Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]([N:14]2[CH2:19][C@H:18]([CH3:20])[N:17]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:16][C@H:15]2[CH3:29])=[O:13])=[C:6]([CH:9]=1)[CH:7]=O.Cl.[CH3:31][O:32][C:33](=[O:37])[CH2:34][NH:35][CH3:36].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:31][O:32][C:33](=[O:37])[CH2:34][N:35]([CH2:7][C:6]1[CH:9]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[O:10][CH2:11][C:12]([N:14]1[CH2:19][C@H:18]([CH3:20])[N:17]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[CH2:16][C@H:15]1[CH3:29])=[O:13])[CH3:36]
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1C=O
Reactant: CNCC(=O)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)CN(C)Cc1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C

Procedure:
To a solution of 5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzaldehyde (0.10 g, 0.24 mmol) in methanol (2.5 ml) was added sarcosine methyl ester hydrochloride salt (0.10 g, 0.72 mmol) followed by sodium triacetoxyborohydride (0.155 g, 0.73 mmol). After 15 hours the solvent was removed and the resultant solid taken up in methylene chloride. After washing with pH 7 phosphate buffer (0.05 M) and saturated aqueous sodium chloride the organic layer was dried over magnesium sulfate. After filtration and concentration the title compound was isolated by chromatography on silica gel (0.051 g).
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9](Cl)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl-].[Al+3].[Cl-].[Cl-]>CCCCCC>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:16])=[CH:3][CH:2]=1
Reactant: COc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCC
Product: COc1ccc(C(=O)c2ccccc2)cc1
Reaction time: 0.25 h

Procedure:
Anisole (0.1 mole, 10.8 grams) and benzoyl chloride (0.1 mole, 14 grams) were dissolved in 200 milliliters of hexane and stirred at room temperature while 15 grams of anhydrous aluminum chloride were added slowly over a period of 15 minutes. The reaction mixture was stirred an additional 15 minutes and then the hexane decanted. The resulting viscous residue in the reaction flask was carefully hydrolyzed with 200 milliliters of a mixture of ice and dilute hydrochloric acid. The resulting organic fraction was taken up in dichloromethane and the resulting solution washed with water. Dichloromethane solvent was removed on a rotary evaporator leaving an oil product that solidified on standing. The solidified product was broken-up and washed with two 50 milliliters portions of pentane. Suction drying afforded 4-methoxybenzophenone in near quantitative yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]2[C:7](=O)[CH2:8][C:9]3([O:16][C:5]=2[CH:4]=1)[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]3.[C:20]1([Mg]Br)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[NH4+].[Cl-].Cl.C(=O)(O)[O-].[K+]>O1CCCC1.C(OCC)C.O.C(O)C>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]2[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:8][C:9]3([O:16][C:5]=2[CH:4]=1)[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]3
Reactant: COc1ccc2c(c1)OC1(CCN(C)CC1)CC2=O
Reactant: Br[Mg]c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc2c(c1)OC1(C=C2c2ccccc2)CCN(C)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 51 %

Procedure:
To a stirred solution of 7-methoxy-N-methylspiro[2H-1-benzopyran-2,4′-piperidine]4(3H)-one (6.19 g, 23.72 mmol), in anhydrous tetrahydrofuran (80 cm3) under an atmosphere of anhydrous nitrogen was added drop-wise a solution of phenylmagnesium bromide in tetrahydrofuran (40 cm3, 1.0 M, 40 mmol) maintaining the reaction temperature below 30° C. When the addition was complete the reaction was stirred at room temperature for 2.5 h at which time the reaction was incomplete but no Grignard reagent was present. A further portion of phenylmagnesium bromide (13.3 Cm3) was carefully added to the reaction and it was allowed to stir overnight. Water (30 cm3) was added followed by saturated aqueous ammonium is chloride solution (30 cm3). The volatiles were removed in vacuo before the resulting material was treated with diethyl ether (100 cm3) and water (100 cm3). The organic layer was separated before the aqueous portion was extracted further with diethyl ether (2×100 cm3). The combined extracts were washed with water (3×100 cm3), dried over sodium sulfate and the ether was removed in vacuo. The residue was triturated with a little diethyl ether and the resulting crystals were isolated by vacuum filtration (4.57 g, 12.15 mmol, 51%). This solid was then taken up into ethyl alcohol (75 cm3) and treated with hydrochloric acid (75 cm3, 2 N) before being heated to reflux for 1.5 h. The solution was concentrated under reduced pressure until a solid began to crystallise. The mixture was then cooled and the solid was isolated by vacuum filtration. This was then treated with a mixture of water (300 cm3), saturated aqueous potassium bicarbonate solution (50 cm3) and diethyl ether (650 cm3) and shaken. The aqueous layer was separated and extracted with diethyl ether (2×100 cm3) before the combined extracts were washed with water (3×250 cm3), dried over sodium sulfate and the volatiles were removed in vacuo to afford the title compound (3.91 g, 12.18 mmol, 51% from ketone).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[NH:8][C:9](=[O:20])[C:10]3[N:15]([CH3:16])[N:14]=[C:13]([CH2:17][CH2:18][CH3:19])[C:11]=3[N:12]=2)=[CH:4][CH:3]=1.O.[C:24]([OH:28])(=[O:27])[CH:25]=O>[Pd].CO>[CH3:16][N:15]1[C:10]2[C:9](=[O:20])[NH:8][C:7]([CH2:6][C:5]3[CH:21]=[CH:22][C:2]([NH:1][CH2:25][C:24]([OH:28])=[O:27])=[CH:3][CH:4]=3)=[N:12][C:11]=2[C:13]([CH2:17][CH2:18][CH3:19])=[N:14]1
Reactant: O=CC(=O)O
Reactant: CCCc1nn(C)c2c(=O)[nH]c(Cc3ccc(N)cc3)nc12
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CCCc1nn(C)c2c(=O)[nH]c(Cc3ccc(NCC(=O)O)cc3)nc12
Reaction time: 3 h

Procedure:
10% w/w Palladium on charcoal (87 mg) was added to a solution of 5-(4-aminobenzyl)-1-methyl-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-7-one (870 mg, 0.00293 mol) and glyoxylic acid hydrate (260 mg, 0.0035 mol) in methanol (20 ml) and the mixture hydrogenated at room temperature at 50 p.s.i. for 3 hours.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].[N:31]1([CH2:38][CH2:39][C:40]2[S:44][C:43]([C:45]([O-])=O)=[CH:42][CH:41]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.[Li+]>>[N:31]1([CH2:38][CH2:39][C:40]2[S:44][C:43]([CH2:45][N:3]([CH2:1][CH3:2])[C:4]3[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=3[C@@H:14]3[CH2:23][CH2:22][C:21]4[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=4[CH2:15]3)=[CH:42][CH:41]=2)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: O=C([O-])c1ccc(CCN2CCCCCC2)s1
Reactant: CCNc1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Agent: [Li+]
Product: CCN(Cc1ccc(CCN2CCCCCC2)s1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 97.5 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4,5-dimethoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (30 mg) and lithium 5-(2-azepan-1-ylethyl)thiophene-2-carboxylate (60 mg) according to an analogous synthetic method to Example 152 and purified by LC-MS, the title compound (39 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:47])[C@H:5]([C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:7])[CH2:4][C@@H:3]1[NH:14][C:15]([C@:17]12[CH2:43][CH2:42][C@@H:41]([C:44]([CH3:46])=[CH2:45])[C@@H:18]1[C@@H:19]1[C@@:32]([CH3:35])([CH2:33][CH2:34]2)[C@@:31]2([CH3:36])[C@@H:22]([C@:23]3([CH3:40])[C@@H:28]([CH2:29][CH2:30]2)[C:27]([CH3:38])([CH3:37])[C@@H:26]([OH:39])[CH2:25][CH2:24]3)[CH2:21][CH2:20]1)=[O:16].[CH3:48][C:49]1([CH3:56])[CH2:54][C:53](=[O:55])[O:52][C:50]1=[O:51]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1.CCOC(C)=O>[CH3:1][C:2]1([CH3:47])[C@H:5]([C:6]([N:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)=[O:7])[CH2:4][C@@H:3]1[NH:14][C:15]([C@:17]12[CH2:43][CH2:42][C@@H:41]([C:44]([CH3:46])=[CH2:45])[C@@H:18]1[C@@H:19]1[C@@:32]([CH3:35])([CH2:33][CH2:34]2)[C@@:31]2([CH3:36])[C@@H:22]([C@:23]3([CH3:40])[C@@H:28]([CH2:29][CH2:30]2)[C:27]([CH3:37])([CH3:38])[C@@H:26]([O:39][C:53](=[O:55])[CH2:54][C:49]([CH3:56])([CH3:48])[C:50]([OH:52])=[O:51])[CH2:25][CH2:24]3)[CH2:21][CH2:20]1)=[O:16]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@H]3C[C@@H](C(=O)N4CCCCC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC1(C)CC(=O)OC1=O
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@H]3C[C@@H](C(=O)N4CCCCC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 61 %

Procedure:
To a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-N-((1S,3R)-2,2-dimethyl-3-(piperidine-1-carbonyl)cyclobutyl)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxamide (Example 11, 0.110 g, 1.697 mmol) 2,2-Dimethylsuccinic anhydride (0.2 ml, 1.697 mmol) and DMAP (0.044 g, 0.338 mmol) in pyridine (5 ml) were added at room temperature then the reaction mixture was refluxed for about 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc, washed with water, 1N HCl, water, brine and dried with Na2SO4, the solvent was evaporated and purified by silica gel column (100-200 mesh, elution 15% EtOAc in hexane) to afford the title compound as an off white solid. Wt: 0.080 g: Yield: 61%; 1H NMR (300 MHz, CDCl3): δ 6.01 (d, 1H, J=8.4 Hz), 4.72 (s, 1H), 4.58 (s, 1H), 4.53-4.43 (m, 1H), 4.16-4.08 (m, 1H), 3.71-3.62 (m, 2H), 3.54-3.35 (m, 3H), 3.18-3.06 (m, 1H), 2.93-2.87 (m, 1H), 2.66 (d, 1H, J=15.9 Hz), 2.56 (d, 1H, J=15.9 Hz), 2.50-2.27 (m, 2H), 1.99-1.88 (m, 2H), 1.80-1.00 (m, 46H), 0.94, 0.92, 0.83 (s, 12H); Mass: [M+1]+ 777 (100%), [M+Na]+ 799 (80%); IR (KBr, cm−1): 3411, 2944, 2867, 1733, 1730, 1625, 1467, 1445, 1368, 1253, 1220, 1192, 1022, 977, 884, 767; M.R: 139.5° C.-141.5° C.; HPLC: 96.7%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C@H:8]([OH:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.CC([O-])(C)C.[K+].F[C:18]1[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=[CH:20][N:19]=1>CN1CCOCC1>[F:25][C:24]([F:27])([F:26])[C:23]1[C:18]([O:10][C@@H:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[N:7]=2)[CH3:9])=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: Fc1ncccc1C(F)(F)F
Reactant: C[C@@H](O)c1ccnc(N)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCOCC1
Product: C[C@@H](Oc1ncccc1C(F)(F)F)c1ccnc(N)n1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
To a solution of (R)-1-(2-aminopyrimidin-4-yl)ethanol (6a) (250 mg) in dry N-methylmorpholine (4 mL) at ambient temperature was added potassium 2-methylpropan-2-olate (222 mg) and the solution was left to stir for 30 min then 2-fluoro-3-(trifluoromethyl)pyridine (282 mg) was added the mixture was stirred for 10 min at ambient temperature and then heated to 100° C. with microwave irradiation for 2 minutes then cooled and quenched into water (50 mL). The precipitated solid was filtered and washed with water and air dried under a slight vacuum. The semi-dried material was taken up in methylene chloride and dried over magnesium sulfate to which activated charcoal was added then filtered through a bed of dicalite and evaporated to give the title compound (359 mg), MS (ES): m/z 285 [M+H]+.
Reaction SMILES: [CH2:1]([Sn](CCCC)(CCCC)C=C)[CH2:2]CC.[Cl-].[Li+].Br[C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:27]=1[NH:26][CH:25]=[CH:24]2.O>CN(C)C=O.C1([Pd-2](Cl)(Cl)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>[CH:1]([C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:27]=1[NH:26][CH:25]=[CH:24]2)=[CH2:2]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Brc1cccc2cc[nH]c12
Agent: Cl[Pd-2](Cl)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: C=Cc1cccc2cc[nH]c12
Temperature: 100 °C
Yield: 79.9 %

Procedure:
Add-tributyl(vinyl)tin (9.8 mL, 33.7 mmol), triphenyl-phosphine (0.4 g, 1.53 mmol), diphenylpalladium(II) dichloride (1.07 g, 1.53 mmol) and lithium chloride (4.0 g, 94.4 mmol) to 7-bromo-1H-indole (6.0 g, 30.6 mmol) in 150 mL of dimethylformamide and heat the resulting mixture at 100° C. overnight. Cool the reaction mixture to 20-24° C. and poured into a mixture of 150 mL of water and 150 mL of ethyl acetate. Wash the aqueous layer with additional ethyl acetate (3×100 mL), combine the organic layers, wash with saturated aqueous sodium chloride, dry over magnesium sulfate, filter, and concentrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with 5-10% ethyl acetate in hexanes. Combine fractions containing product and concentrate them under reduced pressure to provide the desired compound as a clear oil (3.5 g, 80%).
Reaction SMILES: COS(O)(=O)=O.B(OC)(OC)OC.C[C:15]([O:17][CH2:18][C:19]1[CH2:28][S:27][C@@H:22]2[C@H:23]([NH2:26])[C:24](=[O:25])[N:21]2[C:20]=1[C:29]([OH:31])=[O:30])=O>C(OC)(=O)/C=C\C(OC)=O>[NH2:26][CH:23]1[C:24](=[O:25])[N:21]2[C:20]([C:29]([OH:31])=[O:30])=[C:19]([CH2:18][O:17][CH3:15])[CH2:28][S:27][C@H:22]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: COB(OC)OC
Agent: COC(=O)/C=C\C(=O)OC
Agent: COS(=O)(=O)O
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
11.30 g of a methanolic solution of methoxysulfonic acid (prepared as described in Preparation 1) and 3.11 g of trimethyl borate were added to 30 ml of dimethyl maleate. The mixture was cooled to 25° C., and 2.74 g of 7-ACA were added thereto, followed by stirring at 25° C. for 1 hour. After completion of the reaction, the reaction mixture was treated following the procedures described in Example 2 to give 2.04 g (yield 83%) of the desired compound at a high purity.
Reaction SMILES: C(OCC)C1OC1.C.[Na:9][Na:10].C(OCC(O)C[N:17]([CH2:22][P:23]([OH:26])([OH:25])=[O:24])[CH2:18][C:19]([OH:21])=[O:20])C.[H][H].[P]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].O>[Na:9][Na:10].[P:23]([CH2:22][NH:17][CH2:18][C:19]([OH:21])=[O:20])([OH:26])([OH:25])=[O:24]
Reactant: CCOCC(O)CN(CC(=O)O)CP(=O)(O)O
Reactant: [H][H]
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: CCOCC1CO1
Agent: [Cl-]
Solvent: O
Product: O=C(O)CNCP(=O)(O)O
Reaction time: 120 h

Procedure:
A solution of the disodium salt of N-phosphonomethylglycine is prepared as in Example 1. To 27.5 grams (0.0437 mole) of the solution is added 5.1 grams (0.05 mole) of ethyl glycidyl ether. The solution is diluted with 30 ml. water and 1 drop of Aliquat 336 phase-transfer catalyst solution is added. It is then rotated on a polymer wheel for 5 days, treated with 1.0 gram of ethyl glycidyl ether, rotated for 10 days, then warmed with charcoal and filtered to remove resinous material. The solution is then rotoevaporated to dryness, and the solid is redried over potassium hydroxide pellets at 100° C. and <1 mm. Hg. The product, obtained as a tan, brittle foamed glass, is the disodium salt of N-(3-ethoxy-2-hydroxy-1-propyl)-N-phosphonomethylglycine. Elemental analysis shows 31.15% carbon, 5.62% hydrogen and 8.87% phosphorus as against calculated values of 30.49%, 5.12% and 9.83% for C8H16NNa2O7P.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].[CH:31]([C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40]([OH:42])=[O:41])=[CH:35][CH:34]=1)=O>>[C:40]([CH2:39][C:36]1[CH:37]=[CH:38][C:33]([CH2:31][CH2:2][CH2:1][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=2[C@H:14]2[CH2:23][CH2:22][C:21]3[CH:20]=[C:19]([O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[CH:18]=[CH:17][C:16]=3[CH2:15]2)=[CH:34][CH:35]=1)([OH:42])=[O:41]
Reactant: CCNc1cc(OC)c(OC)cc1[C@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=Cc1ccc(CC(=O)O)cc1
Product: COc1cc(NCCCc2ccc(CC(=O)O)cc2)c([C@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)cc1OC
Yield: 98.5 %

Procedure:
Synthesized from pivalic acid (S)-6-(2-ethylamino-4,5-dimethoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (59 mg) and (4-formylphenyl)acetic acid (72 mg) according to an analogous synthetic method to Example 212, the title compound (79 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][CH2:5][NH:6][C:7](=[O:11])[CH:8](Cl)[CH3:9].C(=O)([O-])[O-].[K+].[K+].[Cl:19][C:20]1[C:25]([SH:26])=[CH:24][C:23]([N:27]2[C:32](=[O:33])[CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[N:29]([CH3:38])[C:28]2=[O:39])=[C:22]([F:40])[CH:21]=1.Cl>C(#N)C.C(OCC)(=O)C.O>[CH3:1][O:2][C:3](=[O:12])[CH2:4][CH2:5][NH:6][C:7](=[O:11])[CH:8]([S:26][C:25]1[CH:24]=[C:23]([N:27]2[C:32](=[O:33])[CH:31]=[C:30]([C:34]([F:36])([F:37])[F:35])[N:29]([CH3:38])[C:28]2=[O:39])[C:22]([F:40])=[CH:21][C:20]=1[Cl:19])[CH3:9]
Reactant: COC(=O)CCNC(=O)C(C)Cl
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(S)c(Cl)cc2F)c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)CCNC(=O)C(C)Sc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reaction time: 2 h
Yield: 78 %

Procedure:
To a suspension of 3-(2-chloropropionylamino)propionic acid methyl ester (6.93 g) and potassium carbonate (4.72 g) in acetonitrile (150 mL) was added dropwise a solution of 3-(4-chloro-2-fluoro-5-mercaptophenyl)-1-methyl-6-trifluoromethyl-1H-pyrimidin-2,4-dione (11.54 g) in acetonitrile (75 mL) at 45° C. to 50° C. for 1 hour. The reaction mixture was stirred at the same temperature for 2 hours and neutralized at 5° C. with 1 N hydrochloric acid. Water and ethyl acetate were added to separate the organic layer. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried with magnesium sulfate, filtered, concentrated, and recrystallized with ether to give the target compound (13.00 g, yield 78%, white solid).
Reaction SMILES: Cl.[CH:2]1([CH2:5][CH:6]2[C:15]3[C:10](=[CH:11][C:12]([F:16])=[CH:13][CH:14]=3)[CH2:9][CH2:8][CH:7]2[NH2:17])[CH2:4][CH2:3]1.C1([O:24][C:25](=O)[NH:26][C:27]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:28]=2[CH:29]=[CH:30][N:31]=[CH:32]3)C=CC=CC=1.C(N(C(C)C)CC)(C)C>CS(C)=O>[CH:2]1([CH2:5][CH:6]2[C:15]3[C:10](=[CH:11][C:12]([F:16])=[CH:13][CH:14]=3)[CH2:9][CH2:8][CH:7]2[NH:17][C:25]([NH:26][C:27]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:28]=2[CH:29]=[CH:30][N:31]=[CH:32]3)=[O:24])[CH2:3][CH2:4]1
Reactant: O=C(Nc1cccc2cnccc12)Oc1ccccc1
Reactant: NC1CCc2cc(F)ccc2C1CC1CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(Nc1cccc2cnccc12)NC1CCc2cc(F)ccc2C1CC1CC1
Yield: 28.6 %

Procedure:
1-Cyclopropylmethyl-6-fluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamine hydrochloride (127 mg, 0.49 mmol), isoquinolin-5-yl-carbamic acid phenyl ester (150 mg, 0.49 mmol), and diisopropylethylamine (193 mg, 1.47 mmol) were combined and stirred at ambient temperature in DMSO (3 mL) overnight. The product was purified by directly injecting the crude reaction onto a reverse phase prep-HPLC (10-90% water:acetonitrile gradient). The appropriate fractions were lyophilized to yield 1-(1-cyclopropylmethyl-6-fluoro-1,2,3,4-tetrahydro-naphthalen-2-yl)-3-isoquinolin-5-yl-urea 71 (68 mg, 0.14 mmol). MS (MH+) 390; 1H NMR (CD3OD) δ 0.08-0.87 (m, 2H), 1.60-1.65 (m, 2H), 2.03 (m, 1H), 2.97 (m, 2H), 3.14 (m, 1H), 4.36 (m, 1H), 6.87 (m, 2H), 7.27 (m, 1H), 7.93 (t, 1H, J=2.6 Hz), 8.14 (d, 1H, J=2.7 Hz), 8.32 (d, 1H, J=2.2 Hz), 8.47 (d, 1H, J=2.6 Hz), 8.53 (d, 1H, J=2.2 Hz), 9.63 (s, 1H). HPLC Rt=3.63 min (10-90% water:acetonitrile gradient, 100% pure).
Reaction SMILES: C(=O)([S:3][CH2:4][CH2:5][N:6]1[CH2:10][C:9]([CH3:12])([CH3:11])[NH:8][C:7]1=[O:13])C.[OH-].[Na+]>CO.O>[SH:3][CH2:4][CH2:5][N:6]1[CH2:10][C:9]([CH3:11])([CH3:12])[NH:8][C:7]1=[O:13]
Reactant: CC(=O)SCCN1CC(C)(C)NC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)CN(CCS)C(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.8 %

Procedure:
To a cold (0° C.) solution of S-(2-(4,4-dimethyl-2-oxoimidazolidin-1-yl)ethyl) ethanethioate (1.5 g, 6.9 mmol) in 14 mL of methanol and 7.2 mL of water was added 2.1 mL of 5 N NaOH. The external ice bath was removed and the mixture was allowed to warm to room temperature and stirred for 18 hours. Concentrated HCl (11 mL) was added and the resultant solution was concentrated to about ½ its original volume and extracted with ethyl acetate. The organic layer was washed with a brine solution, dried over sodium sulfate, and concentrated to give 1.2 g of a tan liquid. 1H NMR (CDCl3, 400 MHz) δ 1.32 (s, 6H), 1.39-1.43 (t, J=8.1 Hz, 1H) 2.66-2.27 (q, J=6.8 Hz, 2H), 3.24 (s, 2H), 3.36-3.340 (t, J=7.2 Hz, 2H), 4.94 (br s, 1H); LRMS (ESI/APCI) m/z 175 [M+H]+.
Reaction SMILES: CC1N=C(NC2C=NC=CN=2)SC=1C1C=CN=CC=1.[CH3:20][C:21]1[CH:26]=[C:25]([CH2:27][C:28](=[O:30])[CH3:29])[CH:24]=[C:23]([CH3:31])[N:22]=1.N1C=CN=CC=1NC(N)=S.[C:42]([NH:45][C:46]([NH2:48])=[S:47])(=[O:44])[CH3:43]>>[CH3:20][C:21]1[CH:26]=[C:25]([C:27]2[S:47][C:46]([NH:45][C:42](=[O:44])[CH3:43])=[N:48][C:28]=2[CH3:29])[CH:24]=[C:23]([CH3:31])[N:22]=1.[CH3:20][C:21]1[CH:26]=[C:25]([CH2:27][C:28](=[O:30])[CH3:29])[CH:24]=[C:23]([CH3:31])[N:22]=1
Reactant: CC(=O)NC(N)=S
Agent: CC(=O)Cc1cc(C)nc(C)c1
Agent: Cc1nc(Nc2cnccn2)sc1-c1ccncc1
Agent: NC(=S)Nc1cnccn1
Product: CC(=O)Nc1nc(C)c(-c2cc(C)nc(C)c2)s1

Procedure:
The titled compound is prepared by an analogous procedure to (4-Methyl-5-pyridin-4-yl-thiazol-2-yl)-pyrazin-2-yl-amine (Example 1) by replacing 1-pyridin-4-yl-propan-2-one (1b) in this procedure with 1-(2,6-dimethyl-pyridin-4-yl)-propan-2-one and by replacing and pyrazin-2-yl-thiourea (1a) with N-acetylthiourea. 1-(2,6-dimethyl-pyridin-4-yl)-propan-2-one was prepared according to a method described in Tetrahedron Letters, Vol. 25, No. 5, pp 515-518, 1984. (Authors: Claude Erre et al.)
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[C:4]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[CH:18]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19]1.Cl>C(#N)C.O1CCOCC1.O>[CH:18]1([NH:23][C:2]2[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[C:4]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[N:3]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Cc1nc(NCc2ccccn2)nc(Cl)c1C
Reactant: NC1CCCC1
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Yield: 17.7 %

Procedure:
A solution of 4-chloro-5,6-dimethyl-N-(pyridin-2-ylmethyl)pyrimidin-2-amine (200 mg, 0.8 mmol, Step C) and cyclopentanamine (85 mg, 1 mmol) in acetonitrile (5 mL) was treated with 3.5 M hydrogen chloride in dioxane (0.2 mL), and the resultant mixture was refluxed overnight. The reaction mixture was diluted with water (50 mL), and the resultant precipitate was collected by filtration. The precipitate was purified by crystallization from ethanol (10 mL) to afford 42 mg (19%) of the titled compound as the hydrochloride salt as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.40-1.50 (m, 4H), 1.50-1.67 (m, 4H), 1.88 (s, 3H), 2.27 (s, 3H), 4.00-4.12 (m, 1H), 4.92 (d, J=4.57 Hz, 2H), 7.71-4.83 (m, 2H), 7.83 (d, J=8.06 Hz, 1H), 8.17-8.25 (m, 1H), 8.33-8.39 (m, 1H), 8.76 (d, J=5.10 Hz, 1H), 13.24 (bs, 1H); MS (ESI) m/z 398.5 (ESI) (M+1)+.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([S-:9])=[S:8])=[CH:5][CH:4]=1)#[N:2].[Na+]>O>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([S:9][S:9][C:7](=[S:8])[C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=2)=[S:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(=S)[S-])cc1
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(C(=S)SSC(=S)c2ccc(C#N)cc2)cc1

Procedure:
Potassium ferricyanide(III) (25 g, 76 mmol) was dissolved in deionized water (300 mL) and added dropwise to the sodium 4-cyanodithiobenzoate via an addition funnel over a period of 1 h under vigorous stirring. The red precipitate was filtered and washed with deionized water until the washings became colorless. The solid was dried in vacuo at room temperature overnight. The product bis(4-cyanothiobenzoyl)disulfide was recrystallized from ethanol.