Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8]COC)=[CH:6][CH:5]=[CH:4][N:3]=1.S(O[CH:17]([CH2:21][C:22]#[CH:23])[C:18](=O)[CH3:19])(C)(=O)=O>C(O)C>[OH:8][C:7]1[C:2]2[N:3]([C:17]([CH2:21][C:22]#[CH:23])=[C:18]([CH3:19])[N:1]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: C#CCC(OS(C)(=O)=O)C(C)=O
Reactant: COCOc1cccnc1N
Solvent: CCO
Product: C#CCc1c(C)nc2c(O)cccn12
Temperature: 25 °C
Reaction time: 5 h
Yield: 21.3 %

Procedure:
A solution of 2-amino-3-methoxymethoxypyridine (7.5 g) and 3-mesyloxy-5-hexyn-2-one (10.18 g), in ethanol (150 ml) was refluxed for 46.5 hours and then evaporated in vacuo. To the residue was added 20% sulfuric acid (75 ml) and the mixture was stirred for 5 hours at room temperature. The mixture was made alkaline with sodium bicarbonate and extracted with chloroform. The extract was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (30 g) with chloroform and then a mixture of chloroform and methanol (30:1 to 20:1) as eluents. The eluates were evaporated in vacuo and the residue was recrystallized from a mixture of ethyl acetate and n-hexane to give 8-hydroxy-2-methyl-3-(2-propynyl)imidazo[1,2-a]pyridine (1.93 g).
Reaction SMILES: [C:1]1([N:7]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20]N1C(=O)CCC1=O>C(O)(=O)C>[Br:20][C:16]1[CH:17]=[CH:18][C:19]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: c1ccc(-n2c3ccccc3c3ccccc32)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Product: Brc1ccc2c(c1)c1ccccc1n2-c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.1 %

Procedure:
24.3 g (100 mmol) of 9-phenylcarbazole was put into a 2 L Meyer flask, and dissolved in 600 mL of glacial acetic acid. Then, 17.8 g (100 mmol) of N-bromosuccinimide was slowly added, and the solution was stirred for about 12 hours at room temperature. This solution was dropped into 1 L of ice water while stirring. A white solid precipitated was collected by suction filtration, and then washed with water three times. This solid was dissolved in 150 mL of diethyl ether, and the solution was washed with a saturated aqueous solution of sodium bicarbonate and then with water. The organic layer was dried over magnesium sulfate, filtered, and concentrated, and then the residue was dissolved in ca. 50 mL of ethanol. The precipitate formed as a white solid was collected by suction filtration and dried, giving 28.4 g (88% yield) of 3-bromo-9-phenylcarbazole as white powder.
Reaction SMILES: COC(=O)[C:4]1C=[CH:8][C:7]([NH:10][C:11](=[O:31])[CH2:12][S:13][CH:14]2[C:18]([CH3:19])=[C:17]([CH3:20])[C:16](=[O:21])[N:15]2[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[N:6][CH:5]=1.[NH2:33]C1C=NC=CN=1>>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][N:15]2[C:16](=[O:21])[C:17]([CH3:20])=[C:18]([CH3:19])[CH:14]2[S:13][CH2:12][C:11]([NH:10][C:7]2[CH:8]=[N:33][CH:4]=[CH:5][N:6]=2)=[O:31])=[CH:24][CH:25]=1
Reactant: Nc1cnccn1
Reactant: COC(=O)c1ccc(NC(=O)CSC2C(C)=C(C)C(=O)N2Cc2ccc(OC)cc2)nc1
Product: COc1ccc(CN2C(=O)C(C)=C(C)C2SCC(=O)Nc2cnccn2)cc1

Procedure:
The product from Example 1, Part C (200 mg, 0.6 mmol) and 2-aminopyrazine (89 mg, 0.9 mmol) were reacted as described in Example 5. After evaporation of the reaction solvent the residue was partitioned between water and EtOAc, and the organic phase was washed with EtOAc. The combined organics were washed with brine, dried (Na2SO4), filtered, and evaporated. The title compound was obtained as a tan solid by silica gel chromatography. 1H NMR (400 MHz, CDCl3) δ 9.48 (s, 1H), 8.70 (br s, 1H), 8.36 (d, J=2 Hz, 1H), 8.20 (m, 1H), 7.22 (d, J=8 Hz, 2H), 6.83 (d, J=8 Hz, 2H), 5.14 (d, J=14 Hz, 1H), 4.63 (s, 1H), 4.16 (d, J=14 Hz, 1H), 3.77 (s, 3H), 3.04 (d, J=16 Hz, 1H), 2.97 (d, J=16 Hz, 1H), 1.95 (s, 3H), 1.84 (s, 3H). MS: m/z (MH+) 399.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])=[C:19]([CH3:30])[CH:18]=3)=[O:16])[CH2:6][C:5]=12.C(N(CC)CC)C.[Cl:38][C:39]([Cl:44])([Cl:43])[C:40](Cl)=[O:41]>ClCCl>[Cl:38][C:39]([Cl:44])([Cl:43])[C:40]([C:3]1[N:4]2[C:5]([CH2:6][N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])=[C:19]([CH3:30])[CH:18]=3)=[O:16])[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10]2)=[CH:1][CH:2]=1)=[O:41]
Reactant: Cc1ccccc1-c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1C
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Temperature: 25 °C

Procedure:
To a solution of (10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-10-yl)-(2,2′-dimethyl-biphenyl-4-yl)-methanone of Step C (8.38 mmol) and triethylamine (16.76 mmol) in dichloromethane (30 mL) at −5° C. was added, rapidly dropwise, trichloroacetyl chloride (25 mmol). The mixture was allowed to stir and warm to room temperature overnight. The mixture was washed with 0.1N hydrochloric acid and dilute brine, then dried over anhydrous sodium sulfate, and evaporated to leave a light green oil. The compound was purified by filtration over a plug of Merck silica gel-60 eluting with dichloromethane and then treated with hot ethyl acetate/hexane (3/1) to yield a light yellow crystalline solid, m.p. 212-214° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([O:15][CH2:16][CH3:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.Br[CH2:19][CH:20]=[C:21]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[O:26][CH2:25][O:24][C:23]2[CH:33]=[CH:34][CH:35]=[CH:36][C:22]1=2.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C1C=CC=CC=1>[CH:29]1[C:28]2[C:21](=[CH:20][CH2:19][O:1][C:2]3[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([O:15][CH2:16][CH3:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=3)[C:22]3[CH:36]=[CH:35][CH:34]=[CH:33][C:23]=3[O:24][CH2:25][O:26][C:27]=2[CH:32]=[CH:31][CH:30]=1
Reactant: BrCC=C1c2ccccc2OCOc2ccccc21
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CCOC(=O)C(Cc1ccc(OCC=C2c3ccccc3OCOc3ccccc32)cc1)OCC
Temperature: 60 °C

Procedure:
A mixture of ethyl 3-(4-hydroxyphenyl)-2-ethoxypropionate (0.96 g, 4.0 mmol), 12-(2-bromoethylidene)-12H-dibenzo[d,g]-1,3-dioxocine (1.07 g, 3.3 mmol) and potassium carbonate (0.45 g, 4.5 mmol) in dimethylformamide (15 ml) was heated to 60° C. for 8.5 h. The reaction mixture was diluted with benzene (50 ml), washed with water (2×20 ml), dried (MgSO4) and evaporated. The residue (1.95 g) was purified by column chromatography on silica gel (benzene and benzenelethyl acetate (9:1) eluents). The benzene fractions were discarded, whilst the benzene/ethyl acetate fractions were evaporated to give the title compound as an oil: 0.97 g (62%).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:30])[CH:13]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)[CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[S:9][CH:10]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[CH:15]1([CH2:14][CH:13]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)[C:12]([NH:11][C:8]2[S:9][CH:10]=[C:6]([CH2:4][OH:3])[N:7]=2)=[O:30])[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: CCOC(=O)c1csc(NC(=O)C(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nc(CO)cs2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 46.4 %

Procedure:
A solution of 2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazole-4-carboxylic acid ethyl ester (prepared as in Example 3(B)(b), 130 mg, 0.29 mmol) in diethyl ether (2 mL) was cooled to 0° C. and then slowly treated with lithium aluminum hydride (17 mg, 0.44 mmol). The reaction mixture was allowed to warm to 25° C. where it was stirred for 4 h. After 4 h at 25° C., thin layer chromatography indicated the presence of starting material. An additional amount of lithium aluminum hydride (11 mg, 0.29 mmol) was added to the reaction mixture. The resulting reaction mixture was allowed to stir at 25° C. for 15 h. The reaction mixture was then slowly quenched by the dropwise addition of water. The resulting mixture was then partitioned between water and ethyl acetate. The organic layer was then dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, ethyl acetate) afforded 3-cyclopentyl-N-(4-hydroxymethyl-thiazol-2-yl)-2-(4-methanesulfonyl-phenyl)-propionamide (55 mg, 46%) as a white solid: mp 124-126° C.; EI-HRMS m/e calcd for C19H24N2O4S2 (M+) 408.11-78, found 408.1164.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][N:3]=1.[CH2:15]([N:22]1[CH2:26][CH2:25][C@@H:24]([NH2:27])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[CH2:15]([N:22]1[CH2:26][CH2:25][C@@H:24]([NH:27][C:2]2[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][N:3]=2)[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Reactant: CCOC(=O)/C=C/c1cnc(Cl)nc1
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCN(Cc3ccccc3)C2)nc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of ethyl (2E)-3-(2-chloro-5-pyrimidinyl)acrylate (200 mg), (3R)-1-benzyl-3-pyrrolidinamine (0.244 mL), and N,N-dimethylformamide (5 mL) was stirred for 3 hours at 60° C. The reaction mixture was partitioned between ethyl acetate and H2O. The organic layer was washed with saturated NaHCO3 and brine, dried over MgSO4, filtered, and evaporated in vacuo to give ethyl (2E)-3-(2-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-pyrimidinyl)acrylate (330 mg).
Reaction SMILES: [Br:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[C:12]1([C@@H:18](O)[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.ClCCl.C(OCC)(=O)C>[Br:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([O:5][C@H:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:19])=[O:4]
Reactant: C[C@H](O)c1ccccc1
Reactant: O=C(O)C(Br)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@H](OC(=O)C(Br)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.9 %

Procedure:
To a mixture of α-bromophenylacetic acid (10.75 g, 0.050 mol), (S)-(−)-1-phenylethanol (7.94 g, 0.065 mol) and DMAP (0.61 g, 5.0 mmol) in dry dichloromethane (100 mL) was added solid EDCI (12.46 g, 0.065 mol) all at once. The resulting solution was stirred at room temperature under Ar for 18 hours and then it was diluted with ethyl acetate, washed (H2O×2, brine), dried (Na2SO4), filtered, and concentrated to give a pale yellow oil. Flash chromatography (SiO2/hexane-ethyl acetate, 4:1) of this oil provided the title compound (11.64 g, 73%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.53-7.17 (m, 10H), 5.95 (q, J=6.6 Hz, 0.5H), 5.94 (q, J=6.6 Hz, 0.5H), 5.41 (s, 0.5H), 5.39 (s, 0.5H), 1.58 (d, J=6.6 Hz, 1.5H), 1.51 (d, J=6.6 Hz, 1.5H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[CH:23]=[CH:22][C:11]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:10][CH:9]=2)[CH2:3]1.[CH:24](=O)[CH2:25][CH:26]([CH3:28])[CH3:27].[BH4-].[Na+]>>[CH3:27][CH:26]([CH3:28])[CH2:25][CH2:24][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[CH:9]=[CH:10][C:11]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:22][CH:23]=2)[CH2:3]1
Reactant: NC(=O)c1ccc(Oc2ccc(C3CCCNC3)cc2)nc1
Reactant: CC(C)CC=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)CCN1CCCC(c2ccc(Oc3ccc(C(N)=O)cn3)cc2)C1
Yield: 32.1 %

Procedure:
Using a method similar to Example 324, 6-(4-piperidin-3-yl-phenoxy)-nicotinamide (free base of compound of example 322) (0.0252 g, 0.0847 mmol), isovaleraldehyde (0.0165 mL, 0.154 mmol), and sodium borohydride (0.0082 g, 0.217 mmol) provide 0.0100 g (32%) of the title compound as an off-white foam: high resolution mass spectrum (electrospray): m/z calc for C22H30N3O2 368.2338, found 368.2355; 1H NMR (methanol-d4): 8.66 (d, 1H, J=2.4 Hz), 8.29 (dd, 1H, J=2.4, 8.8 Hz), 7.41-7.36 (m, 2H), 7.17-7.12 (m, 2H), 7.03 (d, 1H, J=8.8 Hz), 3.28-3.19 (m, 2H), 2.96 (tt, 1H, J=3.4, 11.7 Hz), 2.71-2.63 (m, 2H), 2.43-2.28 (m, 2H), 2.06-1.92 (m, 2H), 1.84 (qt, 1H, J=3.9, 13.2 Hz), 1.71-1.51 (m, 4H), 0.99 (d, 6H, J=6.3 Hz).
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[CH:13]=2)[CH:8]([CH3:21])[CH2:7]1)=O)C.[OH-].[K+]>C(O)CO>[CH3:21][CH:8]1[CH:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[CH:13]=2)[CH2:10][CH2:11][NH:6][CH2:7]1
Reactant: CCOC(=O)N1CCC(c2cc3ccccc3s2)C(C)C1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Product: CC1CNCCC1c1cc2ccccc2s1

Procedure:
The whole amount of the 3-methyl-4(benzo[b]thien-2-yl)-1-piperidinecarboxylic acid ethyl ester obtained as crude product according to the following section (a) is dissolved in 100 ml of ethylene glycol. There is then added 30 g of solid potassium hydroxide, and the resulting cloudy solution is heated, with vigorous stirring, for 15 hours at 160°. The reaction solution is subsequently cooled to 20°, and extracted 3 times with 150 ml of toluene each time. The combined toluene solutions are washed 5 times with 250 ml of water each time, and subsequently extracted twice with 200 ml of 2N hydrochloric acid each time. The acid solutions are combined; the pH-value is adjusted to 12 by the addition of 10% sodium hydroxide solution, and extraction is performed with 500 ml of chloroform. The chloroform solution is dried with sodium sulphate, filtered, and concentrated by evaporation to obtain crude 3-methyl-4-(benzo[b]thien-2-yl)-piperidine. The crude base is distilled in a bulb tube (molecular distillation) under high vacuum (0.20 Torr at a bath temperature of 170°-190°). From the distillate there is prepared the hydrochloride with hydrogen chloride in ethyl acetate; the hydrochloride is recrystallised from acetone and then melts at 253°-255°.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[N:24]([C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[CH:28]=1)=[C:25]=[O:26]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:5])[N:24]([C:27]3[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[CH:28]=3)[C:25]2=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: Cc1cc(C)cc(N=C=O)c1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Product: COc1cccc2c1ncc1c(=O)n(-c3cc(C)cc(C)c3)c(=O)n(C3CCCC3)c12
Yield: 24.8 %

Procedure:
1-Cyclopentyl-3-(3,5-dimethyl-phenyl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (33 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.32 mmol) and 1-isocyanato-3,5-dimethyl-benzene (0.48 mmol) following general procedure C. LCMS: m/z 416 [M+1]+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([C:10]2[NH:11][CH:12]=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=O)=[CH:6][CH:5]=[CH:4][N:3]=1.O.[NH2:22][NH2:23]>C(O)C>[C:15]1([C:14]2[CH:13]=[CH:12][NH:11][C:10]=2[C:8]2[C:7]3[C:2](=[N:3][CH:4]=[CH:5][CH:6]=3)[NH:23][N:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NN
Reactant: O=C(c1cccnc1Cl)c1[nH]ccc1-c1ccccc1
Solvent: CCO
Solvent: O
Product: c1ccc(-c2cc[nH]c2-c2n[nH]c3ncccc23)cc1
Temperature: 90 °C
Yield: 56 %

Procedure:
A mixture of (2-chloro-pyridin-3-yl)-(3-phenyl-1H-pyrrol-2-yl)-methanone (150 mg, 0.53 mmol) from above and hydrazine hydrate (0.5 mL) in ethanol (6 mL) was heated at 90° C. for 24 hours. The reaction was concentrated, the residue was triturated with DCM, filtered to give 77 mg (56%) of the titled compound.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]2[CH2:28][N:27]([C:29](=[O:31])[CH3:30])[CH2:26][CH2:25][C:9]=2[N:10]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][CH:23]=[N:22][CH:21]=3)=[CH:16][CH:15]=2)[N:12]=1)(=O)=O.[CH3:34][NH:35][CH2:36][CH:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[OH:38]>CS(C)=O>[OH:38][CH:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:36][N:35]([CH3:34])[C:7]1[C:8]2[CH2:28][N:27]([C:29](=[O:31])[CH3:30])[CH2:26][CH2:25][C:9]=2[N:10]=[C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[O:24][CH:23]=[N:22][CH:21]=3)=[CH:18][CH:19]=2)[N:12]=1
Reactant: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(OS(=O)(=O)C(F)(F)F)c2C1
Reactant: CNCC(O)c1ccccc1
Solvent: CS(C)=O
Product: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(N(C)CC(O)c3ccccc3)c2C1
Reaction time: 8 h
Yield: 64.6 %

Procedure:
6-Acetyl-2-(4-(oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl trifluoromethanesulfonate (35 mg, 0.07 mmol, Example 26a) in DMSO (1 mL) dispensed in a library plate. 2-(methylamino)-1-phenylethanol (10.58 mg, 0.07 mmol) was added and it was left to shake overnight at 80° C. before filtered and purified by preparative HPLC to yield 1-(4-((2-hydroxy-2-phenylethyl)(methyl)amino)-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanone (21.9 mg, 63%).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:10]#[N:11])=[N:4][C:5]([Cl:9])=[C:6]([CH3:8])[CH:7]=1.[Li+].CC([N-]C(C)C)C.[CH:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[Br:1][C:2]1[C:3]([C:10]#[N:11])=[N:4][C:5]([Cl:9])=[C:6]([CH2:8][CH:20]([OH:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:7]=1
Reactant: Cc1cc(Br)c(C#N)nc1Cl
Reactant: O=Cc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1nc(Cl)c(CC(O)c2ccccc2)cc1Br
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 3-bromo-6-chloro-5-methylpicolinonitrile (from the previous step) in THF (0.2 M) was cooled to −78° C. LDA (2N solution, 2 eq) was added dropwise. The reaction was kept stirring at −78° C. for 1 hour, followed by addition of benzaldehyde (1 eq). The reaction was kept stirring at −78° C. for another 30 minutes before allowing it to slowly warm to room temperature. The reaction was quenched with sat. NH4Cl and extracted with EtOAc. Combined organic washes were concentrated. Flash chromatography (silica gel, 20-50% EtOAc in hexanes) afforded the product 3-bromo-6-chloro-5-(2-hydroxy-2-phenylethyl)picolinonitrile as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-])=O.O.[Cl-].[NH4+]>CO.[Fe]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH2:9]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Br
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Nc1cc(Cl)ccc1Br
Temperature: 23 °C
Reaction time: 18 h
Yield: 94.7 %

Procedure:
A solution of 1-bromo-4-chloro-2-nitrobenzene (13.92 g, 58.87 mmol) in MeOH (300 mL) was treated with water (50 mL), ammonium chloride (22.99 g, 429.8 mmol) and iron powder (325 mesh, 16.44 g, 294.4 mmol). The suspension was stirred at 23° C. After 18 hours, the suspension was filtered through celite. The filter cake was washed with MeOH (500 mL). The combined filtrate/washings were concentrated, partitioned in EtOAc/water (500 mL/200 mL), and the organic layer was separated. The aqueous layer was extracted with EtOAc (2×200 mL). The organic layers were combined, washed with brine (200 mL), dried (MgSO4), and concentrated in vacuo affording 11.51 g of 2-bromo-5-chlorobenzenamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[N+:13]([O-])=O.Cl>C(O)(C)C.O.[Fe]>[NH2:13][C:4]1[CH:5]=[C:6]([C:9]([F:10])([F:11])[F:12])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: COc1ccc(C(F)(F)F)cc1N
Temperature: 50 °C
Yield: 82.8 %

Procedure:
4-Methoxy-3-nitrobenzotrifluoride (95 g) in isopropanol (1.0 liter) and water (250 ml) was mixed with concentrated hydrochloric acid (15 ml). Iron powder (180 g) was added and the mixture was heated and stirred under reflux. After 90 minutes the mixture was cooled to 50° C. and filtered. The residue was washed with isopropanol and the combined filtrates evaporated. The residue was dissolved in toluene and the solution dried (MgSO4) and evaporated. The residue was triturated with light petroleum (b.p. 30°-40°) to give the 3-amino-4-methoxybenzotrifluoride as a colourless solid (68 g).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[SH:11].[CH3:12][O:13][C:14]([CH2:16][C:17](=[CH2:21])[C:18]([O-:20])=[O:19])=[O:15].[Na+]>CO>[CH3:12][O:13][C:14]([CH2:16][CH:17]([CH2:21][S:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[C:18]([OH:20])=[O:19])=[O:15]
Reactant: Sc1ccc2ccccc2c1
Reactant: C=C(CC(=O)OC)C(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CC(CSc1ccc2ccccc2c1)C(=O)O
Yield: 53.2 %

Procedure:
A mixture of 2-naphthalenethiol (0.38 g), sodium 3-methoxycarbonyl-2-methylenepropionate (0.39 g), methanol (20 ml), and triton B (40% methanol solution, 10 drops) was refluxed for 12 hours. The reaction mixture was concentrated in vacuo, and the resulting residue was acidified with a dilute hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, and dried over MgSO4. The solvent was evaporated at reduced pressure, and the residue was purified by medium pressure liquid column chromatography on silica eluting with chloroform/methanol (20:1), and recrystallized from isopropyl ether to give 0.38 g of 2-methoxycarbonylmethyl-3-(2-naphthylthio)propionic acid.
Reaction SMILES: C(C1C=C[C:6]([C@:9]23[CH2:35][C:25]4([NH:29][C@H:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:27][S:26]4)[CH2:24][N:10]2[C:11](=[O:23])[N:12]([C:15]2C=C(Cl)C=C(Cl)C=2)[C:13]3=[O:14])=[CH:5]C=1)#N.[C:36](Cl)(=[O:38])[CH3:37]>C(#N)C>[C:36]([N:29]1[C@@H:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:27][S:26][C:25]21[CH2:24][N:10]1[C:11](=[O:23])[N:12]([CH3:15])[C:13](=[O:14])[C@:9]1([CH2:6][CH3:5])[CH2:35]2)(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)[C@@H]1CSC2(CN3C(=O)N(c4cc(Cl)cc(Cl)c4)C(=O)[C@@]3(c3ccc(C#N)cc3)C2)N1
Solvent: CC#N
Product: CCOC(=O)[C@H]1CSC2(CN3C(=O)N(C)C(=O)[C@]3(CC)C2)N1C(C)=O
Temperature: 25 °C

Procedure:
To a solution of ethyl (4′R,7aS)-7a-(4-cyanophenyl)-2-(3,5-dichlorophenyl)-1,3-dioxotetrahydro-1H-spiro[pyrrolo[1,2-c]imidazole-6,2′-[1,3]thiazolidine]-4′-carboxylate (examples 12–13, crude mixture of isomers, 0.30 g, 0.58 mmol) and ET3N (0.10 ml, 0.6 mmol)) in acetonitrile (3 mL) was added acetyl chloride (0.05 ml) and the contents stirred one night at RT. The reaction mixture was concentrated under reduced pressure and partitioned between dichloromethane (25 mL) and 1N Hydrochloric acid (10 mL). The dichloromethane layer was washed with 1N Sodium Bicarbonate, water then dried over sodium sulfate, concentrated and purified by silica gel chromatography using cyclohexane/ethyl acetate as the eluent, diluted with t-butyl methyl ether, washed with water, NaHCO3 solution, water then dried over sodium sulfate, concentrated and purified by silica gel chromatography using dichloromethane/acetone as the eluent. yield: 0.016 g. 1H NMR (CDCl3): 7.6 (2H, d), 7.35 (2H, d), 7.3 (1H, m), 6.8 (2H, m), 4.9 (1H, m), 4.75 (1H, d), 4.3 (2H, q), 4.05 (1H, d), 3.5–3.2 (5H, m), 2.65 (1H, d), 2.15 (3H, s), 1.3 (3H, t).