Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]#[N:17])[C:9](=[O:15])[C:10]([O:12]CC)=O)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]#[N:27])=[CH:21][CH:20]=1.[O-]CC.[Na+].[Na]>O.C(O)(=O)C>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]([C:10](=[O:12])[C:9](=[O:15])[CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:16]#[N:17])[C:26]#[N:27])=[CH:21][CH:20]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: CCOC(=O)C(=O)C(C#N)c1ccc(Cl)cc1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Product: N#CC(C(=O)C(=O)C(C#N)c1ccc(Cl)cc1)c1ccc(Cl)cc1

Procedure:
Ethyl 3-(p-chlorophenyl)-3-cyanopyruvate (40 g., 0.16 mol.) and 49.8 g. (0.33 mol.) of p-chlorophenylacetonitrile were added to an alcoholic solution of sodium ethoxide [prepared from 7.36 g. (0.32 g.-atom) of sodium and 190 ml. of absolute ethanol] and the resulting solution was refluxed for two hours. The reaction mixture was diluted with water, acidified with acetic acid and cooled (ice bath) to yield 2,5-di-(p-chlorophenyl)-3,4-dioxoadiponitrile, m.p. 280°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[N:9]([O-])=O.[Na+].[CH3:13][CH2:14][C@@H:15]([C:34]([C@H:36]([C@@H:38]([OH:54])[C@@H:39]([CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46]([CH3:49])=[C:45]([OH:50])[C:44]=1[C:51]([OH:53])=[O:52])[CH3:40])[CH3:37])=[O:35])[C@H:16]1[O:20][C@@:19]([C@@H:23]2[O:28][C@@H:27]([CH3:29])[C@@:26]([OH:32])([CH2:30][CH3:31])[CH2:25][CH2:24]2)([CH2:21][CH3:22])[CH2:18][C@@H:17]1[CH3:33]>O>[C:2]1([N:1]=[N:9][C:48]2[C:43]([CH2:42][CH2:41][CH:39]([CH3:40])[CH:38]([OH:54])[CH:36]([CH3:37])[C:34](=[O:35])[CH:15]([CH2:14][CH3:13])[CH:16]3[CH:17]([CH3:33])[CH2:18][C:19]([CH2:21][CH3:22])([CH:23]4[CH2:24][CH2:25][C:26]([CH2:30][CH3:31])([OH:32])[CH:27]([CH3:29])[O:28]4)[O:20]3)=[C:44]([C:51]([OH:53])=[O:52])[C:45]([OH:50])=[C:46]([CH3:49])[CH:47]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=N[O-]
Reactant: Nc1ccccc1
Reactant: CC[C@@H](C(=O)[C@@H](C)[C@@H](O)[C@H](C)CCc1ccc(C)c(O)c1C(=O)O)[C@H]1O[C@](CC)([C@H]2CC[C@](O)(CC)[C@H](C)O2)C[C@@H]1C
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCC(C(=O)C(C)C(O)C(C)CCc1c(N=Nc2ccccc2)cc(C)c(O)c1C(=O)O)C1OC(CC)(C2CCC(O)(CC)C(C)O2)CC1C
Reaction time: 0.25 h

Procedure:
To a solution of 0.18 ml. of aniline in 8 ml. of N HCl, cooled to 0°-5° C. in an ice bath as slowly added 150 mg. of NaNO2 in water chilled to the same temperature. To the above solution was added a cold methanolic solution of 550 mg. of crystalline antibiotic X-537A. The reaction mixture was kept at 3° to 5° for 15 minutes and then allowed to slowly reach room temperature. At the end of 2 hours, the reaction mixture was diluted with water and extracted with ethyl acetate. The solvent extract was washed with a saturated solution of Na2CO3, dried over NaSO4 and concentrated to a solid. The solid was chromatographed on a 30 g. silica gel (Grade 62 ) column eluting with a gradient between 300 ml. methylene chloride and 500 ml. ether. The product was eluted in the first peak and crystallized from methylene chloride/hexane, m.p. 212°-215°, [α]D25 -27.30° (0.586 percent CH3OH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[C:5]([NH:7][C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[OH:15])=[O:6].Br[CH2:21][CH2:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:27]([O:26][C:24](=[O:25])[CH2:23][CH2:22][CH2:21][O:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:8]=1[NH:7][C:5](=[O:6])[C:4]1[CH:16]=[CH:17][C:18]([Cl:19])=[C:2]([Br:1])[CH:3]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)CCCBr
Reactant: Cc1cccc(O)c1NC(=O)c1ccc(Cl)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(OCCCC(=O)OC(C)(C)C)c1NC(=O)c1ccc(Cl)c(Br)c1
Yield: 63.6 %

Procedure:
A mixture of 3-bromo-4-chloro-N-(2-hydroxy-6-methyl-phenyl)-benzamide (11.3 g, 33.2 mmol), t-butyl 4-bromobutyrate (8.2 g, 36.6 mmol) and K2CO3 (9.2 g, 66.5 mmol) was heated in DMF (100 mL) at 60° C. for 14 hrs. The mixture was then concentrated to remove DMF and partitioned between ethyl acetate and water. The organic layer was separated and washed with water and brine, dried over MgSO4, then purified by silica gel column chromatography eluting with ethyl acetate/hexane (1/4) to yield a red solid, which was further washed with ether to produce a white powder as 4-[2-(3-bromo-4-chloro-benzoylamino)-3-methyl-phenoxy]-butyric acid tert-butyl ester (10.2 g). MS [M−(t-Bu)+H]+: 425.8/427.8; tR=2.79 min. (method 1)
Reaction SMILES: [CH:1]([O-:3])=[O:2].[K+].[C]=O.[C:7]1([O-])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[K+].C(=O)([O-])[O-:20].[K+].[K+]>O>[OH:20][C:8]1[CH:9]=[CH:10][C:11]2[C:16](=[CH:15][CH:14]=[C:13]([C:1]([OH:3])=[O:2])[CH:12]=2)[CH:7]=1
Reactant: O=C[O-]
Reactant: [O-]c1cccc2ccccc12
Reactant: O=C([O-])[O-]
Agent: [C]=O
Agent: [K+]
Solvent: O
Product: O=C(O)c1ccc2cc(O)ccc2c1
Temperature: 280 °C
Yield: 72 %

Procedure:
A stainless steel pressure autoclave is charged with 100 parts of potassium formate and the melt is freed from residual moisture at 230° C., with stirring and in vacuo. It is then heated to 280° C. and 50 bar of carbon monoxide are injected. Using a metering pump, a mixture of 20 parts of potassium naphtholate with 25 parts of potassium carbonate are metered in as a suspension in kerosene over a period of 5 hours. Some of this kerosene is removed from the reaction vessel by distillation under reduced pressure, and is condensed and expelled. After it has been cooled, the reaction mixture is taken up in water, and the upper, kerosene phase is separated off after settling. The reaction mixture is acidified with sulfuric acid to a pH of 7 and then the unreacted β-naphtholate precipitates and is separated off. On further acidification to pH 4, first the 2-hydroxynaphthalene-6-carboxylic acid precipitates, and finally at pH 1 the other acids do likewise. The reaction mixture is worked up to give 2-hydroxynaphthalene-6-carboxylic acid in a yield of 72% based on the potassium naphtholate employed. Secondary products are 8% of unreacted γ-naphthol, 4% of 2-hydroxynaphthalene-3-carboxylic acid and 12% of 2-hydroxynaphthalene-3,6-dicarboxylic acid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[Mg].[CH3:10][C:11]1[CH:15]=[CH:14][S:13][C:12]=1[CH:16]=[O:17].CCCCCCC.C1COCC1>C(OCC)C>[CH3:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:16]([C:12]1[S:13][CH:14]=[CH:15][C:11]=1[CH3:10])[OH:17]
Reactant: Cc1ccccc1Br
Reactant: Cc1ccsc1C=O
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCCC
Product: Cc1ccccc1C(O)c1sccc1C

Procedure:
The title compound was prepared from 2-bromotoluene (35.55 g, 0.208 mole), magnesium turnings (5.1 g, 0.208 mole) and 3-methylthiophene-2-aldehyde (23.6 g, 0.187 mole) by the method described in Example 6, using diethyl ether (150 ml) as solvent. The yield was 36.0 g (88%). T.l.c. rf=0.39 (SiO2, heptane/THF (7:3)).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[N:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:19]2[CH:20]=[CH:21][C:22]([CH3:26])=[C:23]([CH:25]=2)[NH2:24])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:33][C:34]([CH3:39])([CH3:38])[C:35](Cl)=[O:36]>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[N:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:19]2[CH:20]=[CH:21][C:22]([CH3:26])=[C:23]([NH:24][C:35](=[O:36])[C:34]([CH3:39])([CH3:38])[CH3:33])[CH:25]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc2nc(-c3ccc(C)c(N)c3)c(-c3ccc(F)cc3)n2n1
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: COc1ccc2nc(-c3ccc(C)c(NC(=O)C(C)(C)C)c3)c(-c3ccc(F)cc3)n2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.9 %

Procedure:
A stirred solution of 5-(3-(4-fluorophenyl)-6-methoxyimidazo[1,2-b]pyridazin-2-yl)-2-methylaniline (0.025 g, 0.072 mmol) in acetonitrile (1 mL) containing pyridine (0.215 mmol) is added trimethylacetylchloride (0.072 mmol). The mixture is stirred at room temperature for 4 hours, then concentrated to dryness and purified via chromatography (hexanes to EtOAc) to afford the title compound (0.028 g, 90%) as a yellow solid: Rf 0.28 (1:1 EtOAc:hexanes); LCMS (m/z)=433.5 [M+H]+, tR=2.74 min. (compound same as Example 114)
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)=O.[C:23]([O:30][CH3:31])(=[O:29])[CH2:24][CH2:25][C:26]([CH3:28])=O.Cl[Si](C)(C)C>CN(C=O)C>[CH3:31][O:30][C:23](=[O:29])[CH2:24][C:25]1[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[C:3]2[C:4]3[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=3[S:6][C:2]2=[N:1][C:26]=1[CH3:28]
Reactant: Nc1sc2c(c1C(=O)c1cccc(C(F)(F)F)c1)CCCC2
Reactant: COC(=O)CCC(C)=O
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1cccc(C(F)(F)F)c1)CCCC3
Yield: 62.5 %

Procedure:
This compound was prepared according to the procedure B from (2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(3-trifluoromethylphenyl)methanone (0.325 g; 1 mmol), methyl levulinate (0.141 mL; 1.1 mmol), chlorotrimethylsilane (0.511 mL; 4 mmol) in DMF (4 mL) for 48 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (3-50%) in heptane furnished 0.262 g (62%) of the title compound as a yellow solid.
Reaction SMILES: C=CC.[CH3:4][CH2:5][C:6]([O:8]O)=[O:7]>>[CH2:6]1[O:8][CH:5]1[CH3:4].[C:6]([OH:8])(=[O:7])[CH2:5][CH3:4]
Reactant: CCC(=O)OO
Solvent: C=CC
Product: CC1CO1
Product: CCC(=O)O

Procedure:
The substantially dry organic solution is now fed by the line 121 to a reactor 122 which is conveniently illustrated as a column, although in practice a long tubular reactor would be preferred. Propylene is also fed to this reactor by a line 123 from a storage vessel 124. It will be appreciated that under normal conditions of temperature and pressure, propylene is a gas and therefore the reactor 122 is operated under pressure in order that the propylene should be kept in solution in the organic solution. The propylene reacts with the perpropionic acid in the reactor 122 to give propylene oxide and propionic acid in accordance with step (e). This product mixture is taken by a line 125 to a first distillation column 126 and in this column any unreacted propylene is distilled off as a light fraction and is passed by a line 127 to a condenser 128. In the condenser 128 the propylene is condensed and is fed by a line 129 back to the reactor 122. Any uncondensible gases are passed to waste through a line 130.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=3[O:30][CH3:31])[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[C:35]([O:42][CH3:43])[CH:34]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:31][O:30][C:23]1[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:22]=1[CH2:21][N:15]([C:16]1[S:17][CH:18]=[CH:19][N:20]=1)[S:12]([C:8]1[CH:7]=[C:6]2[C:11]([C:2]([C:36]3[CH:37]=[CH:38][C:33]([F:32])=[CH:34][C:35]=3[O:42][CH3:43])=[N:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1)(=[O:14])=[O:13]
Reactant: COc1cc(F)ccc1B(O)O
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)ncnc3c2)c(OC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(F)cc4OC)ncnc3c2)c(OC)c1

Procedure:
A microwave vial was charged with 4-chloro-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)quinazoline-7-sulfonamide (Intermediate KKKK; 0.040 g, 0.084 mmol), (4-fluoro-2-methoxyphenyl)boronic acid (0.021 g, 0.126 mmol), tetrakis(triphenylphosphine)palladium(0) (9.69 mg, 8.39 μmol), and potassium carbonate (0.058 g, 0.419 mmol). Dioxane (0.419 mL) and water (0.140 mL) were added, the vial was flushed with argon and sealed, and microwaved at 100° C. for 30 minutes. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (12 g silica gel column, gradient elution 0 to 100% EtOAc:Heptane) to afford N-(2,4-dimethoxybenzyl)-4-(4-fluoro-2-methoxyphenyl)-N-(thiazol-2-yl)quinazoline-7-sulfonamide. The material was dissolved in DCM and TFA (0.1 mL, 1.298 mmol) was added. The reaction was stirred overnight at room temperature. The reaction was concentrated and purified via column chromatography (12 g silica gel column, gradient elution 0 to 10% MeOH:DCM) to afford 4-(4-fluoro-2-methoxyphenyl)-N-(thiazol-2-yl)quinazoline-7-sulfonamide as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=13.01 (br. s., 1H), 9.45 (s, 1H), 8.38 (br. s., 1H), 8.06-7.76 (m, 2H), 7.49 (t, J=7.2 Hz, 1H), 7.31 (d, J=4.1 Hz, 1H), 7.21 (d, J=11.2 Hz, 1H), 7.01 (t, J=7.1 Hz, 1H), 6.90 (d, J=4.3 Hz, 1H), 3.70 (br. s., 3H). m/z (ESI) 417.2 (M+H)+.
Reaction SMILES: C(N1C[C@H](OCC)[C@H](NC2C(CC)=NC(C3C=CC(Cl)=CC=3Cl)=C(CC)N=2)C1)(=O)C.[CH2:31]([C:33]1[C:34]([NH:41][C@H:42]2[C@@H:46]([O:47][CH2:48][CH2:49][F:50])[CH2:45][NH:44][CH2:43]2)=[N:35][C:36]([CH2:39][CH3:40])=[CH:37][N:38]=1)[CH3:32].Cl[C:52]([O:54][CH3:55])=[O:53]>>[CH2:31]([C:33]1[C:34]([NH:41][C@H:42]2[C@@H:46]([O:47][CH2:48][CH2:49][F:50])[CH2:45][N:44]([C:52]([O:54][CH3:55])=[O:53])[CH2:43]2)=[N:35][C:36]([CH2:39][CH3:40])=[CH:37][N:38]=1)[CH3:32]
Reactant: COC(=O)Cl
Reactant: CCc1cnc(CC)c(N[C@@H]2CNC[C@@H]2OCCF)n1
Agent: CCO[C@H]1CN(C(C)=O)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCc1cnc(CC)c(N[C@@H]2CN(C(=O)OC)C[C@@H]2OCCF)n1

Procedure:
Following the procedure for the preparation of N-[(cis)-1-acetyl-4-ethoxypyrrolidin-3-yl]-5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-amine but substituting 3,6-diethyl-N-[(3R,4S)-4-(2-fluoroethoxy)pyrrolidin-3-yl]pyrazin-2-amine and methyl chloroformate, and making non-critical variations provided the title compound as an oil: 1H NMR (400 MHz, DMSO-d6) δ) 7.61, 5.82, 4.55, 4.51, 4.39, 4.19, 3.73-3.48, 2.64-2.49, 1.20-1.14; IR (diffuse reflectance) 2967, 2934, 2873, 2450 (w), 2407 (w), 2350 (w), 2334 (w), 2226 (w), 1699 (s), 1499, 1457 (s), 1392 (s), 1158, 1142, 768, cm−1; HRMS (FAB) calcd for C16H25FN4O3+H 341.1989, found 341.1988.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7]1.CN([CH:18]=[O:19])C>>[O:6]1[C:10]2[CH:11]=[CH:12][C:13]([CH:18]=[O:19])=[CH:14][C:9]=2[CH2:8][CH2:7]1
Reactant: c1ccc2c(c1)CCO2
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc2c(c1)CCO2
Temperature: 82.5 °C
Reaction time: 4.5 h
Yield: 85 %

Procedure:
Phosphorous oxychloride (255.58 g, 1.666 mol) was slowly added to a solution of DMF (355.0 ml) and 2,3-dihydrobenzofuran (100 g, 0.833 mol) maintaining the temperature 80-85° C. The reaction mixture was stirred for 4-5 hr and the reaction progress monitored by HPLC. The reaction mixture was then poured into ice water and extracted with toluene (2000 ml). The organic layer was washed with 5% sodium bicarbonate solution (500 ml) and then 10% brine solution (500 ml). The organic layer was distilled off under vacuum at 50-60° C. A liquid product was isolated. Yield: 85-90%, Purity: 90-92%
Reaction SMILES: [OH-].[NH4+:2].[I:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7]>>[I:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH2:2])=[O:7]
Reactant: [NH4+]
Reactant: O=C(Cl)c1ccccc1I
Agent: [OH-]
Product: NC(=O)c1ccccc1I

Procedure:
A total of 50 ml of a 15 M ammonium hydroxide solution was reacted with 15 g o-iodobenzoyl chloride for 20 minutes. The crude product was recovered as in Example 1. The product was recrystallized from ethanol to yield 7.8 g of o-iodobenzamide, m.p. 187°-189°, Rf 0.63.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S[CH2:11][CH2:12][C:13]([OH:15])=O.C1(C)C=CC([S:22](O)(=O)=O)=CC=1>C(OCC)C>[CH2:8]([O:9][C:13](=[O:15])[CH:12]([SH:22])[CH3:11])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCc1ccccc1
Reactant: O=C(O)CCS
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: CC(S)C(=O)OCCc1ccccc1

Procedure:
Into a 250 cc reaction flask equipped with stirrer, thermometer and reflux condenser are placed 120 grams phenylethyl alcohol; 26 grams 3-mercaptopropionic acid; and 0.5 grams of para-toluene sulphonic acid. With stirring, the reaction mass is heated to reflux and refluxed for a period of 8 hours. At the end of the 8 hour period, the reaction mass is mixed with 200 ml diethyl ether and washed with two 100 ml portions of 10% aqueous sodium bicarbonate followed by one 100 ml portion of water. The organic phase is separated and dried and the solvents are recovered on a Buchi evaporator. The resulting product is then distilled using a micro distillation apparatus yielding the following fractions:
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=1.B(O)(O)[C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=1>>[CH3:17][C:7]1[C:6]2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=[C:2]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)[C:10]=2[N:9]2[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]=12
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCCNC2=O
Reactant: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(-c2cc(C#N)cc3c(C)c4n(c23)CCCNC4=O)cc1

Procedure:
The title compound, grey solid (20 mg, 24%), MS (ISP) m/z=330.6 [(M+H)+], mp 287° C., was prepared in accordance with the general method of example 1 from 7-bromo-11-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 17) (79.5 mg, 0.25 mmol) and commercially available p-tolylboronic acid (44.2 mg, 0.325 mmol).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[N:9][C:10]([Cl:15])=[N:11][C:12]=2Cl)[N:7]([CH3:16])[C:6]1=[O:17])[C:2]#[C:3][CH3:4].[C:18]([O:22][C:23](=[O:31])[NH:24][CH:25]1C[CH2:29][CH2:28][NH:27][CH2:26]1)([CH3:21])([CH3:20])[CH3:19].C([N:34](CC)CC)C.O>C(#N)C>[C:18]([O:22][C:23](=[O:31])[NH:24][CH:25]1[NH:34][CH2:29][CH2:28][N:27]([C:12]2[N:11]=[C:10]([Cl:15])[N:9]=[C:8]3[C:13]=2[N:5]([CH2:1][C:2]#[C:3][CH3:4])[C:6](=[O:17])[N:7]3[CH3:16])[CH2:26]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Reactant: CC#CCn1c(=O)n(C)c2nc(Cl)nc(Cl)c21
Solvent: O
Solvent: CC#N
Product: CC#CCn1c(=O)n(C)c2nc(Cl)nc(N3CCNC(NC(=O)OC(C)(C)C)C3)c21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
7-(2-Butynyl)-2,6-dichloro-9-methyl-7,9-dihydropurin-8-one (compound 1e) (100 mg) was dissolved in acetonitrile (1.5 mL). Piperidin-3-yl-carbamic acid t-butyl ester (compound 25b) (111 mg) and triethylamine (77 μL) were then added to this solution. After stirring the reaction solution at room temperature for 24 hours, water (6 mL) was added. After stirring this reaction solution at room temperature for 30 minutes, the precipitate was filtered, and the white solid obtained was washed with water and hexane to give the title compound (88 mg).
Reaction SMILES: [I-:1].[Na+].[C:3]([O:7][C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([CH2:15]Cl)=[CH:11][CH:10]=1)([CH3:6])([CH3:5])[CH3:4]>CC(C)=O>[C:3]([O:7][C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][I:1])=[CH:11][CH:10]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)c1ccc(CCl)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(CI)cc1
Temperature: 25 °C
Yield: 100 %

Procedure:
Sodium iodide (229.2 g) was added to a solution of 4-chloromethyl benzoic acid tert-butyl ester (315.2 g) in acetone (1.5 L). The reaction mixture was heated to reflux for about 2 h and then allowed to cool to room temperature. The precipitate was removed by filtration and the filtrate concentrated under reduced pressure. The residue was partitioned between water (500 mL) and MTBE (1500 mL). The organic phase was washed with saturated sodium bicarbonate and dried over magnesium sulfate. Concentration under reduced pressure afforded 442.2 g (97% yield) dark oil. HNMR: CDCl3, 1.59 ppm (s, 9H), 4.47 (s, 2H), 7.42 (d, 2H), 7.91 (d, 2H)
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:8][C:9]2[N:13]3[CH2:14][CH2:15][N:16]([C:21]4[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[C:24]([C:31]([O:33]CC)=[O:32])=[CH:23][N:22]=4)[C@H:17]([CH:18]([CH3:20])[CH3:19])[C:12]3=[N:11][C:10]=2[CH:36]=1)(=O)C.O[Li].O>CO.O>[OH:4][CH2:5][C:6]1[C:7]([S:37]([CH3:40])(=[O:38])=[O:39])=[CH:8][C:9]2[N:13]3[CH2:14][CH2:15][N:16]([C:21]4[N:26]=[C:25]([C:27]([F:29])([F:28])[F:30])[C:24]([C:31]([OH:33])=[O:32])=[CH:23][N:22]=4)[C@H:17]([CH:18]([CH3:20])[CH3:19])[C:12]3=[N:11][C:10]=2[CH:36]=1.[OH:4][CH2:5][C:6]1[C:7]([S:37]([CH3:40])(=[O:38])=[O:39])=[CH:8][C:9]2[N:13]3[CH2:14][CH2:15][N:16]([C:21]4[N:26]=[C:25]([C:27]([F:29])([F:28])[F:30])[C:24]([C:31]([OH:33])=[O:32])=[CH:23][N:22]=4)[C@@H:17]([CH:18]([CH3:20])[CH3:19])[C:12]3=[N:11][C:10]=2[CH:36]=1
Reactant: CCOC(=O)c1cnc(N2CCn3c(nc4cc(COC(C)=O)c(S(C)(=O)=O)cc43)[C@H]2C(C)C)nc1C(F)(F)F
Agent: [Li]O
Solvent: O
Solvent: CO
Product: CC(C)[C@@H]1c2nc3cc(CO)c(S(C)(=O)=O)cc3n2CCN1c1ncc(C(=O)O)c(C(F)(F)F)n1
Product: CC(C)[C@H]1c2nc3cc(CO)c(S(C)(=O)=O)cc3n2CCN1c1ncc(C(=O)O)c(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40 %
Yield: 7 %

Procedure:
(R)-ethyl 2-(8-(acetoxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylate (0.1 g, 0.17 mmol) in MeOH/H2O (5 mL/1 mL) was added LiOH H2O (86 mg, 2 mmol). The mixture was stirred at rt for 16 h. The excess methanol was removed by vacuum at 40° C. Water (5 ml) was added and the mixture was neutralized by 1N HCl at 0° C. slowly to pH=6. The aqueous layer was extracted with CH2Cl2 (4×10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give crude product. The crude product was purified by SFC to afford (R)-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylic acid (34.50 mg, 40% yield, isomer 1) as a white solid and (S)-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylic acid (6.40 mg, 7% yield, isomer 2) as white solid.