Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:41])[CH2:7][C@@:8]1([C:25]([NH:27][CH:28]2[CH2:33][CH2:32][N:31]([C:34](OC(C)(C)C)=O)[CH2:30][CH2:29]2)=[O:26])[C@H:12]([CH3:13])[CH2:11][N:10]([CH2:14][C:15]2[C:20]([CH:21]([F:23])[F:22])=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:24])[CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O.C(N(CC)CC)C.[C:56]1(C=O)[CH2:61][CH2:60][CH2:59][CH2:58][CH:57]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O1CCCC1>[Cl:24][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([CH:21]([F:22])[F:23])[C:15]=1[CH2:14][N:10]1[CH2:11][C@@H:12]([CH3:13])[C@@:8]([CH2:7][C:6]([OH:5])=[O:41])([C:25](=[O:26])[NH:27][CH:28]2[CH2:33][CH2:32][N:31]([CH2:34][C:56]3[CH2:61][CH2:60][CH2:59][CH2:58][CH:57]=3)[CH2:30][CH2:29]2)[CH2:9]1
Reactant: O=CC1=CCCCC1
Reactant: C[C@@H]1CN(Cc2c(Cl)cccc2C(F)F)C[C@]1(CC(=O)OC(C)(C)C)C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: C[C@@H]1CN(Cc2c(Cl)cccc2C(F)F)C[C@]1(CC(=O)O)C(=O)NC1CCN(CC2=CCCCC2)CC1
Reaction time: 2 h
Yield: 26.9 %

Procedure:
tert-Butyl 4-[(3R*,4S*)-3-[2-(tert-butoxy)-2-oxoethyl]-1-{[2-chloro-6-(difluoromethyl)phenyl]methyl}-4-methylpyrrolidin-3-amido]piperidine-1-carboxylate obtained in Example 12a (332 mg, 0.553 mmol) was dissolved in dichloromethane (3.0 ml), trifluoroacetic acid (3.0 ml) was added thereto, and the mixture was then left to stand at mom temperature. After two hours and 30 minutes, the reaction liquid was concentrated and azeotropically distilled with dichloromethane twice to give an intermediate. 186 mg of the resulting intermediate (372 mg) was dissolved in tetrahydrofuran (5 ml), triethylamine (116 μl, 0.831 mmol) and cyclohex-1-ene-1-carbaldehyde (91.5 mg, 0.831 mmol) were added, and the mixture was left to stand at room temperature. After 30 minutes, sodium triacetoxyborohydride (176 mg, 0.831 mmol) was added thereto, and the mixture was stirred at mom temperature. After 10 hours and 50 minutes, the mixture was concentrated. The residue was purified by silica gel column chromatography (ODS, elution solvent: water/methanol) to give the title compound (80 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+]([O-])=O)[CH:5]=[C:4]([Cl:11])[N:3]=1.[Cl:12][C:13]1[CH:18]=[C:17]([S:19][CH3:20])[C:16]([Cl:21])=[CH:15][C:14]=1[OH:22].C([O-])([O-])=O.[K+].[K+].O>CC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:22][C:14]2[CH:15]=[C:16]([Cl:21])[C:17]([S:19][CH3:20])=[CH:18][C:13]=2[Cl:12])[CH:5]=[C:4]([Cl:11])[N:3]=1
Reactant: CSc1cc(Cl)c(O)cc1Cl
Reactant: O=[N+]([O-])c1cc(Cl)nc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CSc1cc(Cl)c(Oc2cc(Cl)nc(Cl)c2)cc1Cl
Reaction time: 3 h

Procedure:
Quantities of 19.3 gm (0.1 mol) of 2,6-dichloro-4-nitropyridine and 23.1 gm (0.11 mol) of 2,5-dichloro-4-methylmercaptophenol were dissolved in 100 ml of acetone, 13.8 gm (0.1 mol) of K2CO3 were added, and the resulting mixture was stirred for 3 hours under reflux. It was then stirred into 500 ml of water, and the precipitate formed was recovered by suction filtration.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([O:13][C@H:14]2[CH2:19][C@H:18]([CH3:20])[CH2:17][CH2:16][C@H:15]2[C:21]([CH3:29])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH3:22])[O:10][C:9]1=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:31](=[O:40])[CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.B(F)(F)F.CCOCC.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:1]([N:8]1[CH:12]([C:11]([O:13][C@H:14]2[CH2:19][C@H:18]([CH3:20])[CH2:17][CH2:16][C@H:15]2[C:21]([CH3:29])([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH3:22])=[O:10])[CH:31]([CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:40][C:9]1=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H]1CC[C@@H](C(C)(C)c2ccccc2)[C@@H](Oc2cn(Cc3ccccc3)c(=O)o2)C1
Reactant: O=CCCc1ccccc1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@@H]1CC[C@@H](C(C)(C)c2ccccc2)[C@@H](OC(=O)C2C(CCc3ccccc3)OC(=O)N2Cc2ccccc2)C1
Temperature: -78 °C
Yield: 98 %

Procedure:
Under argon atmosphere, in 3 ml of methylene chloride was dissolved 202.8 mg (0.5 mmol) of 3-benzyl-5-((1S,2S,5R)-5-methyl-2-(1-methyl-1-phenylethyl)cyclohexyloxy)-2(3H)-oxazolone, and after the solution was cooled to −78° C., 67.1 mg (0.5 mmol) of hydrocinnamaldehyde and 63 μl (0.1 mmol) of boron trifluoride diethyl etherate were added to the solution and the mixture was reacted for 1.0 hour. After the temperature of the mixture was raised up to the room temperature, 15 ml of a saturated aqueous sodium hydrogen carbonate solution was added to the resulting reaction mixture and the mixture was extracted with 15 ml of methylene chloride. The organic layer was washed twice with 15 ml of water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 264.9 mg (0.49 mmol) of 3-benzyl-4-((1S,2S,5R)-5-methyl-2-(1-methyl-1-phenylethyl)cyclohexyloxy)carbonyl-5-(2-phenylethyl)-2-oxazolidinone as pale yellowish viscous liquid. A formation ratio of cis/trans isomers was cis isomer/trans isomer=29/71 according to 1H-NMR, and they were each single diastereomer. Yield based on 3-benzyl-5-((1S,2S,5R)-5-methyl-2-(1-methyl-1-phenylethyl)cyclohexyloxy)2(3H)oxazolone was 98.2%.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:44]=[C:43]([C:45]([NH:47][C:48]3[CH:53]=[CH:52][C:51]([C:54]4[CH:62]=[C:61]5[C:57]([CH2:58][N:59]([C@@H:64]([CH:69]([CH3:71])[CH3:70])[C:65]([O:67]C)=[O:66])[C:60]5=[O:63])=[CH:56][CH:55]=4)=[CH:50][CH:49]=3)=[O:46])[O:42][N:41]=2)=[CH:36][CH:35]=1>>[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:44]=[C:43]([C:45]([NH:47][C:48]3[CH:49]=[CH:50][C:51]([C:54]4[CH:62]=[C:61]5[C:57]([CH2:58][N:59]([C@@H:64]([CH:69]([CH3:71])[CH3:70])[C:65]([OH:67])=[O:66])[C:60]5=[O:63])=[CH:56][CH:55]=4)=[CH:52][CH:53]=3)=[O:46])[O:42][N:41]=2)=[CH:36][CH:35]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4cc(-c5ccc(Cl)cc5)no4)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4cc(-c5ccc(Cl)cc5)no4)cc3)cc2C1=O
Yield: 94 %

Procedure:
The compound of example 618 was prepared analogous to the compound of example 98 by hydrolysis of compound of example 617.
Reaction SMILES: Cl[CH2:2][C:3]([CH3:5])=[CH2:4].[N+:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])([O-:8])=[O:7]>>[CH3:2][C:3]([CH3:5])=[CH:4][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[N+:6]([O-:8])=[O:7]
Reactant: C=C(C)CCl
Reactant: O=[N+]([O-])c1ccccc1O
Product: CC(C)=COc1ccccc1[N+](=O)[O-]

Procedure:
3-Chloro-2-methylpropene was reacted with o-nitrophenol to yield 2-(2-methylprop-1-en-oxy) nitrobenzene; which was reduced to the corresponding aniline; reacted with N-chloromethyl-2-pyrrolidone to form the corresponding N-methylenepyrrolidonyl derivative.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH:27]([CH3:28])[CH2:26][N:25](CC5C=CC(OC)=CC=5)[C:24]4=[O:38])=[N:21][CH:22]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.FC(F)(F)S(O)(=O)=O.C(=O)([O-])O.[Na+]>FC(F)(F)C(O)=O>[CH3:1][C:2]1[C:3]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH:27]([CH3:28])[CH2:26][NH:25][C:24]4=[O:38])=[N:21][CH:22]=3)=[O:16])[CH2:13][CH2:14]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: COc1ccc(CN2CC(C)N(c3ccc(C(=O)N4CCN(c5ncc(C)cc5C)CC4)cn3)C2=O)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)NCC4C)nc3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
Using (6-bromopyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 127 and 1-(4-methoxybenzyl)-4-methylimidazolidin-2-one (106 mg) described in Preparation Example 52 and by the reaction and treatment in the same manner as in Example 1, 3-{5-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]pyridin-2-yl}-1-(4-methoxybenzyl)-4-methylimidazolidin-2-one (132 mg) was obtained. The obtained 3-{5-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]pyridin-2-yl}-1-(4-methoxybenzyl)-4-methylimidazolidin-2-one (132 mg) was dissolved in trifluoroacetic acid (2 mL), trifluoromethanesulfonic acid (0.11 mL) was added, and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added 5% aqueous sodium hydrogen carbonate solution, and the solvent was evaporated, and the mixture was extracted with ethyl acetate. The organic layer was washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (ethyl acetate:methanol) to give the title compound (83 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]([C:16]3[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=3)=[N:9][N:10]3[CH2:15][CH2:14][CH2:13][S:12][C:11]=23)=[CH:3][CH:2]=1.[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([N:33]=[C:34]=[O:35])(=[O:32])=[O:31])=[CH:26][CH:25]=1>ClCCl>[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH:33][C:34]([NH:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([C:8]3[C:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)=[C:11]4[S:12][CH2:13][CH2:14][CH2:15][N:10]4[N:9]=3)[CH:17]=2)=[O:35])(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: Nc1cccc(-c2nn3c(c2-c2ccncc2)SCCC3)c1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC(=O)Nc2cccc(-c3nn4c(c3-c3ccncc3)SCCC4)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(3-pyridin-4-yl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]thiazin-2-yl)-phenylamine (prepared as described in Example 3) (50 mg, 0.162 mmol) in dichloromethane (5 mL), 4-methyl-benzenesulfonyl isocyanate (28 mg, 0.178 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 2 hours and evaporated to dryness. The reaction mixture was purified by flash chromatography over silica gel using dichloromethane-methanol (97:3) as the eluant system. 1-(4-methyl-benzenesulfonyl)-3-[3-(3-pyridin-4-yl-6,7-dihydro-5H-pyrazolo-[5,1-b][1,3]thiazin-2-yl)-phenyl]-urea was obtained as a colorless solid (21 mg, 32%).
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:23][CH:22]=[C:21]([C:24]([OH:26])=O)[CH:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.Cl.[CH3:59][N:60]([CH3:78])[C:61]([CH:63]1[CH2:67][CH2:66][N:65]([CH2:68][C:69]2[CH:74]=[CH:73][C:72]([CH2:75][NH:76][CH3:77])=[CH:71][CH:70]=2)[CH2:64]1)=[O:62]>C(Cl)Cl>[CH:1]1([N:4]([CH2:18][C:19]2[O:23][CH:22]=[C:21]([C:24]([N:76]([CH2:75][C:72]3[CH:71]=[CH:70][C:69]([CH2:68][N:65]4[CH2:66][CH2:67][CH:63]([C:61]([N:60]([CH3:59])[CH3:78])=[O:62])[CH2:64]4)=[CH:74][CH:73]=3)[CH3:77])=[O:26])[CH:20]=2)[S:5]([C:8]2[C:9]([CH3:17])=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=2[CH3:14])(=[O:7])=[O:6])[CH2:2][CH2:3]1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2cc(C(=O)O)co2)C2CC2)c(C)c1
Reactant: CNCc1ccc(CN2CCC(C(=O)N(C)C)C2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N(Cc2cc(C(=O)N(C)Cc3ccc(CN4CCC(C(=O)N(C)C)C4)cc3)co2)C2CC2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 5-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)furan-3-carboxylic acid (40 mg, 0.105 mmol), EDCI (28 mg, 0.158 mmol), HOBt (21 mg, 0.16 mmol), DIPEA (0.04 mL, 0.21 mmol), N,N-dimethyl-1-{4-[(methylamino)methyl]benzyl}pyrrolidine-3-carboxamide dihydrochloride (40 mg, 0.12 mmol) and DCM (5 mL).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH3:7])[C:3](Cl)=[O:4].[C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9]>>[C:8]([C:12]1[CH:17]=[CH:16][C:15]([C:3](=[O:4])[CH:2]([CH3:1])[CH2:6][CH3:7])=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)c1ccccc1
Reactant: CCC(C)C(=O)Cl
Product: CCC(C)C(=O)c1ccc(C(C)(C)C)cc1

Procedure:
The procedure of Example 3 was followed for the reaction of 60g (0.5 mole) of 2-methylbutyryl chloride with 67g (0.5 mole) of tert-butylbenzene. Obtained was 98.6g of a clear liquid: ir (film) 3.4 (s), 5.95 (s), 8.2 (m) microns; nmr (CDCl3) 7.66 (4H, d of d) 3.37 (1H, q), 1.77 (2H, m), 1.28 (9H, s), 1.16 (3H, d), 0.88 (3H, t) ppm. A VPC analysis indicated a single pure product.
Reaction SMILES: C([O:3][P:4]([CH2:9][O:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([C:18]2[NH:22][C:21]3[CH:23]=[C:24]([C:27](=[O:39])[NH:28][C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:30]=4)[CH:25]=[CH:26][C:20]=3[N:19]=2)=[C:13]([Cl:40])[CH:12]=1)(=[O:8])[O:5]CC)C.C[Si](Br)(C)C>C(Cl)Cl>[Cl:17][C:15]1[CH:16]=[C:11]([CH:12]=[C:13]([Cl:40])[C:14]=1[C:18]1[NH:22][C:21]2[CH:23]=[C:24]([C:27](=[O:39])[NH:28][C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=3)[CH:25]=[CH:26][C:20]=2[N:19]=1)[O:10][CH2:9][P:4](=[O:3])([OH:8])[OH:5]
Reactant: CCOP(=O)(COc1cc(Cl)c(-c2nc3ccc(C(=O)Nc4ccc5ccccc5n4)cc3[nH]2)c(Cl)c1)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: O=C(Nc1ccc2ccccc2n1)c1ccc2nc(-c3c(Cl)cc(OCP(=O)(O)O)cc3Cl)[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {3,5-dichloro-4-[6-(quinolin-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-phenoxymethyl}-phosphonic acid diethylester (50 mg, 0.083 mmol) in CH2Cl2 (5 mL) was added TMSBr (0.11 ml, 0.83 mmol) and the solution was stirred at ambient temperature overnight. The solvent was removed under reduced pressure and the residue was purified by HPLC to give the title compound as a white solid. 1H NMR (Methanol-d4, 400 MHz): δ 8.84 (d, 1H), 8.56 (d, 1H), 8.21 (d, 2H), 8.15 (d, 1H), 8.03 (m, 2H), 7.90 (d, 1H), 7.80 (t, 1H), 7.37 (s, 2H), 4.49 (d, 2H). MS (m/z) 543.3 (M+1); Retention time: 1.10 min. (method 10).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH:4]([C:5](Cl)=[O:6])[C:3]1([CH3:9])[CH3:8].[NH2:11][CH2:12][CH2:13][S:14]([OH:17])(=[O:16])=[O:15]>[OH-].[Na+].ClCCl>[CH3:1][C:2]1([CH3:10])[C:3]([CH3:9])([CH3:8])[CH:4]1[C:5]([NH:11][CH2:12][CH2:13][S:14]([OH:17])(=[O:16])=[O:15])=[O:6]
Reactant: NCCS(=O)(=O)O
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC1(C)C(C(=O)NCCS(=O)(=O)O)C1(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2,2,3,3-tetramethylcyclopropanecarbonyl taurine (TMC-taurine) is synthesized by adding tetramethylcyclopropanecarbonyl chloride (TMC-chloride) to taurine dissolved in a sodium hydroxide solution, preferably 5–15% NaOH aqueous solution, more preferably 10% NaOH aqueous solution. The reaction mixture is stirred for 3–10 hrs, preferably for 5 hr at room temperature (20–25° C.). The water is evaporated and the product is extracted by boiling ethanol. The insoluble salts are filtered off and TMC-taurine is crystallized using ethanol:diethyl ether solution. TMC-taurine is chlorinated in dry dichloromethane using thionyl chloride and the suitable amides (compound XXVII in reaction scheme II) are synthesized by slowly adding of the TMC-taurine chloride in dichloromethane to an aqueous solution of the corresponding amine (compound XXVI in reaction scheme II). After the addition, the reaction mixture is stirred for 2–5 hr, preferably for 2 hr at room temperature (20–25° C.), the organic solvent is evaporated, water is added and the products are extracted with a suitable organic medium such as chloroform. The organic fraction is dried using a drying agent such as Na2SO4 or MgSO4, filtered, evaporated and the products are crystallized using chloroform:hexane mixtures to get the desirable product. The chemical structures are identified by elemental analysis and spectroscopic methods.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]([C:17]([F:20])([F:19])[F:18])=[N:9]2)=[CH:4][CH:3]=1.[C:21]1([CH3:30])[C:22]([C:27](Cl)=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=1.C(N(CC)CC)C>C(Cl)Cl>[F:18][C:17]([F:20])([F:19])[C:10]1[CH:11]=[C:12]([C:13]([F:14])([F:15])[F:16])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:27](=[O:28])[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH3:30])=[CH:7][CH:6]=2)[N:9]=1
Reactant: Nc1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1
Reactant: Cc1ccccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1
Reaction time: 72 h
Yield: 46.3 %

Procedure:
A mixture of 1-(4′-aminophenyl)-3,5-bis(trifluoromethyl)pyrazole (0.10 g, 0.34 mmol), o-toluoyl chloride (0.062 mL, 0.43 mmol), and triethylamine (0.06 mL, 0.43 mmol) in methylene chloride (7 mL) was stirred under argon for three days. The reaction mixture was diluted with methylene chloride, washed with 1N hydrochloric acid (2×50 mL), brine (2×40 mL), dried (magnesium sulfate) and concentrated to give an off-white solid. Recrystallization from methylene chloride/hexanes gave the above-named compound (0.065 g). m.p. 175° C. NMR (CDCl3, 400 MHz): δ 7.83 (d, 2H), 7.64 (br s, 1H), 7.53 (m, 3H), 7.43 (m, 1H), 7.31 (m, 2H), 7.10 (s, 1H), 2.56 (s, 3H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>>[CH:33]1([C:36]([NH:1][C@H:2]2[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]3[C:15]4[N:16]=[CH:17][N:18]=[C:19]([C:20]5[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=5[O:28][CH2:29][CH:30]5[CH2:31][CH2:32]5)[C:14]=4[NH:13][CH:12]=3)=[O:10])[CH2:4][CH2:3]2)=[O:37])[CH2:35][CH2:34]1
Reactant: O=C(Cl)C1CC1
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c[nH]c23)c1
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)C5CC5)CC4)c[nH]c23)c1

Procedure:
Starting from trans-4-(2-cyclopropylmethoxy-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A153) and cyclopropanecarbonyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1.Br[C:18]1[CH:19]=[CH:20][C:21]2[N:25]=[C:24]([CH:26]3[CH2:28][CH2:27]3)[N:23]([CH2:29][CH2:30][CH3:31])[C:22]=2[CH:32]=1.CNCCNC.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.CS(C)=O>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:18]3[CH:19]=[CH:20][C:21]4[N:25]=[C:24]([CH:26]5[CH2:27][CH2:28]5)[N:23]([CH2:29][CH2:30][CH3:31])[C:22]=4[CH:32]=3)[C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=c1cc(OCc2ccc(Cl)cc2)cc[nH]1
Reactant: CCCn1c(C2CC2)nc2ccc(Br)cc21
Agent: I[Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: CCCn1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cc21
Temperature: 120 °C
Yield: 11 %

Procedure:
The mixture of 4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (50 mg, 0.21 mmol), 6-bromo-2-cyclopropyl-1-propyl-1H-benzimidazole (65.2 mg, 0.23 mmol), copper iodide (40.4 mg, 0.21 mmol), N,N′-dimethylethylenediamine (0.024 ml, 0.21 mmol), potassium carbonate (73.3 mg, 0.53 mmol) and DMSO (1.5 ml) was heated at 120° C. for 1 h under microwave irradiation. The mixture was quenched with 28% NH3 solution at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by NH silica gel column chromatography (hexane/EtOAc). The solid was recrystallized from EtOAc/hexane to give the title compound (10 mg) as an off-white solid.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([CH3:58])([CH3:57])[C@H:7]([NH:49][C:50]([O:52][C:53](C)(C)C)=[O:51])[C:8](=[O:48])[NH:9][C@@H:10]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C@@H:11]([OH:40])[CH2:12][C@H:13]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)=[CH:30][CH:29]=1)[NH:14][C:15](=[O:26])[C@H:16]([C:22]([CH3:25])([CH3:24])[CH3:23])[NH:17][C:18](=[O:21])[O:19][CH3:20])(=[O:3])[CH3:2].Cl.C(N(C(C)C)CC)(C)C.ClC(OC)=O>O1CCOCC1.O>[C:1]([O:4][CH2:5][C:6]([CH3:58])([CH3:57])[C@H:7]([NH:49][C:50]([O:52][CH3:53])=[O:51])[C:8](=[O:48])[NH:9][C@@H:10]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C@@H:11]([OH:40])[CH2:12][C@H:13]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)=[CH:32][CH:33]=1)[NH:14][C:15](=[O:26])[C@H:16]([C:22]([CH3:24])([CH3:23])[CH3:25])[NH:17][C:18](=[O:21])[O:19][CH3:20])(=[O:3])[CH3:2]
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)COC(C)=O)C(C)(C)C
Agent: COC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)COC(C)=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.4 %

Procedure:
To a solution of the product of Example 174F (0.030 g, 0.037 mmol) in dioxane (0.50 mL) at 0° C. was added a solution of HCl in dioxane (3.0 mL, 4 N), and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated, and the residue was dissolved in tetrahydrofuran (0.40 mL) and diisopropylethylamine (0.030 mL, 0.172 mmol) and methyl chloroformate (0.0032 mL, 0.041 mmol) were added at room temperature. After 1 hour water was added and the reaction was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with a gradient starting with dichloromethane and ending with 50% acetone in dichloromethane to give the title compound (0.019 g, 67% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.80-0.82 (m, 15 H), 1.41-1.58 (m, 2 H), 2.00 (s, 3 H), 2.54-2.57 (m, 1 H), 2.71-2.79 (m, 3 H), 3.49 (s, 3 H), 3.55 (s, 3 H), 3.61-3.73 (m, 2 H), 3.78-3.84 (m, 1 H), 4.03-4.24 (m, 3 H), 4.90 (d, J=5.5 Hz, 1 H), 6.62 (d, J=9.6 Hz, 1 H), 7.09 (d, J=9.6 Hz, 1 H), 7.10-7.21 (m, 7 H), 7.29-7.31 (m, 1 H), 7.57 (d, J=8.8 Hz, 1 H), 7.80 (d, J=9.9 Hz, 1 H), 7.85-7.89 (m, 4 H), 8.64 (m, 1 H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.CC(C)([O-])C.[K+].Cl[CH2:15][O:16][CH3:17]>C1COCC1.CN(C=O)C>[CH3:15][O:16][CH2:17][O:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccnc1
Reactant: COCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COCOc1cccnc1
Temperature: -15 °C
Reaction time: 1 h

Procedure:
Dissolve 3-hydroxypyridine (7 g, 74 mmol) in THF (20.6 mL) and DMF (34.4 mL) and cool to −15° C. Add potassium tert-butoxide (8.3 g, 74 mmol) and stir at −15° C. for 30 min. Treat the mixture with chloromethylmethyl ether (5.81 mL, 77 mmol) dropwise over 40 min. After the addition is complete, stir the mixture at −15° C. for an additional 1 h. Remove the ice bath and allow the mixture to warm slowly to 15° C. Pour the mixture into saturated aqueous sodium chloride and stir vigorously for 10 min. Extract the resulting solution with three portions of ethyl acetate. Combine the organic extracts and wash with saturated aqueous sodium chloride, dry over sodium sulfate, filter, and concentrate in vacuo. 1H NMR (400 MHz, CDCl3) δ 8.42 (d, J=3 Hz, 1H), 828 (d, J=5 Hz, 1H), 7.37-7.42 (m, 1H), 7.21-7.27 (m, 1H), 5.20 (s, 2H), 3.49 (s, 3H).