Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1.O[N:21]1[C:25]2N=CC=C[C:24]=2N=N1.C(N)C.O>O1CCCC1.C(Cl)(Cl)Cl>[CH2:25]([NH:21][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([B:11]2[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]2)[CH:4]=1)[CH3:24]
Reactant: On1nnc2cccnc21
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Agent: CCN
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CCNC(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1
Reaction time: 24 h
Yield: 831.3 %

Procedure:
4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (1.3 g) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.44 g) and 3H-[1,2,3] 1-hydroxy-7-azabenzotriazole (0.077 g) was added to a stirred solution of ethylamine in tetrahydrofuran (2M, 5 ml) in chloroform (30 ml) and the mixture was stirred for 24 h. The mixture was poured into water, passed through a hydrophobic filter tube and the organic phase was concentrated under vacuum. The residual solid was purified on an SCX cartridge eluting with methanol to give the title compound as a pale yellow solid (1.36 g)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20].[Br-].[CH:24]1([Zn+])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C1COCC1>CN1CCCC1=O.CC(P(C(C)(C)C)C(C)(C)C)(C)C.CC(P(C(C)(C)C)C(C)(C)C)(C)C.[Pd]>[CH:24]1([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[CH:4][C:3]=2[C:19]([F:22])([F:21])[F:20])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: [Zn+]C1CCCCC1
Reactant: COc1ccc(COCc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: COc1ccc(COCc2ccc(C3CCCCC3)c(C(F)(F)F)c2)cc1
Temperature: 105 °C

Procedure:
1-Chloro-4-(4-methoxy-benzyloxymethyl)-2-trifluoromethyl-benzene (2 g, 6.51 mmol), Pd(t-Bu3P)2 (66.54 mg, 0.13 mmol) and cyclohexylzinc bromide/THF solution (0.5 M, 40 mL, 19.5 mmol) are mixed in 1-methyl-2-pyrrolidinone (NMP) (40 mL). The mixture is purged with N2 (g) and then heated at 105° C. for 16 hours. The reaction mixture is poured into saturated aqueous NH4Cl (250 mL) and extracted with EtOAc. The combined extracts are washed with brine and dried over Na2SO4. After concentration, the residue is purified by silica gel chromatography (8:1 hexanes/EtOAc) to give 1-Cyclohexyl-4-(4-methoxy-benzyloxymethyl)-2-trifluoromethyl-benzene. To a solution of this material in DCM (8 mL) is added TFA (8 mL). The reaction mixture is stirred at room temperature for 16 hours. After concentration, the residue is partitioned between saturated aqueous NH4Cl and EtOAc. The aqueous phase is extracted with EtOAc. The combined organic extracts are washed with brine and dried over Na2SO4. After concentration, the residue is purified by silica gel chromatography (4:1 hexanes/EtOAc) to give (4-Cyclohexyl-3-trifluoromethyl-phenyl)-methanol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]([S:8][C:9](=O)[CH3:10])([CH3:7])[CH3:6])[CH3:2].C[O-].[Na+].CC1C=CC(S([O:26][CH2:27][C@H:28]2COC[CH2:30][O:29]2)(=O)=O)=CC=1>C(O)C>[O:26]1[CH2:27][CH2:28][O:29][CH2:30][C@@H:10]1[CH2:9][S:8][C:5]([CH3:7])([CH3:6])[C:4]([O:3][CH2:1][CH3:2])=[O:12]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COCCO2)cc1
Reactant: CCOC(=O)C(C)(C)SC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(C)(C)SC[C@H]1COCCO1
Temperature: 130 °C
Yield: 48.2 %

Procedure:
To a solution of 0.27 g (1.42 mmol) of 2-acetylsulfanyl-2-methyl-propionic acid ethyl ester in ethanol (4 mL, degassed) are added 0.31 g (5.7 mmol) of sodium methoxide, followed by 0.39 g (1.42 mmol) of (2R)-1,4-dioxan-2-ylmethyl 4-methylbenzene-1-sulfonate (prepared according to WO2008/119663, F. Hoffmann-La Roche AG) under nitrogen atmosphere. The reaction is heated in a microwave to 130° C. for 0.5 h. The solvent is removed under reduced pressure. The residue is dissolved in DCM (10 mL) and washed with saturated aqueous NaHCO3 solution (10 mL). The aqueous layer is extracted with DCM (10 mL). The combined organic extracts are dried over Na2SO4, filtered and the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography (silica, eluent: heptanes, 20% ethyl acetate) to afford 0.17 g of ethyl 2-{[(2R)-1,4-dioxan-2-ylmethyl]sulfanyl}-2-methylpropanoate (UV purity: 77%). Yield: 61%, m/z 271 [M+Na]; 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.29 (3H, t, J=7.17 Hz), 1.49-1.54 (6H, m), 2.59-2.66 (1H, m), 2.70-2.77 (1H, m), 3.28-3.36 (1H, m), 3.55-3.63 (1H, m), 3.64-3.76 (3H, m), 3.77-3.85 (2H, m), 4.18 (2H, q, J=7.17 Hz)
Reaction SMILES: C(O[C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[N:9]2[CH:24]=[CH:25][CH:26]=[C:8]2[C:7]=1[OH:27])=[O:5])C.[NH2:28][CH2:29][C:30]([O-:32])=[O:31].[Na+]>>[F:23][C:20]([F:22])([F:21])[C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:10]2[C:11](=[O:12])[C:6]([C:4]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:5])=[C:7]([OH:27])[C:8]3=[CH:26][CH:25]=[CH:24][N:9]23)=[CH:15][CH:16]=1
Reactant: NCC(=O)[O-]
Reactant: CCOC(=O)c1c(O)c2cccn2n(Cc2ccc(C(F)(F)F)cc2)c1=O
Agent: [Na+]
Product: O=C(O)CNC(=O)c1c(O)c2cccn2n(Cc2ccc(C(F)(F)F)cc2)c1=O

Procedure:
Prepared according to the glycinolysis condition used in Example 1 step d) from 1-(4-trifluoromethyl-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (1.0 eq.) and sodium glycinate (15 eq.). ESI (m/z): 410 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:12]([CH3:13])[C:11]3[CH:14]=[C:15](/[CH:20]=[CH:21]/[CH3:22])[CH:16]=[C:17]([O:18][CH3:19])[C:10]=3[O:9]2)=[CH:4][C:3]=1[O:23][CH3:24].[CH2:25]=[O:26].Cl>[OH-].[K+]>[CH3:19][O:18][C:17]1[C:10]2[O:9][C@@H:8]([C:5]3[CH:4]=[C:3]([O:23][CH3:24])[C:2]([OH:1])=[C:7]([CH:6]=3)[CH2:25][OH:26])[C@H:12]([CH3:13])[C:11]=2[CH:14]=[C:15](/[CH:20]=[CH:21]/[CH3:22])[CH:16]=1
Reactant: C/C=C/c1cc(OC)c2c(c1)[C@@H](C)[C@H](c1ccc(O)c(OC)c1)O2
Reactant: C=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: C/C=C/c1cc(OC)c2c(c1)[C@@H](C)[C@H](c1cc(CO)c(O)c(OC)c1)O2
Reaction time: 24 h

Procedure:
In a nitrogen atmosphere 10 g trans-2,3-dihydro-2-(4-hydroxy-3-methoxyphenyl)-7-methoxy-3-methyl-5-(E)-propenylbenzofuran are dissolved in 400 ml 2 N potash lye and treated with 37 ml 35 percent formalin solution, then held for 24 hours at 74° C. and treated twice within this period with the same amount of formaline solution. After cooling follows acidification with dilute hydrochloric acid until a pH of 1 is attained, then extraction with ether, washing of the ether phase with water, 5 percent NaHCO3 solution and water, and drying over Na2SO4. The oil remaining upon removal of the ether is crystallized from methylenechloride/petroleum ether (boiling point 60°-80° C.) and yields 7 g 5-[trans-2,3-dihydro-7-methoxy-3-methyl-5-(E)-propenylbenzofuran-2-yl]-2-hydroxy-3-methoxybenzyl alcohol, melting point 117°-119° C.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].Br[CH2:22][CH:23]1[CH2:25][CH2:24]1>>[CH:23]1([CH2:22][N:8]2[C:9]([O:10][C:11]3[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]2=[O:19])[CH2:25][CH2:24]1
Reactant: Cc1cc(C)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: BrCC1CC1
Product: Cc1cc(C)cc(Oc2c(C(C)C)c(=O)[nH]c(=O)n2CC2CC2)c1
Yield: 40.2 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and bromomethyl cyclopropane were reacted by the same way with the example 1 to obtain the titled compound (132 mg, yield: 40.2%).
Reaction SMILES: C(OCCOCCO)C.[BH4-].[Na+].[O:12](C)[C:13]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=O.S(=O)(=O)(O)O>C1(C)C(C)=CC=CC=1>[CH2:13]([OH:12])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCC(=O)OC
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCCOCCO
Solvent: Cc1ccccc1C
Product: CCCCCCCCCCO
Temperature: 25 °C
Yield: 97 %

Procedure:
11.2 g (0.083 mole) of diethylene glycol monoethyl ether was added dropwise to a mixture consisting of 1.6 g (0.042 mole) of sodium borohydride, 10 ml of xylene and 5 g (0.027 mole) of methyl caprate at 90° C. over two hours while agitating the mixture. Subsequently, the mixture was agitated at the same temperature for 2.5 hours. After cooling to room temperature, the mixture was neutralized with dilute sulfuric acid. As a result, n-decanol was obtained in 97% yield.
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[CH2:3][C:4](=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>CN(C=O)C>[CH3:15][N:16]([CH:18]=[C:5]([C:4](=[O:11])[CH2:3][CH:2]([CH3:1])[CH3:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:17]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)CC(=O)CC(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C(=CN(C)C)C(=O)CC(C)C
Yield: 100 %

Procedure:
According to Scheme 1 Step 1: A solution of ethyl 5-methyl-3-oxohexanoate (11.6 mmol, 2.00 g) and of 1,1-dimethoxy-N,N-dimethylmethanamine (11.6 mmole, 1.54 mL) in DMF (10 mL) was microwaved for 30 minutes at 120° C. After evaporation of the solvent, 2.64 g (11.6 mmol) of ethyl 2-((dimethylamino)methylene)-5-methyl-3-oxohexanoate as an orange oil were obtained and used without further purification.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2[N:6]=[CH:7][N:8]=[CH:9][C:4]=2[C@@:3]21[CH2:25][C:13]1=[N:14][CH:15]=[C:16]([C:18]([O:20]C(C)(C)C)=[O:19])[CH:17]=[C:12]1[CH2:11]2.[ClH:26].[CH2:27]([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[CH3:28]>Cl>[O:1]=[C:2]1[NH:10][C:5]2[N:6]=[CH:7][N:8]=[CH:9][C:4]=2[C@@:3]21[CH2:25][C:13]1=[N:14][CH:15]=[C:16]([C:18]([OH:20])=[O:19])[CH:17]=[C:12]1[CH2:11]2.[ClH:26].[ClH:26].[CH2:27]([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[CH3:28]
Reactant: CC(C)(C)OC(=O)c1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncncc21
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(O)c1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncncc21
Reaction time: 16 h

Procedure:
To solid tert-butyl (6S)-6′-oxo-5,6′,7,7′-tetrahydrospiro[cyclopenta[b]pyridine-6,5′-pyrrolo[2,3-d]pyrimidine]-3-carboxylate (255 mg, 0.536 mmol) containing one equivalent of triethylamine hydrochloride (from previous step) was added hydrochloric acid solution (20 mL, 4 M in dioxane). After 16 h, the mixture was concentrated to give the title compound as a bis hydrochloric acid salt with one equivalent of triethylamine hydrochloride. MS: m/z=283.2 (M+1). 1H NMR (500 MHz, DMSO): δ 11.75 (s, 1H); 9.50 (s, 1H); 8.90 (s, 1H); 8.80 (s, 1H); 8.40 (s, 1H); 8.20 (s, 1H); 3.50-3.40 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[NH:12][CH2:11][C:10]3=[CH:13][CH:14]=[CH:15][N:9]3[CH2:8][C:7]=2[CH:16]=1.[CH3:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[Br:29])[C:23](Cl)=[O:24].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[N:12]([C:23]([C:22]3[CH:26]=[CH:27][C:28]([Br:29])=[C:20]([CH3:19])[CH:21]=3)=[O:24])[CH2:11][C:10]3=[CH:13][CH:14]=[CH:15][N:9]3[CH2:8][C:7]=2[CH:16]=1
Reactant: COc1cc2c(cc1OC)NCc1cccn1C2
Reactant: Cc1cc(C(=O)Cl)ccc1Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)N(C(=O)c1ccc(Br)c(C)c1)Cc1cccn1C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.5 %

Procedure:
To a solution of 7,8-dimethoxy-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of Step B (3.20 g) in dichloromethane (20 mL) was added 3-methyl-4-bromo benzoyl chloride (3.4 g, 1.1 equiv) and triethylamine (2.0 g, 1.5 equiv) and the mixture was stirred at room temperature overnight. The solvent was then removed in vacuo and the residue chromatographed on silica gel eluting with a solvent gradient from 5 to 50% ethyl acetate in petroleum ether to provide the title compounds as a yellow crystalline solid (3.5 g), m.p. 165-168° C.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].[NH2:5][C@@H:6]1[C:13](=[O:14])[N:12]2[C@@H:7]1[S:8][CH2:9][C:10]([CH:18]=O)=[C:11]2[C:15]([OH:17])=[O:16]>O>[NH2:5][CH:6]1[C:13](=[O:14])[N:12]2[C:11]([C:15]([OH:17])=[O:16])=[C:10]([CH:18]=[N:4][O:3][CH3:2])[CH2:9][S:8][C@H:7]12
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(C=O)CS[C@H]12
Reactant: CON
Agent: Cl
Solvent: O
Product: CON=CC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reaction time: 8 h

Procedure:
A solution of 0.5 g of the hydrochloride of O-methylhydroxylamine in 10 ml of water is treated under stirring at 0° with 1.38 g of 7-amino-3-formyl-3-cephem-4-carboxylic acid and stirred for ca. 8 hours at 0°. 7-Amino-3-[(methoxyimino)methyl]-3-cephem-4-carboxylic acid precipitates in form of almost white crystals, which are filtered off, washed with 5 ml of cold water and 5 ml of acetone and dried.
Reaction SMILES: [OH:1][CH:2]([CH2:41][N:42]1[C:46](=[O:47])[C:45]2([CH2:52][C:51]([CH3:54])([CH3:53])[NH:50][C:49]([CH3:56])([CH3:55])[CH2:48]2)[NH:44][C:43]1=[O:57])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]([OH:40])[CH2:23][N:24]3[C:28](=[O:29])[C:27]4([CH2:34][C:33]([CH3:36])([CH3:35])[NH:32][C:31]([CH3:38])([CH3:37])[CH2:30]4)[NH:26][C:25]3=[O:39])=[CH:16][CH:15]=2)([CH3:13])[CH3:12])=[CH:7][CH:6]=1.[CH3:58][N:59]=[C:60]=[O:61]>>[CH3:58][NH:59][C:60]([O:40][CH:22]([CH2:23][N:24]1[C:28](=[O:29])[C:27]2([CH2:34][C:33]([CH3:35])([CH3:36])[NH:32][C:31]([CH3:37])([CH3:38])[CH2:30]2)[NH:26][C:25]1=[O:39])[CH2:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]([C:8]2[CH:7]=[CH:6][C:5]([O:4][CH2:3][CH:2]([O:1][C:25](=[O:39])[NH:24][CH3:23])[CH2:41][N:42]3[C:46](=[O:47])[C:45]4([CH2:48][C:49]([CH3:56])([CH3:55])[NH:50][C:51]([CH3:54])([CH3:53])[CH2:52]4)[NH:44][C:43]3=[O:57])=[CH:10][CH:9]=2)([CH3:13])[CH3:12])=[CH:15][CH:16]=1)=[O:61]
Reactant: CN=C=O
Reactant: CC1(C)CC2(CC(C)(C)N1)NC(=O)N(CC(O)COc1ccc(C(C)(C)c3ccc(OCC(O)CN4C(=O)NC5(CC(C)(C)NC(C)(C)C5)C4=O)cc3)cc1)C2=O
Product: CNC(=O)OC(COc1ccc(C(C)(C)c2ccc(OCC(CN3C(=O)NC4(CC(C)(C)NC(C)(C)C4)C3=O)OC(=O)NC)cc2)cc1)CN1C(=O)NC2(CC(C)(C)NC(C)(C)C2)C1=O

Procedure:
A mixture of 5.0 g of 2,2-bis{4-[2-hydroxy-3-(7,7,9,9-tetramethyl-2,4-dioxo-1,3,8-triazaspiro[4.5]dec-3-yl)propoxy]phenyl}propane (prepared as described in Example 2) and 25.0 g of methyl isocyanate was refluxed for 8.5 hours. After completion of the reaction, excess methyl isocyanate was evaporated from the reaction mixture and then the residue was purified by column chromatography through silica gel eluted with a 24:12:2:1 by volume mixture of ethyl acetate, benzene, triethylamine and ethanol and then by recrystallisation from ethanol. The desired Compound No. 31 was obtained in the form of white crystals, melting point 238°-242° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]1[O:15][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([Mg]Br)[CH3:17]>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C@@H:13]([OH:15])[CH2:14][CH2:16][CH3:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[Mg]Br
Reactant: c1ccc(COCCCC[C@@H]2CO2)cc1
Product: CCC[C@H](O)CCCCOCc1ccccc1

Procedure:
(R)-6-Benzyloxyhex-1-ene oxide was prepared by copper catalyzed addition of 3-benzyloxypropyl-1-magnesium bromide to R-epichlorohydrin to form R-1-chloro-6-benzyloxyhexan-2-ol, which was then ring closed under basic conditions to (R)-6-benzyloxyhex-1-ene oxide. This epoxide was then treated with ethyl magnesium bromide (1.5 M in diethyl ether) in the presence of dilithiotetrachlorocuprate (0.02 molar equivalents, 0.1 M in tetrahydrofuran) to yield (S)-1-benzyloxy-5-hydroxyoctane.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[Br:9]Br>CC(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>[Br:9][C:3]1[CH:4]=[C:5]([CH:7]=[O:8])[S:6][C:2]=1[CH3:1]
Reactant: Cc1ccc(C=O)s1
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1sc(C=O)cc1Br
Reaction time: 48 h
Yield: 67.9 %

Procedure:
A solution of 5-methylthiophene-2-carbaldehyde (10 g, 79 mmol) in 30 ml of AcOH was added over a 7-hour period, with a syringe pump, to a stirring mixture of bromine (4.9 ml, 95 mmol) and 30 ml of AcOH, while the reaction was kept in the dark. The reaction was allowed to stir for 2 days and then poured slowly in 600 ml of 2M sodium carbonate. The mixture was stirred for 1 hour and extracted (3×) with ether. The organic layer was washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate, loaded unto silica and purified by column chromatography on silica gel using a gradient of 5 to 25% EtOAc in hexanes to give 4-bromo-5-methylthiophene-2-carbaldehyde (11 g, 68% yield) as yellow solid. MP 58° C. as reported in literature.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([NH:31][CH3:32])[C:17]4[CH2:22][CH2:21][CH:20]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=5[F:30])[C:18]=4[N:19]=3)=[CH:9][C:8]=2[O:33][CH3:34])[CH:6]=1>C(=O)=O.CO>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([NH:31][CH3:32])[C:17]4[CH2:22][CH2:21][C@H:20]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=5[F:30])[C:18]=4[N:19]=3)=[CH:9][C:8]=2[O:33][CH3:34])[CH:6]=1
Reactant: CNc1nc(Nc2ccc(-n3cnc(Cl)c3)c(OC)c2)nc2c1CCC2c1ccc(F)cc1F
Agent: O=C=O
Solvent: CO
Product: CNc1nc(Nc2ccc(-n3cnc(Cl)c3)c(OC)c2)nc2c1CC[C@@H]2c1ccc(F)cc1F

Procedure:
A racemic mixture of N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-trideuteromethyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (180 mg, 0.206 mmol from Example 109) was purified using chiral supercritical fluid chromatography (SFC) to afford 28.4 mg of peak A (Example 109A) and 27.4 mg of peak B (Example 109B). SFC Method: Chiralpak OJ-H (21×250 mm, 5 μM), 35% methanol (0.1% diethylamine) in CO2, 35° C., flow rate 45 mL/min for 10 min, absorbance 268 nm, injection 0.75 mL of 20 mg/mL solution in methanol (multiple stacked injections), tR (peak A)=3.6 min, tR (peak B) 7.2 min. The absolute stereochemistry of individual enantiomers (Examples 109A and 109B) was not determined LC-MS and 1H NMR analytical data for the separated enantiomers was identical to the racemate (Example 109).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][C@H:11]([CH2:14][NH2:15])[O:10][C:9]=2[CH:16]=1)(=[O:4])=[O:3].[F:17][C:18]([F:23])([F:22])[CH2:19][CH2:20]I>C(#N)C>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][C@H:11]([CH2:14][NH:15][CH2:20][CH2:19][C:18]([F:23])([F:22])[F:17])[O:10][C:9]=2[CH:16]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc2c(c1)O[C@@H](CN)CO2
Reactant: FC(F)(F)CCI
Solvent: CC#N
Product: CS(=O)(=O)c1ccc2c(c1)O[C@@H](CNCCC(F)(F)F)CO2
Temperature: 120 °C

Procedure:
A mixture of [(2S)-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methylamine (0.31 g, 1.27 mmol), 1,1,1-trifluoro-3-iodopropane (0.16 ml, 1.4 mmol) K2CO3 (0.35 g, 2.5 mmol) and ACN (4 ml) was heated under microwave radiation at 120° C. for 40 min. The product was evaporated to dryness and was purified by preparative HPLC (MeOH/NH3 buffer). Yield: 0.19 g, 44%. The amine was converted to the hydrochloric acid salt and was crystallized from MeOH/Et2O. M.p. 204° C. MS m/z (rel. intensity, 70 eV) 339 (M+, 3), 127 (5), 126 (bp), 79 (4), 51 (4). [α]=−52° (MeOH).
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20]([OH:22])=O.C(Cl)(=O)C(Cl)=O.[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([NH2:36])=[N:34][CH:35]=1.CN1CCOCC1>ClCCl>[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([NH:36][C:20](=[O:22])[CH2:19][N:3]2[CH2:4][CH2:5][C:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:2]2=[O:1])=[N:34][CH:35]=1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: Nc1ccc(Cl)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)Nc1ccc(Cl)cn1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.050 g, 0.169 mmol) in dichloromethane (0.5 mL) at room temperature was added a solution of oxalyl chloride in dichloromethane (2.0 M, 0.102 mL, 0.203 mmol). The reaction was stirred for 1 hour and then concentrated under a stream of nitrogen. The resulting acid chloride was dissolved in dichloroethane (0.5 mL), and 5-chloropyridin-2-amine (0.024 g, 0.186 mmol) was added followed by N-methyl morpholine (0.028 mL, 0.254 mmol). The reaction was heated to 70° C. After stirring for 3 hours, the reaction was loaded directly onto a SF15-12 silica gel column (Analogix®, Burlington, Wis.), and the product was eluted using a gradient of 5% ethyl acetate/hexanes to 75% ethyl acetate/hexanes over 25 minutes (flow=30 mL/minute). The product was contaminated with aminopyridine starting material. A second silica gel column chromatography (SF15-24, Analogix®) eluting with a gradient of 5% ethyl acetate/hexanes to 50% ethyl acetate/hexanes over 30 minutes (flow=30 mL/minute) gave the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 8.44-8.46 (br s, 1H), 8.22 (dd, J=2.5, 0.7 Hz, 1H), 8.09 (d, J=8.8 Hz, 1H), 7.65 (ddd, J=8.8, 2.6, 0.5 Hz, 1H), 7.21-7.39 (m, 10H), 4.19 (s, 2H), 3.54 (t, J=6.5 Hz, 2H), 2.88 (t, J=6.5 Hz, 2H); MS (ESI+) m/z 406 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([C:15]([CH3:17])=[CH2:16])[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]>CO.[Pt](=O)=O>[Cl:1][C:2]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: C=C(C)c1ccc(C(=O)OC(C)(C)C)c(Cl)c1
Agent: O=[Pt]=O
Solvent: CO
Product: CC(C)c1ccc(C(=O)OC(C)(C)C)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.5 %

Procedure:
To a solution of tert-butyl 2-chloro-4-(prop-1-en-2-yl)benzoate (200 mg, 0.79 mmol) in methanol (20 mL) was added platinum(IV) oxide (20 mg). The resultant reaction mixture was stirred at room temperature for 24 hours under hydrogen atmosphere. Insoluble matters were removed using celite, and the filtrate was concentrated in vacuo to give tert-butyl 2-chloro-4-isopropylbenzoate (150 mg, 74.4%) as a white solid which was used in the next step directly. LRMS (M+H+) m/z: calcd 255.11. found 255 1H NMR (300 MHz, CD3OD) δ 7.67 (d, J=8.1 Hz, 1H), 7.36 (d, J=1.8 Hz, 1H), 7.28 (dd, J1=8.1 Hz, J2=1.8 Hz, 1H), 2.98 (m, 1H), 1.63 (s, 9H), 1.29 (d, J=6.9 Hz, 6H).
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:16])[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:9](=O)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:23]=[N:22][CH:21]=[CH:20][N:19]=1>>[C:1]([C:5]1[C:6](=[O:16])[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:9](=[N:17][C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1=CC(=O)C=C(C(C)(C)C)C1=O
Reactant: Nc1cnccn1
Product: CC(C)(C)C1=CC(=Nc2cnccn2)C=C(C(C)(C)C)C1=O
Temperature: 150 °C
Reaction time: 6 h

Procedure:
A mixture of 11.02 of 2,6-di-tert-butyl-1,4-benzoquinone and 4.76 g of aminopyrazine was heated with stirring at 150° C. for 6 hours. The reaction mixture was cooled to room temperature and purified by silica gel column chromatography (eluent: diethyl ether-hexane=1:4), giving 3.95 g of Compound 1a.