Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH:12]([NH2:16])[CH2:11]2)[N:9]=1)[C:2]([NH2:4])=[NH:3].[CH3:17][N:18]=[C:19]=[S:20].C(Cl)(Cl)Cl.CO.N>C(O)C>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH:12]([NH:16][C:19]([NH:18][CH3:17])=[S:20])[CH2:11]2)[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: CN=C=S
Reactant: N=C(N)Nc1nc(C2CCCC(N)C2)cs1
Agent: N
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CNC(=S)NC1CCCC(c2csc(NC(=N)N)n2)C1

Procedure:
To a solution of 2-guanidino-4-(3-aminocyclohexyl)thiazole (0.6 g.) in ethanol (20 ml) was added methylisothiocyanate (0.18 g.) and the resulting solution was heated under reflux for two hours. The residue obtained on evaporation of the ethanol was subjected to column chromatography on silica gel (Kiesilgel 60, Merck) using chloroform/methanol/ammonia (s.g. 0.88) 8:2:0.3 v/v/v for development. The product, 2-guanidino-4-[3-(3-methylthioureido)cyclohexyl]thiazole, (0.4 g.) was obtained as a glass. The n.m.r. spectrum, in d6 dimethylsulphoxide, included resonances at 1.2-2.2(m,9H);2.8(d,3H); 4.0(m,1H); 6.2(s,1H); 6.8(br s,4H); and 7.2(br d,2H).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([CH2:10][NH2:11])[N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:19][CH2:20][C:21]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32](=O)[O:33]C2C=CC=CC=2)=[CH:27][CH:26]=1)([CH3:24])[CH2:22][OH:23]>CC#N>[C:1]([C:5]1[CH:9]=[C:8]([CH2:10][NH:11][C:32]([NH:31][C:28]2[CH:27]=[CH:26][C:25]([C:21]([CH3:24])([CH2:22][OH:23])[CH2:20][OH:19])=[CH:30][CH:29]=2)=[O:33])[N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(CN)n(-c2cccc(Cl)c2)n1
Reactant: CC(CO)(CO)c1ccc(NC(=O)Oc2ccccc2)cc1
Solvent: CC#N
Product: CC(C)(C)c1cc(CNC(=O)Nc2ccc(C(C)(CO)CO)cc2)n(-c2cccc(Cl)c2)n1
Reaction time: 16 h
Yield: 72.6 %

Procedure:
To a stirred solution of (3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methanamine (80 mg, 0.31 mmol, 1.0 eq) in MeCN (7 mL) was added TEA (0.17 mL, 1.2 mmol, 4 eq) followed by phenyl 4-(1,3-dihydroxy-2-methylpropan-2-yl)phenylcarbamate (94 mg, 0.31 mmol, 1 eq) and the mixture was stirred for 16 h at reflux. The reaction mixture was concentrated under vacuum and the residue was purified by CC using EtOAc/n-hexane 1:1 as eluent to get 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(4-(1,3-dihydroxy-2-methylpropan-2-yl)phenyl)urea (106 mg; 73%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[C:18]([C:19](O)=[O:20])=[CH:17][N:16]=1.[NH2:28][CH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[C:18]([C:19]([NH:28][CH:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:20])=[CH:17][N:16]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1cc(C(F)(F)F)c(C(=O)O)cn1
Reactant: NC1CCOCC1
Product: Cc1onc(-c2ccccc2)c1COc1cc(C(F)(F)F)c(C(=O)NC2CCOCC2)cn1
Yield: 45 %

Procedure:
As described for example 12, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-4-trifluoromethyl-nicotinic acid (200 mg, 0.53 mmol) instead of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid was converted using 4-aminotetrahydropyran instead of 2,2,2-trifluoroethylamine to the title compound (SiO2, ethyl acetate:dichloromethane=50:50 to 100:0, 109 mg, 45%) which was obtained as a white solid. MS: m/e=462.2 [M+H]+.
Reaction SMILES: B1(Br)OC2C(=CC=CC=2)O1.[OH:11][C:12]1[C:13]2[C:14](=[O:45])[CH2:15][CH2:16][C@H:17]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)[C:18]=2[C:19]([O:33][CH3:34])=[C:20]2[C:25]=1[C:24]([O:26]COC)=[C:23]([CH:30]=[O:31])[C:22]([CH3:32])=[CH:21]2>ClCCl.C(=O)(O)[O-].[Na+]>[OH:26][C:24]1[C:25]2[C:20](=[C:19]([O:33][CH3:34])[C:18]3[C@@H:17]([O:35][CH2:36][C:37]4[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=4)[CH2:16][CH2:15][C:14](=[O:45])[C:13]=3[C:12]=2[OH:11])[CH:21]=[C:22]([CH3:32])[C:23]=1[CH:30]=[O:31]
Reactant: COCOc1c(C=O)c(C)cc2c(OC)c3c(c(O)c12)C(=O)CC[C@@H]3OCc1ccc(OC)cc1
Agent: BrB1Oc2ccccc2O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(CO[C@H]2CCC(=O)c3c2c(OC)c2cc(C)c(C=O)c(O)c2c3O)cc1
Temperature: 23 °C
Reaction time: 0.83 h
Yield: 82.9 %

Procedure:
A solution of B-bromocatecholborane (418 mg, 2.10 mmol, 2.0 equiv) in dichloromethane (15 mL) was added to a solution of (S)-9-hydroxy-10-methoxy-5-(4-methoxybenzyloxy)-1-(methoxymethoxy)-3-methyl-8-oxo-5,6,7,8-tetrahydroanthracene-2-carbaldehyde (490 mg, 1.05 mmol, 1 equiv) in dichloromethane (15 mL) at −78° C. After 50 min, the reaction mixture was diluted with saturated aqueous sodium bicarbonate solution (25 mL) and dichloromethane (100 mL). The cooling bath was removed, and the partially frozen mixture was allowed to warm to 23° C. The biphasic mixture was diluted with 0.2 M aqueous sodium hydroxide solution (100 mL). The layers were separated. The aqueous layer was extracted with dichloromethane (100 mL). The organic layers were combined. The combined solution was washed sequentially with 0.1 M aqueous hydrochloric acid solution (100 mL), water (2×100 mL), then saturated aqueous sodium chloride solution (100 mL) and the washed solution was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated to provide 380 mg of the product, (S)-1,9-dihydroxy-10-methoxy-5-(4-methoxybenzyloxy)-3-methyl-8-oxo-5,6,7,8-tetrahydroanthracene-2-carbaldehyde, as a yellow foam (86%). 1H NMR (500 MHz, CDCl3): 15.89 (br s, 1H), 12.81 (br s, 1H), 10.51 (s, 1H), 7.27-7.26 (m, 3H), 6.86 (d, 2H, J=9.2 Hz), 5.14 (app s, 1H), 4.62 (d, 1H, J=11.0 Hz), 4.51 (d, 1H, J=11.0 Hz), 3.85 (s, 3H), 3.80 (s, 3H), 3.21 (m, 1H), 2.73 (s, 3H), 2.62 (m, 1H), 2.54 (m, 1H), 2.07 (m, 1H). 13C NMR (125 MHz, CDCl3): 204.4, 192.7, 166.6, 164.3, 159.3, 144.4, 142.7, 137.9, 130.4, 130.2, 129.4, 114.9, 114.2, 113.9, 113.8, 109.4, 70.4, 67.1, 62.8, 55.3, 31.8, 26.5. FTIR, cm−1 (thin film): 3316 (br w), 2938 (m), 1678 (m), 1610 (s), 1514 (m), 1393 (m), 1246 (s). HRMS (ESI): Calcd for (C25H24O7+Na)+ 459.1414; Found 459.1354. TLC (50% ethyl acetate-hexanes): Rf=0.30 (CAM).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[NH:10][C:9]=2[C:18]([OH:20])=O)=[CH:4][CH:3]=1.Cl.[NH2:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]([O:32][CH3:33])=[O:31])=[N:28][CH:29]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[NH:10][C:9]=2[C:18]([NH:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]([O:32][CH3:33])=[O:31])=[N:28][CH:29]=2)=[O:20])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(CN)cn1
Reactant: O=C(O)c1[nH]c(-c2cccs2)cc1-c1ccc(F)cc1
Agent: Cl
Product: COC(=O)c1ccc(CNC(=O)c2[nH]c(-c3cccs3)cc2-c2ccc(F)cc2)cn1
Yield: 66 %

Procedure:
This material was prepared using a method substantially similar to that of Example 5 from 3-(4-fluorophenyl)-5-(2-thienyl)-1H-pyrrole-2-carboxylic acid and methyl 5-(aminomethyl)pyridine-2-carboxylate hydrochloride, yielding the title compound. Methyl 5-[({[3-(4-fluorophenyl)-5-(2-thienyl)-1H-pyrrol-2-yl]carbonyl}amino)methyl]pyridine-2-carboxylate: Yield 66%; m.p. 174-175° C.; IR 3398, 3255, 1733, 1643, 1541, 1432, 1258, 1121 cm−1; 1H-NMR (500 MHz, δ ppm, CDCl3) 9.59 (sb, 1H), 8.56 (s, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.66 (dd, J=8.0 Hz, J′=2.1 Hz, 1H), 7.41 (dd, J=5.3 Hz, J′=2.1 Hz, 2H), 7.25 (dd, J=5.1 Hz, J′=1.0 Hz, 1H), 7.22 (dd, J=3.6 Hz, J′=1.0 Hz, 1H), 7.10 (t, J=8.6 Hz, 2H), 7.05 (dd, J=5.0 Hz, J′=3.6 Hz, 1H), 6.38 (d, J=3.0 Hz, 1H), 6.01 (tb, J=5.9 Hz, 1H), 4.53 (d, J=6.1 Hz, 2H), 4.01 (s, 3H); 13C-NMR (126 MHz, δ ppm, CDCl3) 165.6, 163.8, 161.8, 161.4, 149.1, 147.3, 137.9, 136.2, 134.3, 131.4, 131.3, 131.2, 129.7, 128.1, 127.6, 125.2, 124.8, 123.5, 121.6, 116.5, 116.3, 110.4, 53.1, 40.8.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1C(O)=O.[N-:12]=[N+]=[N-].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[NH2:12]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)c1cccc(F)c1Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Nc1cccc(F)c1Cl
Temperature: 50 °C
Reaction time: 16 h
Yield: 1024.6 %

Procedure:
To a solution of 2-chloro-3-fluorobenzoic acid (4 g, 23 mmol) in CHCl3 (50 mL), sulfonic acid (64 mL) was added and then sodium azide (2.62 g, 1.75 mmol) was added by portion. After addition, the reaction mixture was stirred at 50° C. for 16 hours. The solvent was evaporated and basicified with ammonium hydroxide at ice-bath. Then was extracted with ethyl acetate (3×). The combine organic phase was dried and conc. to give the desired product (2.61 g, 78%). LC-MS m/z 146.2 (M+).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH2:13][C:14](=[O:16])[CH3:15])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])(=[O:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH2:13][CH:14]([OH:16])[CH3:15])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])(=[O:3])[CH3:2]
Reactant: COc1ccc(CC(C)=O)cc1NC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CC(C)O)cc1NC(C)=O
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 95.1 %

Procedure:
To a solution of compound 12 (0.25 g, 1.13 mmol) in methanol was added NaBH4 in portions in the period of 20 min at 0° C. The resulting solution was stirred at such temperature for another 40 min. No more starting materials were detected on TLC. Ice water was added to the reaction slowly. It was extracted with CHCl3 three times. The combined organic phases were washed with brine, and dried over Na2SO4. Removal of the solvent afforded the crude product. Purification of the crude product by using a silica gel column gave the desired product 13 (0.24 g, 95%). 1HNMR(CDCl3): 8.24 (d, J=1.8 Hz, 1H), 7.75 (br, 1H), 6.82 (m, 2H), 4.00 (m, 1H), 3.86 (s, 3H), 2.70 (m, 2H), 2.20 (s, 3H), 1.24 (d, J=6.1 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:40]=[CH:41][CH:42]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=2)[C:34](O)=[O:35])=[O:30])[CH:11]=1)=[O:9].FC(F)(F)C1C=C(C=CC=1)CNC(C1C=CN=C(C2C=C(N3CCCCC3)C=CC=2NC(=O)C2C=CC=C(C(N(CCC(NCCOC)=O)C)=O)C=2)C=1)=O.[NH:99]1[CH2:104][CH2:103][CH:102]([NH:105][C:106](=[O:108])[CH3:107])[CH2:101][CH2:100]1>>[C:106]([NH:105][CH:102]1[CH2:103][CH2:104][N:99]([C:34]([C:33]2[CH:32]=[C:31]([CH:39]=[CH:38][CH:37]=2)[C:29]([NH:28][C:17]2[CH:18]=[CH:19][C:20]([N:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)=[CH:21][C:16]=2[C:12]2[CH:11]=[C:10]([CH:15]=[CH:14][N:13]=2)[C:8]([NH:7][CH2:6][C:5]2[CH:40]=[CH:41][CH:42]=[C:3]([C:2]([F:1])([F:44])[F:43])[CH:4]=2)=[O:9])=[O:30])=[O:35])[CH2:100][CH2:101]1)(=[O:108])[CH3:107]
Reactant: O=C(O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: CC(=O)NC1CCNCC1
Agent: COCCNC(=O)CCN(C)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Product: CC(=O)NC1CCN(C(=O)c2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)CC1

Procedure:
This compound was prepared from 3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)benzoic acid 4.1e using the procedure described for the preparation of N1-(2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)-N3-(3-(2-methoxyethylamino)-3-oxopropyl)-N3-methylisophthalamide 4.2. N-(piperidin-4-yl)acetamide was used as the amine component in this coupling. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.98 (d, J=3.5 Hz, 1H), 8.85 (d, J=9.0 Hz, 1H), 8.47 (s, 1H), 8.24 (d, J=2.4 Hz, 1H), 8.12˜8.09 (m, 2H), 7.90˜7.88 (m, 1H), 7.77˜7.68 (m, 5H), 6.62˜7.55 (m, 2H), 4.72 (s, 2H), 4.58 (s, 1H), 3.99˜3.93 (m, 1H), 3.73˜3.70 (m, 5H), 3.27˜3.12 (m, 2H), 2.09˜2.02 (m, 5H), 1.94 (s, 3H), 1.85 (d, J=4.8 Hz, 1H), 1.60˜1.35 (m, 2H). MS (ES, m/z): 727 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[NH:16][N:15]=[N:14][N:13]=2)=[C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]2[C:4](=[CH:5][C:6]([F:24])=[C:7]([Cl:23])[CH:8]=2)[N:3]=1.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[Cl:23][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[F:24])[N:3]=[C:2]([N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[C:11]([C:12]1[N:16]=[N:15][NH:14][N:13]=1)=[C:10]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C1CCNCC1
Reactant: Fc1cc2nc(Cl)c(-c3nnn[nH]3)c(-c3ccccc3)c2cc1Cl
Product: Fc1cc2nc(N3CCCCC3)c(-c3nn[nH]n3)c(-c3ccccc3)c2cc1Cl

Procedure:
The title compound was prepared in analogy to example 102 step C from 2,6-dichloro-7-fluoro-4-phenyl-3-(1H-tetrazol-5-yl)-quinoline and piperidine. Off-white solid. MS (ESI): 409.5 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.[C:9]1([C:15]([CH:17](Cl)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(N(CC)CC)C.C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15](=[O:16])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1
Reactant: O=C(c1ccccc1)C(Cl)c1ccccc1
Reactant: O=c1ncc(Cl)c[nH]1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)C(c1ccccc1)n1cc(Cl)cnc1=O
Yield: 40.3 %

Procedure:
A solution of 5-chloropyrimidin-2-one (406 mg) and desyl chloride (2-chloro-2-phenyl acetophenone) (692 mg) in triethylamine (1 ml) and ethanol (20 ml) was stirred at ambient temperature for one hour, then heated at reflux for 11/2 hours. After evaporation of solvents, the residue was dissolved in ethyl acetate (150 ml). The solution was washed with water (100 ml), dried (MgSO4) and evaporated to a foam which was crystallised from ethyl acetate to give the title pyrimidinone (393 mg,); m.p. 145°-146°; λmaxEtOH 230 nm (ε 15960), 250 nm (ε 15000), 335 nm (ε 4700), λinf 262.5 nm (ε 8400), 269 n, (ε 4420).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:14](=[O:19])C(Cl)(Cl)Cl)[N:5]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:6]=1.[NH2:20][C:21]1[C:29]([Br:30])=[CH:28][C:27]([Br:31])=[CH:26][C:22]=1[C:23](O)=[O:24].C(N(CC)CC)C.CS(Cl)(=O)=O>C(#N)C.O>[Br:1][C:2]1[N:3]=[C:4]([C:14]2[O:19][C:23](=[O:24])[C:22]3[CH:26]=[C:27]([Br:31])[CH:28]=[C:29]([Br:30])[C:21]=3[N:20]=2)[N:5]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:6]=1
Reactant: Nc1c(Br)cc(Br)cc1C(=O)O
Reactant: O=C(c1nc(Br)cn1-c1ncccc1Cl)C(Cl)(Cl)Cl
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=c1oc(-c2nc(Br)cn2-c2ncccc2Cl)nc2c(Br)cc(Br)cc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 41.7 %

Procedure:
To a solution of 0.50 g of 1-[4-bromo-1-(3-chloro-2-pyridinyl)-1H-imidazol-2-yl]-2,2,2-trichloroethanone and 0.37 g of 2-amino-3,5-dibromobenzoic acid in 10 ml of acetonitrile was added 0.43 ml of triethylamine. The resulting mixture was stirred at room temperature for 1 day. Thereto 0.12 ml of methanesulfonyl chloride was added, and the mixture was stirred at room temperature for 3 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.29 g of 2-[4-bromo-1-(3-chloro-2-pyridinyl)-1H-imidazol-2-yl]-6,8-dibromo-4H-3,1-benzoxazine-4-one of the formula:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>CN(C=O)C>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To the solution of p-acetylphenol (10 g) in DMF (50 ml) were added potassium carbonate (12.2 g) and t-butyl bromoacetate (16.2 ml), and the mixture was stirred at room temperature for 2 hours. After the reaction mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate, washed with water and dried over anhydrous magnesium sulfate. After the solvents were removed by distillation, crystals thus obtained were washed with n-hexane to give 17.7 g of t-butyl 4-acetylphenoxyacetate (yield, 96%).
Reaction SMILES: C([O:9][C@@H:10]1[C@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@@H:13]([CH2:24][O:25]C(=O)C2C=CC=CC=2)[O:12][C@H:11]1[N:34]1[C:52]2[N:51]=[C:50](Cl)[N:49]=[C:38]([NH:39][C@H](C)CSC3SC=CN=3)[C:37]=2[N:36]=[CH:35]1)(=O)C1C=CC=CC=1>N>[C@@H:11]1([N:34]2[C:52]3[N:51]=[CH:50][N:49]=[C:38]([NH2:39])[C:37]=3[N:36]=[CH:35]2)[O:12][C@H:13]([CH2:24][OH:25])[C@@H:14]([OH:15])[C@H:10]1[OH:9]
Reactant: C[C@H](CSc1nccs1)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: N
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 20 °C
Reaction time: 40 h
Yield: 79.8 %

Procedure:
2',3',5'-Tri-O-benzoyl-2-chloro-N-[(R)-1-(2-thiazolyl)thio-2-propyl]adenosine (1.2 g, 1.5 mmol) was dissolved in methanolic ammonia (25 ml) (previously saturated at -10° C.) and stirred at 20° C. for 40 h. The reaction mixture was concentrated to an oil at reduced pressure and purified by flash chromatography eluting with a mixture of dichloromethane, ethanol and ammonia (90:10:1), to provide the title 2-chloro-N-[(R)-1-(2-thiazolyl)thio-2-propyl)]adenosine (0.32 g, 46%) as a foam, 1H NMR (DMSO-d6) δ1.31 (3H, d, CHCH3), 3.95 (1H, q, H-4'), 4.12 (1H, q, H-3'), 4.51 (1H, q, H-2'), 5.07 (1H, t, 5'-OH), 5.22, 5.50 (2H, 2d, 2'-and 3'-OH), 5.82 (1H, d, H-1'), 7.63 (1H, d, Ar--H), 7.72 (1H, d, Ar--H), 8.41 (1H, s, H-8), 8.48 (1H, d, N--H).
Reaction SMILES: Br[C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11](=[O:12])[C:4]=2[CH:3]=1.O1CCOCC1.[N:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].ClCCl>C(OCC)(=O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[N:19]1[CH:24]=[CH:23][C:22]([C:2]2[S:6][C:5]3[CH2:7][CH2:8][CH2:9][CH2:10][C:11](=[O:12])[C:4]=3[CH:3]=2)=[CH:21][CH:20]=1
Reactant: OB(O)c1ccncc1
Reactant: O=C1CCCCc2sc(Br)cc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C1CCCCc2sc(-c3ccncc3)cc21
Temperature: 110 °C
Yield: 67.5 %

Procedure:
To a pressure tube were added 2-bromo-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophen-4-one (2.15 g, 8.77 mmol), 1,4-dioxane (54.8 mL, 702 mmol), pyridine-4-boronic acid (1.40 g, 11.4 mmol), cesium carbonate (8.50 g, 26.0 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (380 mg, 0.460 mmol) and water (7.90 mL, 439 mmol). The tube was sealed and the mixture was heated at 110° C. for 16 hr. The reaction mixture was allowed to cool to rt then diluted with ethyl acetate (15 mL) and water (10 mL) and transferred to a separatory funnel. The organic layer was separated and the aqueous phase was extracted with ethyl acetate (3×10 mL). The combined organic phases were washed with brine (10 mL) then dried over anhydrous MgSO4. Insoluble materials were removed by filtration, the filtrate was concentrated and the obtained residue was purified by column chromatography (SiO2, elution with 0-100% EA/DCM) to give the title compound as a yellow foam (1.44 g, 68% yield). LCMS: (FA) ES+ , 244. 1H NMR (300 MHz, DMSO-d6) δ: 8.55-8.57 (dd, J=1.7 Hz, J=4.9 Hz, 2H), 7.91-7.92 (br s, 1H), 7.62-7.64 (dd, J=1.5 Hz, J=4.9 Hz, 2H), 3.15-3.20 (m, 2H), 2.69-2.73 (m, 2H), 1.80-1.90 (m, 4H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1>[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=1
Reactant: Cc1ccccc1B(O)O
Reactant: CC(C)(C)c1ccc(Br)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1ccccc1-c1ccc(C(C)(C)C)cc1
Yield: 96.5 %

Procedure:
4-tert-butylbromobenzene (220 mg, 1.03 mmol) reacted with 2-methylphenylboronic acid (178 mg, 1.31 mmol) using 1 mol % of Pd(dba)2/Ph5FcP(t-Bu)2 and K3PO4 (424 mg, mmol) in toluene at 80° C. to give the title compound (223 mg, 97%) as a colorless oil: 1H-NMR (300 MHz, CDCl3): δ 7.49 (d, 2H, J=8.4 Hz), 7.34-7.30 (m, 6H), 2.36 (s, 3H), 1.44 (s, 9H). 13C{1H}-NMR (125 MHz, CDCl3): δ 149.50, 141.79, 138.88, 135.42, 130.26, 129.88, 128.81, 127.00, 125.69, 124.92, 34.51, 31.42, 20.58. GC/MS(EI): m/z (M+). Anal. Calcd for C17H20: C, 91.01; H, 8.99. Found: C, 90.72; H, 8.88.
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:37])[C:26]2[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([C:33]([F:36])([F:35])[F:34])[CH:27]=2)=[O:22])[CH2:17]1>>[F:32][C:30]1[CH:31]=[C:26]([CH:27]=[C:28]([C:33]([F:36])([F:34])[F:35])[CH:29]=1)[C:25]([NH:24][CH2:23][C:21](=[O:22])[NH:20][CH:18]1[CH2:19][N:16]([CH:5]2[CH2:6][CH2:7][C:2]([OH:1])([C:9]3[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=3)[CH2:3][CH2:4]2)[CH2:17]1)=[O:37]
Reactant: O=C(CNC(=O)c1cc(F)cc(C(F)(F)F)c1)NC1CNC1
Reactant: Cc1ccc(C2(O)CCC(=O)CC2)cn1
Product: Cc1ccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cc(F)cc(C(F)(F)F)c4)C3)CC2)cn1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-hydroxy-4-(6-methyl-pyridin-3-yl)-cyclohexanone, as prepared in Example 13 Step B, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-5-fluoro-benzamide, as prepared in the previous step, using the procedure described in Step E of Example 1.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=O)[O:19]C4C=CC=CC=4)=[C:13]([O:27][CH3:28])[CH:12]=3)=[CH:9][N:8]([CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[Br:35][C:36]1[N:37]=[CH:38][S:39][C:40]=1[CH2:41][OH:42]>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:19])[O:42][CH2:41][C:40]4[S:39][CH:38]=[N:37][C:36]=4[Br:35])=[C:13]([O:27][CH3:28])[CH:12]=3)=[CH:9][N:8]([CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)Oc1ccccc1
Reactant: OCc1scnc1Br
Solvent: c1ccncc1
Product: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)OCc1scnc1Br
Temperature: 100 °C

Procedure:
Phenyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (28 mg, 0.061 mmol) was mixed with (4-bromo-1,3-thiazol-5-yl)methanol (50 mg, 0.434 mmol) in pyridine (0.5 mL). The reaction mixture was heated at 100° C. overnight. The solvent was removed and the residue was purified by preparative reverse phase LC/MS to give (4-bromo-1,3-thiazol-5-yl)methyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate. 1H NMR (CDCl-d) δ 2.07(m, 4H), 3.65(m, 2H), 3.92(s, 3H), 4.13(m, 2H), 4.98(m, 1H), 5.35(s, 1H), 5.40(s, 2H), 6.97(s, 1H), 7.04(s, 1H), 7.09(m, 1H), 7.35(s, 1H), 8.17(s, 1H), 8.32(s, 1H), 8.78(s, 1H). LC/MS MH+=481.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:13][OH:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1(C2(C[O:27][S:28]([CH3:31])(=O)=[O:29])CCCC2)C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:13][O:14][S:28]([CH3:31])(=[O:29])=[O:27])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)OCC1(c2ccccc2)CCCC1
Reactant: OCC1(c2ccc(Cl)cc2)CCCC1
Product: CS(=O)(=O)OCC1(c2ccc(Cl)cc2)CCCC1
Yield: 93.08 %

Procedure:
Methanesulfonic acid 1-(4-chlorophenyl)-cyclopentylmethyl ester (24-02) (32 g, 93.08%) was synthesized from [1-(4-chlorophenyl)-cyclopentyl]-methanol (23-02) (25 g, 119.04 mmol) as a crude product as a yellow liquid following the procedure as described for methanesulfonic acid 1-phenyl-cyclopentylmethyl ester (24-01).