Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]=[C:4]([O:10][CH3:11])[N:3]=1.[N:12]#[C:13][NH2:14].[Na].O.Cl>CN1CCCC1=O>[CH3:11][O:10][C:4]1[N:3]=[C:2]([NH:14][C:13]#[N:12])[C:7]([O:8][CH3:9])=[CH:6][N:5]=1
Reactant: N#CN
Reactant: COc1ncc(OC)c(Cl)n1
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ncc(OC)c(NC#N)n1
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 76.4 %

Procedure:
4-Chloro-2,5-dimethoxypyrimidine (CDMP; 15 g, 0.086 mol) was dissolved in N-methyl-2-pyrrolidinone (NMP; 62.5 g) at ambient temperature. Sodium hydrogen cyanamide (12.1 g, 2.2 eq) was added all at once, and the mixture was heated to 50° C. with stirring for 2.5 h. The resulting slurry was cooled to 25° C., and 150 mL of water was added. Concentrated hydrochloric acid was added drop-wise until a pH of 5.5 was reached. The thick slurry was filtered and washed twice with 10 mL of water to afford 2,5-dimethoxy-4-cyanoamino-pyrimidine (2) as a white solid (11.83 g, 76% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[F:8].[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[CH2:9][Br:10]
Reactant: Cc1ccc(F)c(Br)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(CBr)cc1Br
Yield: 98.3 %

Procedure:
3-Bromo-4-fluorotoluene (9.36 g; 49.5 mmol) was dissolved in carbon tetrachloride (100 ml), and N-bromosuccinimide (8.82 g; 49.6 mmol) and benzoyl peroxide (200 mg) were added thereto. The mixture was heated under reflux for 1 hour, and then cooled. Insoluble matter was filtered off, followed by washing with carbon tetrachloride. The filtrate was concentrated under reduced pressure, and n-hexane (120 ml) was added thereto. The mixture was left to stand, and insoluble matter was filtered off, followed by washing with n-hexane. The filtrate was evaporated, to thereby yield 13.04 g of a mixture of the target-compound, the starting compound, and the dibromo compound (yield based on the weight of the mixture: 98.2%).
Reaction SMILES: CN(C=O)C.[C:6](Cl)(=[O:10])[C:7](Cl)=O.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]#[N:22])[CH:19]=2)C=[CH:13]1>ClCCl>[CH:6]([C:7]1[C:15]2[C:20](=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)[NH:12][CH:13]=1)=[O:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: N#Cc1ccc2cc[nH]c2c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(C=O)c[nH]c2c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
DMF (0.389 mL) was added dropwise to a solution of oxalyl chloride (0.440 mL) in dry dichloromethane (5 mL) at 0° C. The resulting solution was stirred at 0° C. for 10 min. A solution of 1H-indole-6-carbonitrile (D12) (0.650 g) in dry dichloromethane (5 mL) was added to the reaction mixture. The reaction mixture was warmed to RT and stirred at that temperature for 45 min. The solvent was evaporated. THF (50 mL) was added, followed by addition of aqueous NaOH (2 M, 50 mL) and water (200 mL). The biphasic mixture was allowed to stand for 10 min. EtOAc (300 mL) and water (100 mL) was added. The organic fraction was separated and was dried over anhydrous magnesium sulfate. The dried solution was concentrated to afford 3-formyl-1H-indole-6-carbonitrile (D13) as a orange solid (604 mg). δH (DMSO-d6, 400 MHz): 7.59 (1H, dd), 8.05 (1H, d), 8.24 (1H, m), 8.56 (1H, s), 10.00 (1H, s), 12.62 (1H, br s). MS (ES): C10H6N2O requires 170; found 169.0 (M−H+).
Reaction SMILES: [O:1]=[C:2]1[CH2:16][CH:5]2[CH2:6][N:7](C(OC(C)(C)C)=O)[CH2:8][CH:4]2[CH2:3]1.[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20]>ClCCl>[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20].[CH2:6]1[CH:5]2[CH2:16][C:2](=[O:1])[CH2:3][CH:4]2[CH2:8][NH:7]1
Reactant: CC(C)(C)OC(=O)N1CC2CC(=O)CC2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC2CNCC2C1

Procedure:
tert-Butyl 5-oxo-hexahydro-cyclopenta[c]pyrrole-2-carboxylate 1e (0.32 g, 1.42 mmol) was dissolved in 10 mL of dichloromethane with stirring. Upon cooling by an ice-water bath, trifluoroacetic acid (3.27 mL, 42.7 mmol) was added and the reaction mixture was reacted for 30 minutes at 0° C. The mixture was concentrated under reduced pressure to obtain the crude title compound hexahydro-cyclopenta[c]pyrrol-5-one trifluoroacetate 1f, which was directly used in the next step.
Reaction SMILES: [N:1]1([C:10]2[S:14][C:13]([C:15]([O:17]C)=O)=[C:12]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])[CH:11]=2)[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.[NH3:31]>CO>[N:1]1([C:10]2[S:14][C:13]([C:15]([NH2:31])=[O:17])=[C:12]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:28])([F:29])[F:30])[CH:11]=2)[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1
Reactant: N
Reactant: COC(=O)c1sc(-n2cnc3cnccc32)cc1OCc1ccccc1C(F)(F)F
Solvent: CO
Product: NC(=O)c1sc(-n2cnc3cnccc32)cc1OCc1ccccc1C(F)(F)F

Procedure:
In a similar manner as described for example 1, 195 mg of methyl 5-(1H-imidazo[4,5-c]pyridin-1-yl)-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxylate (compound B1a) and 36 ml of a saturated solution of ammonia in methanol yield the title compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.[C:13]1([CH2:19][CH2:20][NH2:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[F:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH2:4][NH:21][CH2:20][CH2:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1F
Reactant: NCCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(F)c(CNCCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 24 h
Yield: 81.2 %

Procedure:
2-Fluoro-5-nitro-benzaldehyde (11.9 g, 70 mmol) and 2-phenylethylamine (13 mL, 0.1 mol) were dissolved in methanol (150 mL) and glacial acetic acid (15 mL). The solution was cooled to 0° C., and sodium cyanoborohydride (6.6 g, 0.1 mol) was added portionwise. The reaction was adjusted to pH 6 with acetic acid and stirred at room temperature for 24 h. The reaction mixture was quenched with ice and diluted with water. The pH was adjusted to 11 with sodium hydroxide and the mixture was extracted with EtOAc. The organic extracts were washed with cold dilute HCl solution and a solid precipitated. Filtration yielded the title compound (15.6 g, 82%). Mp 235-6° C.; MS m/e 275 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C:13](O)=O)=[CH:6][CH:5]=1)([O-])=O.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.CCN=C=NCCCN(C)C.[ClH:33].C1C=CC2N(O)N=NC=2C=1.Cl.C(OCC)(=O)C>CN(C=O)C>[ClH:33].[ClH:33].[N:16]1([CH2:13][CH2:12][CH2:11][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C1CCNCC1
Reactant: O=C(O)CCCc1ccc([N+](=O)[O-])cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1ccc(CCCCN2CCCCC2)cc1

Procedure:
4-(4-nitrophenyl)butanoic acid and piperidine were allowed to undergo the reaction in DMF using WSC hydrochloride and HOBt, subjected to catalytic hydrogenation in the same manner as shown in Reference Example 3 to reduce the nitro group, and then reduced in the same manner as in Reference Example 2, and the resulting compound was subjected to salt formation using 4 M hydrogen chloride/ethyl acetate solution to obtain 4-(4-piperidin-1-ylbutyl) aniline dihydrochloride. F: 233.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][CH2:20][S:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=1[O:31][CH3:32].CC#N>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][CH2:20][S:21][C:22]4[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=4[O:31][CH3:32])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: COc1cc(C(C)=O)ccc1SCCCCl
Solvent: O
Solvent: CC#N
Product: COc1cc(C(C)=O)ccc1SCCCN1CCC(c2noc3cc(F)ccc23)CC1
Reaction time: 65 h
Yield: 113 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.0 g, 13.6 mmol), 1-[4-[(3-chloropropyl)-thio]-3-methoxyphenyl]ethanone (3.5 g, 13.6 mmol), KC2CO3 (2.3 g, 16.6 mmol), KI (200 mg) and CH3CN (100 ml) was stirred at reflux under nitrogen for 7.5 hours and then was left at ambient temperature for 65 hours. The reaction was poured into water and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was washed twice with water, once with brine and dried over MgSO4. The solvent was removed in vacuo to afford 6.8 g of a light brown oil. The sample was purified by flash chromatography. Concentration of appropriate fractions yielded 3.0 g. Recrystallization from ethanol provided 2.4 g (41%) of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl]thio]-3-methoxyphenyl]-ethanone as a beige solid, m.p.=93-95° C.
Reaction SMILES: [N:1]1[C:10]2[CH:9]([NH:11][CH2:12][C:13]3[CH:28]=[CH:27][C:16]([CH2:17][NH:18][C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)=[O:20])=[CH:15][CH:14]=3)[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[C:30]1[CH:38]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[NH:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[C:30]1[CH2:38][N:11]([CH2:12][C:13]1[CH:28]=[CH:27][C:16]([CH2:17][NH:18][C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[O:20])=[CH:15][CH:14]=1)[CH:9]1[C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6][CH2:7][CH2:8]1
Reactant: O=Cc1nc2ccccc2[nH]1
Reactant: O=C(NCc1ccc(CNC2CCCc3cccnc32)cc1)c1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: O=C(NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1)c1ccccn1

Procedure:
Reaction of pyridine-2-carboxylic acid 4-[(5,6,7,8-tetrahydro-quinolin-8-ylamino)-methyl]-benzylamide (AMD9397) (40 mg, 0.11 mmol), 1H-benzoimidazole-2-carbaldehyde (16 mg, 0.11 mmol), and NaBH(OAc)3 (68 mg, 0.32 mmol) for 2 h at 60° C. followed by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH 198:1:1) gave AMD9401 (28 mg, 52%) as a white foam. 1H NMR (300 MHz, CD3OD) δ 1.60-1.63 (m, 1H), 1.95-2.06 (m, 2H), 2.20-2.22 (m, 1H), 2.66-2.83 (m, 2H), 3.51 (d, 1H, J=13.2 Hz), 3.58 (d, 1H, J=13.2 Hz), 3.94 (d, 1H, J=15.3 Hz), 4.04-4.09 (m, 3H), 4.42 (br s, 2H), 7.09-7.15 (m, 4H), 7.20 (dd, 1H, J=7.8, 4.8 Hz), 7.20 (d, 1H, J=8.1 Hz), 7.28 (d, 2H, J=8.1 Hz), 7.41-7.47 (m, 2H), 7.48-7.52 (m, 2H), 7.91 (ddd, 1H, J=7.5, 7.5, 1.8 Hz), 8.06 (d, 1H, J=7.8 Hz), 8.55 (d, 1H, J=4.5 Hz), 8.60 (d, 1H, J=4.5 Hz); 13C NMR (75.5 MHz, CD3OD) δ 22.84, 24.33, 30.62, 44.13, 51.41, 56.15, 63.13, 123.55, 124.03, 128.13, 128.61, 130.80, 137.39, 138.95, 139.14, 139.51, 139.67, 148.35, 150.17, 151.40, 156.31, 158.31, 166.94. ES-MS m/z 503 (M+H). Anal. Calcd. for C31H30N6O.0.8H2O.0.3CH2Cl2: C, 69.30; H, 5.98; N, 15.49. Found: C, 69.63; H, 6.14; N, 15.19.
Reaction SMILES: [N+](=[CH2:3])=[N-].[Cl:4][C:5]1[CH:23]=[CH:22][C:8]([O:9][C:10]([C:18]([F:21])([F:20])[F:19])([C:14]([F:17])([F:16])[F:15])[C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1>CCOCC>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][C:10]([C:14]([F:17])([F:16])[F:15])([C:18]([F:19])([F:20])[F:21])[C:11]([O:13][CH3:3])=[O:12])=[CH:22][CH:23]=1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)C(Oc1ccc(Cl)cc1)(C(F)(F)F)C(F)(F)F
Solvent: CCOCC
Product: COC(=O)C(Oc1ccc(Cl)cc1)(C(F)(F)F)C(F)(F)F

Procedure:
An excess of a solution of diazomethane in ether is added to an ethereal solution of 2-(4-chlorophenoxy)-3,3,3-trifluoro-2-trifluoromethylpropionic acid (0.25 g.) at 0° C. Evaporation of the resulting solution yields methyl 2(4chlorophenoxy)-3,3,3-trifluoro-2-trifluoromethylpropionate (0.25 g.), b.p. (bath temperature) 140° C. at 30 mm. pressure.
Reaction SMILES: C([O:4][C:5]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:6]=1[C:7](Cl)=[O:8])(=O)C.[C:15](#[N:19])[CH2:16][C:17]#[N:18]>>[NH2:18][C:17]1[O:4][C:5]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:6]=2[C:7](=[O:8])[C:16]=1[C:15]#[N:19]
Reactant: CC(=O)Oc1ccc(Cl)cc1C(=O)Cl
Reactant: N#CCC#N
Product: N#Cc1c(N)oc2ccc(Cl)cc2c1=O

Procedure:
-- In the same way as described in Example 3, 2-acetoxy-5-chlorobenzoyl chloride and malononitrile are reacted to give crystals, mp 340°C.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[NH2:21][C:22]1[C:27]([C:28]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=2)=[O:29])=[C:26](Cl)[N:25]=[CH:24][N:23]=1.CCN(C(C)C)C(C)C.[F-].[Cs+]>C(O)(C)(C)C>[NH2:21][C:22]1[C:27]([C:28]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=2)=[O:29])=[C:26]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:16])[C:7]3=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[N:25]=[CH:24][N:23]=1
Reactant: COc1cccc(CNC(=O)c2c(N)ncnc2Cl)c1
Reactant: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Agent: [Cs+]
Agent: [F-]
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(CNC(=O)c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)c1
Yield: 59.4 %

Procedure:
(S)-2-(1-Aminoethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (92 mg, 0.34 mmol), 4-amino-6-chloro-N-(3-methoxybenzyl)pyrimidine-5-carboxamide (100 mg, 0.34 mmol), DIEA (360 μl, 2.07 mmol) and cesium fluoride (157 mg, 1.03 mmol) were suspended in tert-butanol (10 ml) and the mixture was heated to reflux for 48 h. The solvent was evaporated under reduced pressure and the crude was diluted with ethyl acetate and washed with saturated ammonium chloride solution and brine. After evaporation of the solvent, the residue was purified by flash chromatography using SP1® Purification System (0% to 40%, dichloromethane-ethyl acetate) to obtain 106 mg (59% yield) of the title compound.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH:5]1[CH2:9][CH2:8][C@H:7]([CH2:10][N:11]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:6]1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([N:5]1[CH2:9][CH2:8][C@H:7]([CH2:10][N:11]([CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: O=C(OCc1ccccc1)N(Cc1ccccc1)C[C@H]1CCNC1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CC[C@H](CN(Cc2ccccc2)C(=O)OCc2ccccc2)C1
Yield: 63 %

Procedure:
Acetyl chloride (2.86 g) was added to a stirred solution of benzyl N—((S)-pyrrolidin-3-ylmethyl)-N-benzylcarbamate (Intermediate 166, 5.9 g) and triethylamine (3.68 g) in DCM (80 mL) with ice cooling. The resultant mixture was stirred at room temperature for 2 hours then concentrated under vacuum. The residue was treated with saturated aqueous sodium bicarbonate and extracted with ethyl acetate, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with ethyl acetate to give benzyl N—((S)-1-acetylpyrrolidin-3-ylmethyl)-N-benzylcarbamate (4.2 g) as a yellow oil.
Reaction SMILES: [H-].[Li+].[CH2:3](S)CC.C[O:8][C:9]1[CH:26]=[C:25]2[C:12]([C@H:13]3[C@H:22]([CH2:23][S:24]2(=[O:28])=[O:27])[C@:21]2([CH3:29])[C@H:16]([C:17]([CH3:31])([CH3:30])[CH2:18][CH2:19][CH2:20]2)[CH2:15][CH2:14]3)=[C:11]([C:32]([O-:34])=[O:33])[CH:10]=1>CN(P(N(C)C)(N(C)C)=O)C>[OH:8][C:9]1[CH:26]=[C:25]2[C:12]([C@@:13]3([CH3:3])[C@H:22]([CH2:23][S:24]2(=[O:28])=[O:27])[C@:21]2([CH3:29])[C@H:16]([C:17]([CH3:30])([CH3:31])[CH2:18][CH2:19][CH2:20]2)[CH2:15][CH2:14]3)=[C:11]([C:32]([OH:34])=[O:33])[CH:10]=1
Reactant: COc1cc(C(=O)[O-])c2c(c1)S(=O)(=O)C[C@H]1[C@H]2CC[C@H]2C(C)(C)CCC[C@]12C
Reactant: CCCS
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC1(C)CCC[C@]2(C)[C@H]3CS(=O)(=O)c4cc(O)cc(C(=O)O)c4[C@]3(C)CC[C@@H]12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
A mixture of lithium hydride (0.88 g, 110 mmol), 1-propanethiol (11.7 mL, 133 mmol) in HMPA (20 mL) was prepared under N2. The mixture was stirred at room temperature for 30 min. To the mixture, (1R,10S,11S,16S)-5-methoxy-11,15,15-trimethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-3-carboxylate (64) (4.8 g, 11 mmol) in HMPA (10 mL) was added. The mixture was heated at 130° C. for 1 h. The mixture was cooled to room temperature and quenched with 1 M HCl, then extracted with EtOAc. The organic layer was concentrated to dryness. The crude product was purified by flash chromatography on silica gel (CH2Cl2/MeOH, 10:1) to yield (1R,10R,11S,16S)-5-hydroxy-1,11,15,15-tetramethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]-octadeca-2,4,6-triene-3-carboxylic acid (65) (4.2 g, 93%) as a white solid. 1H NMR (CD3OD): δ 7.18 (s, 1H), 6.88 (s, 1H), 3.45 (m, 1H), 2.83 (m, 1H), 2.10 (d, 1H), 1.82-1.35 (m, 10H), 1.20 (m, 2H) 1.00 (m, 5H), 0.89 (s, 3H), 0.85 (s, 3H). MS m/z 405 (C22H30NO5S−H+).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[C:17]1([CH2:23][CH2:24][CH2:25][CH2:26][NH2:27])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:27][CH2:26][CH2:25][CH2:24][CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: NCCCCc1ccccc1
Solvent: CCN(CC)CC
Product: Clc1nc(NCCCCc2ccccc2)c2ncn(C3CCCC3)c2n1

Procedure:
2-Chloro-6-(4-phenylbutylamino)-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-phenylbutylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: C([O:3][C:4](=[O:41])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[CH:25]=[C:24](Br)[CH:23]=2)[C:10]=1[CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])C.[F:42][C:43]1[CH:44]=[C:45](B(O)O)[CH:46]=[C:47]([F:49])[CH:48]=1>>[C:36]([CH2:35][CH2:34][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:45]3[CH:44]=[C:43]([F:42])[CH:48]=[C:47]([F:49])[CH:46]=3)[CH:25]=[C:26]([C:28](=[O:32])[N:29]([CH3:30])[CH3:31])[CH:27]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:41])=[O:3])([OH:38])=[O:37]
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(C(=O)N(C)C)c2)c1CCC(=O)OCC
Product: CN(C)C(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2cc(F)cc(F)c2)c1

Procedure:
The title compound was prepared according to the general procedure described in Steps 3 and 4 of Method F starting from 4-[3-[6-(3-bromo-5-dimethylcarbamoyl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester and 3,5-difluorophenylboronic acid. LC/MS indicated a purity of 100% as measured by UV 214 nM.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[N:3]1[CH2:9][CH2:10][NH:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]([F:42])=[C:18]([NH:20][C:21]([C:23]2[N:27]3[CH:28]=[CH:29][C:30]([C:32]4[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[C:34]([F:41])[CH:33]=4)=[CH:31][C:26]3=[N:25][CH:24]=2)=[O:22])[CH:19]=1)=[O:13].[NH2:43][C:44]([CH3:48])([CH3:47])[CH2:45][OH:46]>>[CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[N:3]1[CH2:9][CH2:10][NH:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]([F:42])=[C:18]([NH:20][C:21]([C:23]2[N:27]3[CH:28]=[CH:29][C:30]([C:32]4[CH:40]=[CH:39][C:35]([C:36](=[O:37])[NH:43][C:44]([CH3:48])([CH3:47])[CH2:45][OH:46])=[C:34]([F:41])[CH:33]=4)=[CH:31][C:26]3=[N:25][CH:24]=2)=[O:22])[CH:19]=1)=[O:13]
Reactant: C[C@@H]1CCC[C@H](C)N1CCNC(=O)c1ccc(F)c(NC(=O)c2cnc3cc(-c4ccc(C(=O)O)c(F)c4)ccn23)c1
Reactant: CC(C)(N)CO
Product: C[C@@H]1CCC[C@H](C)N1CCNC(=O)c1ccc(F)c(NC(=O)c2cnc3cc(-c4ccc(C(=O)NC(C)(C)CO)c(F)c4)ccn23)c1

Procedure:
The title compound was prepared from 4-(3-(5-(2-(2,6-cis-dimethylpiperidin-1-yl)ethylcarbamoyl)-2-fluorophenyl carbamoyl)imidazo[1,2-a]pyridin-7-yl)-2-fluorobenzoic acid (step 1) and 2-amino-2-methylpropan-1-ol analogously to Example 8.1, step 2;
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[CH2:3][N:4]1[C:9](=[O:10])[C:8]([O:11][CH2:12][C:13]([OH:16])([CH3:15])[CH3:14])=[C:7]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[CH:6]=[N:5]1.[C:29](OC(=O)C)(=[O:31])[CH3:30].C(N(CC)CC)C>CN(C)C1C=CN=CC=1>[F:28][C:2]([F:27])([F:1])[CH2:3][N:4]1[C:9](=[O:10])[C:8]([O:11][CH2:12][C:13]([OH:16])([CH3:15])[CH3:14])=[C:7]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([NH:26][C:29](=[O:31])[CH3:30])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[CH:6]=[N:5]1
Reactant: CC(C)(O)COc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(CC(F)(F)F)c1=O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: CC(=O)NS(=O)(=O)c1ccc(-c2cnn(CC(F)(F)F)c(=O)c2OCC(C)(C)O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-(2,2,2-trifluoroethyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone (Example 484, 1 equivalent), acetic anhydride (3 equivalents), 4-(dimethylamino)pyridine (0.3 equivalents), and triethylamine (1.2 equivalents) is stirred at room temperature for 16 hours. The reaction mixture is partitioned between ethyl acetate and water. The organic layer is washed with brine then dried over MgSO4 and filtered. The filtrate is concentrated in vacuo to give the title compound.
Reaction SMILES: [CH:1](=[CH:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1(=[O:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[OH-].[Na+]>C(O)C>[C:2]1([CH:1]([CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][C:17]2=[O:23])[CH2:8][C:9](=[O:10])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(C=Cc1ccccc1)c1ccccc1
Reactant: O=C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(CC(c1ccccc1)C1CCCCC1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ten parts of benzalacetophenone and 5 parts of cyclohexanone was dissolved in 200 mL of ethyl alcohol and a solution of 5 parts of sodium hydroxide in 100 ml of ethanol was added to the reaction mixture. After 30 minutes the solution became cloudy and white solid was appeared. The reaction mixture was stirred for 10 hours at room temperature and solid was filtered, washed with water and then with 100 ml of ethyl alcohol. The white solid was dried under reduced pressure,with a yield of 12 parts. The reaction proceeded as follows:
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[S:2].[C:13]1([NH:19][CH2:20][CH2:21][NH2:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(Cl)Cl>C1COCC1>[C:13]1([N:19]2[CH2:20][CH2:21][NH:22][C:1]2=[S:2])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: NCCNc1ccccc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: S=C1NCCN1c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.3 %

Procedure:
1,1′-Thiocarbonyldiimidazole (4.51 g, 25.3 mmol) was added to a solution of N-phenylethylenediamine (3 mL, 23.02 mmol) in THF (230 mL) and the mixture was stirred for 2 h at room temperature. DCM was added and the solution was washed with 1N HCl, dried over anhydrous sodium sulfate and concentrated under reduced pressure affording title compound 301 (1.45 g, 8.13 mmol, 35.3% yield). m/z: 179.1 (M+H)+