 mmol) and active charcoal (15 mg, 1.2 mmol). The suspension is heated to reflux. Hydrazine hydrate (1.0 mL) is added, and reflux is continued for 3 h. After the mixture is cooled to room temperature, the active charcoal is filtered off through Celite, and the MeOH is removed under reduced pressure. The residue (200 mg, 61%) is directly used in the next step.
Reaction SMILES: [F:1][C:2]1([F:33])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:18]=[C:19]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:20]5[C:25]([CH:26]=4)=[CH:24][CH:23]=[CH:22][CH:21]=5)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.BrC1C2C(=CC=CC=2)C=C(NC(C2(C3C=CC4OC(F)(F)OC=4C=3)CC2)=O)N=1.[CH3:62][N:63]1[CH2:68][CH2:67][N:66]([C:69](C2C=CC(B(O)O)=CC=2)=[O:70])[CH2:65][CH2:64]1>>[F:33][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:18]=[C:19]([C:27]5[CH:28]=[CH:29][C:30]([C:69]([N:66]6[CH2:67][CH2:68][N:63]([CH3:62])[CH2:64][CH2:65]6)=[O:70])=[CH:31][CH:32]=5)[C:20]5[C:25]([CH:26]=4)=[CH:24][CH:23]=[CH:22][CH:21]=5)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: O=C(Nc1cc2ccccc2c(-c2ccccc2)n1)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Reactant: CN1CCN(C(=O)c2ccc(B(O)O)cc2)CC1
Agent: O=C(Nc1cc2ccccc2c(Br)n1)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Product: CN1CCN(C(=O)c2ccc(-c3nc(NC(=O)C4(c5ccc6c(c5)OC(F)(F)O6)CC4)cc4ccccc34)cc2)CC1

Procedure:
1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-phenylisoquinolin-3-yl)cyclopropanecarboxamide was made by the procedure shown above starting from N-(1-bromoisoquinolin-3-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide and 4-(4-methylpiperazine-1-carbonyl)phenylboronic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]([N+:12]([O-:14])=[O:13])=[CH:9][C:10]=1[F:11])[C:5](O)=[O:6].CO>C1COCC1>[F:11][C:10]1[C:2]([F:1])=[CH:3][C:4]([CH2:5][OH:6])=[C:8]([N+:12]([O-:14])=[O:13])[CH:9]=1
Reactant: O=C(O)c1cc(F)c(F)cc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CO
Product: O=[N+]([O-])c1cc(F)c(F)cc1CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3,4-difluoro-6-nitrobenzoic acid (3.05 g, 15 mmol) in THF (20 mL) was added BH3 THF (30 mL). The resulting mixture was stirred at room temperature for 2 h and then at 50° C. for 5 h. The resulting mixture was then cooled to room temperature, and methanol (20 mL) was added slowly. The resulting mixture was concentrated, and the residue was treated with methanol twice more, to yield a yellow solid.