Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.Cl.[Br:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][CH2:12][C@@H:13]2[OH:18].C(=O)([O-])O.[Na+]>C(Cl)Cl.O1CCOCC1>[Br:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][CH2:12][C@@H:13]2[O:18][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1
Reactant: C1=COCCC1
Reactant: O[C@H]1CCc2c(Br)cccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Brc1cccc2c1CC[C@@H]2OC1CCCCO1

Procedure:
3,4-dihydro-2H-pyran (10.6 mL) was dissolved in methylene chloride (16.2 mL), and to the resultant solution, a 4M hydrogen chloride solution in 1,4-dioxane (31.1 μL) was added, and to the resultant reaction mixture, (1S)-4-bromo-2,3-dihydro-1H-inden-1-ol (10.0 g) that is commercially available or can be obtained by a publicly known method was added, followed by stirring the resultant reaction mixture at room temperature for 3 hours. To the reaction mixture, a saturated sodium hydrogen carbonate aqueous solution (60 mL) was added, followed by extracting the resultant reaction mixture with methylene chloride (60 mL), and the organic phase was washed with a saturated saline (60 mL), followed by drying the organic phase over anhydrous sodium sulfate. From the organic phase, the solvent was distilled off under reduced pressure, followed by purifying the resultant residue by silica gel column chromatography (eluate; n-hexane:ethyl acetate=95:5), and from the resultant, the solvent was distilled off under reduced pressure to obtain the subject compound (15 g). The compound is a mixture of diastereomers.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[OH:6][C:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH2:8]1)[CH2:14]2>>[Cl:1][CH2:2][C:3]([O:6][C:7]12[CH2:8][CH:9]3[CH2:15][CH:13]([CH2:12][CH:11]([CH2:10]3)[CH2:16]1)[CH2:14]2)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: OC12CC3CC(CC(C3)C1)C2
Product: O=C(CCl)OC12CC3CC(CC(C3)C1)C2

Procedure:
A mixture of 24.8 g (0.22 mol) of chloroacetyl chloride and 30.4 g (0.2 mol) of 1-hydroxyadamantane is heated in an oil bath at 50°-60° until a solution is obtained.
Reaction SMILES: C[N:2]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:24]=1N1CCCCC1C)[C:3](=O)C1C=C(C(F)(F)F)C=C(C(F)(F)F)C=1.[CH3:32][O:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][C:39]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.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>[CH3:32][O:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][C:39]=1[C:24]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[NH:2][CH3:3]
Reactant: CC1CCCCN1c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COc1cnccc1B(O)O
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: CN(C)C=O
Product: CNc1cnccc1-c1ccncc1OC
Temperature: 100 °C

Procedure:
To a solution of (4-bromo-pyridin-3-yl)-methyl-amine (50 mg, 0.267 mmol, example 25, intermediate b) and 3-methoxypyridine-4-boronic acid (CAS RN 1008506-24-8) (61.35 mg, 0.4 mmol) in dry DMF (3 mL) in a sealed tube was added potassium carbonate (2.14 mmol) and the reaction mixture was purged with argon for 10 min. Then, Pd(PPh3)4 (30.89 mg, 0.03 mmol) was added and again purged with nitrogen for 15 min. The reaction mixture was heated at 100° C. for 16 hours. After cooling to room temperature the reaction mixture was filtered through a bed of celite and the filter cake washed with EtOAc. The solvent was evaporated, the residue was dissolved in EtOAc and washed with water. The organic layer was dried over sodium sulphate and evaporated to get compound that was used in next step without further purification. Brown solid (55 mg, 95%). MS (ESI): m/z=216.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([S:15][CH3:16])=[CH:12][CH:13]=2)[C:8]([OH:17])=[N:7]1.[H-].[Na+].[OH:24][C:25]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][C:26]=1[CH2:27]Cl.O>CS(C)=O>[OH2:17].[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([S:15][CH3:16])=[CH:12][CH:13]=2)[C:8](=[O:17])[N:7]1[CH2:27][C:26]1[CH:29]=[C:30]([N+:33]([O-:35])=[O:34])[CH:31]=[CH:32][C:25]=1[OH:24]
Reactant: CSc1ccc2c(c1)c(O)nn2Cc1ccc(Cl)c(Cl)c1
Reactant: O=[N+]([O-])c1ccc(O)c(CCl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CSc1ccc2c(c1)c(=O)n(Cc1cc([N+](=O)[O-])ccc1O)n2Cc1ccc(Cl)c(Cl)c1
Reaction time: 2 h

Procedure:
3.6 g (11 mmol) of 1-(3,4-dichlorobenzyl)-5-methylthio-1H-indazol-3-ol are dissolved in 100 ml of DMSO and treated in portions with 0.34 g (13.2 mmol) of sodium hydride (95 percent). After stirring for 2 hours, a solution of 2.1 g (11 mmol) of 2-hydroxy-5-nitrobenzyl chloride in 20 ml of DMSO is added dropwise and the mixture is stirred at 60° C. for 3 hours. After cooling, 200 ml of water are added dropwise, the mixture is stirred for 4 hours and the solid is filtered off with suction. The precipitate is extracted by stirring with methanol whilst hot and recrystallized from 2-propanol.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[NH2:27][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:25])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:29][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:21][CH2:20]1
Reactant: ICC1CCCC1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCNCC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCC3CCN(CC4CCCC4)CC3)c2n1

Procedure:
Prepared similarly to Example 82 from 2-(butyloxy)-8-(methyloxy)-9-[4-(4-piperidinyl)butyl]-9H-purin-6-amine and iodomethylcyclopentane.
Reaction SMILES: Cl.O1CCOCC1.[Cl:8][C:9]1[N:10]=[C:11]([C:16]([NH:18][C@H:19]2[CH2:24][CH2:23][N:22]([C:25](OC(C)(C)C)=O)[CH2:21][C@H:20]2[F:32])=[O:17])[NH:12][C:13]=1[CH2:14][CH3:15].BrC1[S:35][C:36]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[C:37]([CH3:39])[N:38]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[Cl:8][C:9]1[N:10]=[C:11]([C:16]([NH:18][C@H:19]2[CH2:24][CH2:23][N:22]([C:25]3[S:35][C:36]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[C:37]([CH3:39])[N:38]=3)[CH2:21][C@H:20]2[F:32])=[O:17])[NH:12][C:13]=1[CH2:14][CH3:15]
Reactant: CCOC(=O)c1sc(Br)nc1C
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2F)nc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](F)C2)nc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.3 %

Procedure:
A 4 N hydrochloric acid/1,4-dioxane solution (3 mL) was added to tert-butyl cis(±)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-fluoropiperidine-1-carboxylate obtained in Example (196b) (159 mg, 0.424 mmol) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and DMF (4 mL) was added. Ethyl 2-bromo-4-methyl-1,3-thiazole-5-carboxylate (117 mg, 0.467 mmol) and sodium carbonate (225 mg, 2.12 mmol) were added, and the mixture was stirred at 90° C. for three hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and brine, and dried over anhydrous sodium sulfate, and then the insoluble matter was separated by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: hexane:ethyl acetate=1:1 v/v) to obtain 106 mg of the title compound (56%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[N:8]=[CH:9][NH:10][C:4]=2[CH:3]=1.CC1(C)CCCC(C)(C)N1.Cl[C:22]1([C:28]([O:30][CH3:31])=[O:29])[C:26](=[O:27])[CH:25]=[CH:24][S:23]1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[N:8]([C:24]3[S:23][C:22]([C:28]([O:30][CH3:31])=[O:29])=[C:26]([OH:27])[CH:25]=3)[CH:9]=[N:10][C:4]=2[CH:3]=1
Reactant: Clc1cc2[nH]cnc2cn1
Reactant: COC(=O)C1(Cl)SC=CC1=O
Agent: CC1(C)CCCC(C)(C)N1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1sc(-n2cnc3cc(Cl)ncc32)cc1O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 0.68 g of 6-chloro-1H-imidazo[4,5-c]pyridine and 0.65 g of 2,2,6,6-tetramethylpiperidine in 100 ml chloroform were slowly added a solution of 0.87 g of methyl 2-chloro-3-oxo-2,3-dihydrothiophene-2-carboxylate in 40 ml chloroform. The reaction mixture was stirred for 12 h at room temperature. After washing with water (3×50 ml) the organic layer was separated, dried with MgSO4 and concentrated to a volume of about 100 ml. The residue was treated with n-hexane until precipitation takes place. The solid was filtered and the procedure was repeated once again. The combined solids were dried under vacuum to yield the title compounds as an isomeric mixture, which was used for the next step (example B3) without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])=[C:10]([O:20][CH3:21])[CH:9]=2)[C:4](=[O:22])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:28]#[C:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)CCC>CN(C=O)C.C(Cl)Cl.[Cu]I.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>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([C:29]#[C:28][C:2]2[CH:7]=[CH:6][N:5]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])=[C:10]([O:20][CH3:21])[CH:9]=3)[C:4](=[O:22])[CH:3]=2)=[CH:31][CH:32]=1
Reactant: CCCC[Sn](C#Cc1ccc(Cl)cc1)(CCCC)CCCC
Reactant: COc1cc(-n2ccc(Cl)cc2=O)ccc1OCC(C)(C)O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(-n2ccc(C#Cc3ccc(Cl)cc3)cc2=O)ccc1OCC(C)(C)O
Temperature: 70 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
A mixture of 4-chloro-1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyridin-2(1H)-one Part D of Procedure 9 (100 mg, 0.31 mmol), tributyl((4-chlorophenyl)ethynyl)stannane Part A (237 mg, 0.56 mmol), copper (I) iodide (17.6 mg, 0.09 mmol), and PalladiumTetrakis (54 mg, 0.05 mmol) in DMF (1.5 mL) was stirred under nitrogen at 70° C. overnight. The reaction was diluted with DCM, filtered, washed with 1N HCl, sat. NaHCO3, dried (MgSO4), and concentrated. The residue was purified using ISCO flash chromatography (silica gel/hexanes/ethyl acetate 100:0 to 0:100 gradient). The product was repurified using HPLC (Phen Luna Axia C18 5μ 10:90:0.1 to 90:100.1 MeOH—H2O-TFA) to afford the desired product 4-((4-chlorophenyl)ethynyl)-1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyepyridin-2(1H)-one F-4 (90 mg, 0.21 mmol, 66.7% yield) as a light yellow solid. LC/MS 424 (M+H)+, tR 1.00 min (method 5). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.49-7.54 (2H, m), 7.37-7.44 (3H, m), 6.96-7.02 (2H, m), 6.93 (1H, d, J=2.26 Hz), 6.89 (1H, dd), 6.50 (1H, d, Hz), 3.88 (5H, s), 1.38 (6H, s)
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8]O)=[C:6]([F:10])[CH:5]=[CH:4][C:3]=1[OH:11].P(Br)(Br)[Br:13]>C(OCC)C.ClCCl>[Br:13][CH2:8][C:7]1[C:2]([F:1])=[C:3]([OH:11])[CH:4]=[CH:5][C:6]=1[F:10]
Reactant: BrP(Br)Br
Reactant: OCc1c(F)ccc(O)c1F
Solvent: CCOCC
Solvent: ClCCl
Product: Oc1ccc(F)c(CBr)c1F
Reaction time: 0.5 h
Yield: 44 %

Procedure:
To a stirred solution of 2,4-difluoro-3-(hydroxymethyl)phenol (step 1, 410 mg, 256 mmol) in diethyl ether (4 mL) and dichloromethane (1 mL) was added phosphorus tribromide (0.257 mL, 2.71 mmol) at 0° C. The mixture was stirred for 30 min, and then the mixture was poured onto ice-aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate (200 mL), and the organic layer washed with water and brine, dried over magnesium sulfate and evaporated to afford 266 mg (47%) of the title compound as a colorless oil, which was used in the next step without purification:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:42]2[CH:43]=[CH:44][C:45]([N:48]3[CH2:53][CH2:52][N:51]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:50][CH2:49]3)=[N:46][CH:47]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC.O>[F:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][N:14]1[CH:15]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:42]4[CH:43]=[CH:44][C:45]([N:48]5[CH2:53][CH2:52][N:51]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:50][CH2:49]5)=[N:46][CH:47]=4)[CH:3]=3)[N:8]([S:24]([C:27]3[CH:28]=[CH:29][C:30]([CH3:31])=[CH:32][CH:33]=3)(=[O:25])=[O:26])[CH:9]=2)[CH:12]=[N:13]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)nc4)cnc32)cc1
Yield: 69 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (compound of Step-i of example 9) (150 mg, 0.286 mmol) was coupled with tert-butyl 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylate (intermediate 69C) (167 mg, 0.429 mmol) in sodium carbonate (76 mg, 0.715 mmol), Pd(PPh3)2Cl2 (10 mg, 0.014 mmol), DME/water (5/1 mL). This afforded 140 mg (69.0% yield) after purification by column chromatography (60-120 silica gel) using 2% methanol in DCM as eluent. MS: m/z=708.3 (M+1).
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.[CH2:10]([N:17]1[CH2:24][CH:23]2[O:25][CH:19]([CH2:20][NH:21][CH2:22]2)[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:26]([NH2:30])(=[O:29])[CH:27]=[CH2:28]>C(O)C>[CH2:10]([N:17]1[CH2:24][CH:23]2[O:25][CH:19]([CH2:20][N:21]([CH2:28][CH2:27][C:26]([NH2:30])=[O:29])[CH2:22]2)[CH2:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C=CC(N)=O
Reactant: c1ccc(CN2CC3CNCC(C2)O3)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: NC(=O)CCN1CC2CN(Cc3ccccc3)CC(C1)O2
Yield: 77.2 %

Procedure:
Triethylamine (3.60 g, 35.7 mmol) was added slowly to a solution of 3-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane dihydrochloride (see Preparation B(iv) above; 5 g, 17 mmol) in ethanol (50 mL). Acrylamide (1.34 g, 18 mmol) was added to this mixture, which was then heated at reflux for 7 hours. The reaction mixture was then concentrated under reduced pressure. Water (50 mL) and sodium hydroxide (1 M, 150 mL) were added to the residue and the mixture extracted with ethyl acetate (2×200 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a colourless solid. This was recrystallised from ethyl acetate (50 mL) to give the sub-title compound (3.80 g, 76%).
Reaction SMILES: CO[C:3](=[O:17])[CH2:4][C@:5]([NH2:16])([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)[CH3:6].[CH2:18]([NH:25][C:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=S)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:31]([O:30][C:29](=[O:35])[NH:28][C:26]1[N:25]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:3](=[O:17])[CH2:4][C@@:5]([CH3:6])([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=2)[N:16]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)NC(=S)NCc1ccccc1
Reactant: COC(=O)C[C@](C)(N)c1cccc([N+](=O)[O-])c1
Product: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cccc([N+](=O)[O-])c2)CC(=O)N1Cc1ccccc1

Procedure:
Starting from (S)-3-amino-3-(3-nitro-phenyl)-butyric acid methyl ester (0.42 mmole) and tert-butyl [(benzylamino)carbonothioyl]carbamate, the product [(S)-1-benzyl-4-methyl-4-(3-nitro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (165 mg) was obtained as a white solid. MS (ESI): m/z=439.3 [ M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:6]=1.C(O[CH:14]=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C>>[C:21]([C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:6]=1)([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CC(C)(C)c1csc(N)n1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1nc(C(C)(C)C)cs1)C(=O)OCC

Procedure:
2-Amino-4-(2-methyl-2-propyl)thiazole (15.6 g., 0.1 mole) and diethyl ethoxymethylenemalonate (23.8 g., 0.11 mole) were combined and heated on a steam bath for 2 hours. 2-(2,2-Dicarbethoxyethenylamino)-4-(2-methyl-2-propyl)thiazole was obtained as a wet solid on cooling and used directly in the next step.
Reaction SMILES: [OH:1][C@H:2]1[CH2:22][C@@:21]2([CH3:23])[C@@H:13]([CH2:14][CH:15]=[C:16]2[C:17](=[O:20])[CH2:18]O)[C@H:12]2[C@H:3]1[C@:4]1([CH3:25])[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:24])[CH:6]=[CH:5]1.[O:26]1[CH:31]=[CH:30][CH2:29][CH2:28][CH2:27]1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[O:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]1[CH2:18][C:17](=[O:20])[C:16]1[C@:21]2([CH3:23])[C@H:13]([C@H:12]3[C@H:3]([C@@H:2]([OH:1])[CH2:22]2)[C@:4]2([CH3:25])[C:9](=[CH:8][C:7](=[O:24])[CH:6]=[CH:5]2)[CH2:10][CH2:11]3)[CH2:14][CH:15]=1
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)C(C(=O)CO)=CC[C@@H]12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)C(C(=O)CC3CCCCO3)=CC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.2 %

Procedure:
To a solution of 11β,21-dihydroxy-1,4,16-pregnatriene-3,20-dione (200 mg, 0.58 mmole) in dichloromethane (40 ml) were added 2,3-dihydropyran (0.2 ml, 2.19 mmole) and anhydrous pyridinium tosylate (70 mg, 0.32 mmole). After stirring for 4 hours at room temperature, the reaction mixture was washed with water (100 ml) and evaporated to give a yellowish oil. This oil was placed on silica gel column and eluted with benzene ethyl acetate (2:1). Evaporating the solvent afforded pure white foam of 21-tetrahydropyranyl-11β-hydroxy-1,4,16-pregnatriene-3,20-dione (191 mg. 77.1%), 1H--NMR (CDCl3) δ 1.25 (s, 3H, 13--CH3), 1.49 (s, 3H, 10--CH3), 4.63-4.38 (m, 3H, 20--CH2 -- and 11--H), 4.68 (t, 1H, J=5 Hz, --O--CH--O--), 3.5, 3.85, 1.1 (m. pyranyl H), 6.01 (s, 1H, 4--H), 6.27(dd, 1H, J=10 and 2 Hz, 2--H), 6.73(m, 1H, 16--H), 7.31(d, 1H, J=10 Hz, 1--H).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C(N(CC)CC)C>C(Cl)Cl>[C:9]([O:8][C:6]([N:13]1[CH2:18][CH2:17][N:16]([C:3](=[O:4])[CH2:2][Br:1])[CH2:15][CH2:14]1)=[O:7])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(Br)CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CBr)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.9 %

Procedure:
A solution of bromoacetyl bromide (8.5 ml, 97 mmol) in DCM (250 ml) at 0° C. was treated dropwise with a solution of 1-Boc-piperazine (15.9, 85.3 mmol) and triethylamine (18.0 ml, 130 mmol) in DCM (150 ml). After addition was complete, the mixture was stirred at room temperature for 4 h. The solution was washed with ice-cold 1M HCl, sat. aq. NaHCO3, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 20% EtOAc:80% cyclohexane to 50% EtOAc:50% cyclohexane) to yield the title compound (15.7 g, 60.0%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[F:24][C:25]1([F:37])[O:29][C:28]2[CH:30]=[CH:31][CH:32]=[C:33]([C:34](O)=[O:35])[C:27]=2[O:26]1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:34]([C:33]3[C:27]4[O:26][C:25]([F:37])([F:24])[O:29][C:28]=4[CH:30]=[CH:31][CH:32]=3)=[O:35])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Reactant: O=C(O)c1cccc2c1OC(F)(F)O2
Product: Nc1nc(C(=O)N2[C@H](CNC(=O)c3cccc4c3OC(F)(F)O4)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with 2,2-difluoro-benzo[1,3]dioxole-4-carboxylic acid. LC-MS (basic): tR=0.86 min; [M+H]+=517.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([Cl:12])=[CH:5]2.C([Sn](CCCC)(CCCC)[C:18]([O:20][CH2:21][CH3:22])=[CH2:19])CCC>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:12][C:6]1[N:7]=[CH:8][C:9]2[C:4]([CH:5]=1)=[CH:3][C:2]([C:18]([O:20][CH2:21][CH3:22])=[CH2:19])=[CH:11][CH:10]=2
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Clc1cc2cc(Br)ccc2cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: C=C(OCC)c1ccc2cnc(Cl)cc2c1
Temperature: 50 °C
Yield: 103.1 %

Procedure:
A solution of 6-bromo-3-chloro-isoquinoline (972 mg, 4 mmol) and tributyl-(1-ethoxy-vinyl)-stannane (2.5 g, 2.5 mL, 7 mmol) in toluene (12 mL) was degassed with nitrogen for 30 minutes. Bis(triphenylphosphine)palladium(II) dichloride (280 mg, 0.4 mmol) was added and the reaction mixture was heated at 50° C. for 18 h. The reaction mixture was cooled to room temperature and the mixture was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 20:1 to 10:1 to afford the title compound (964 mg). 1H NMR (300 MHz, CDCl3) δ1.51 (t, J=7.0 Hz, 3H), 4.01 (q, J=7.0 Hz, 2H), 4.45 (d, J=2.8 Hz, 1H), 4.90 (d, J=2.8 Hz, 1H), 7.76 (s, 1H), 7.85-7.97 (m, 2H), 8.04 (s, 1H), 0.94 (s, 1H). LCMS (m/z) 234/236 [M+H], Tr=5.40 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5](=[CH:9]N(C)C)[C:6](=O)[CH3:7])[CH3:2].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][NH2:21]>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[CH:9]=[N:21][N:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=2)[C:6]=1[CH3:7])=[O:13])[CH3:2]
Reactant: NNc1ccccn1
Reactant: CCOC(=O)C(=CN(C)C)C(C)=O
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2ccccn2)c1C
Yield: 84.8 %

Procedure:
Dissolve 2-dimethylaminomethylene-3-oxo-butyric acid ethyl ester (0.662 g, 3.57 mmol) and pyridin-2-yl-hydrazine (0.410 g, 3.75 mmol) in ethanol (15 mL) and reflux for 2 hr. Evaporate the mixture then dilute with saturated sodium bicarbonate and extract 3 times with ethyl acetate. Dry the solution (sodium sulfate), filter and concentrate. Purify using silica gel chromatography, eluting with 50:50 ethyl acetate:hexane to give 5-methyl-1-pyridin-2-yl-1H-pyrazole-4-carboxylic acid ethyl ester as a white solid (0.700 g, 85%). MS (ES): m/z=232 [M+H]+.