Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH3:6])[C:3]#[C:4][CH3:5].[NH2:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=1I.[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(OCC)(=O)C.O.CN(C)C=O>[CH3:5][C:4]1[C:16]2[C:9](=[CH:10][CH:11]=[C:12]([C:13]#[N:14])[CH:15]=2)[NH:8][C:3]=1[Si:2]([CH3:7])([CH3:6])[CH3:1]
Reactant: CC#C[Si](C)(C)C
Reactant: N#Cc1ccc(N)c(I)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c([Si](C)(C)C)[nH]c2ccc(C#N)cc12
Temperature: 100 °C
Reaction time: 16 h

Procedure:
1-(Trimethylsilyl)propyne (2.23 ml, 1.68 g, 15.0 mmol), 4-amino-3-iodobenzonitrile (3.33 g, 13.65 mmol), lithium chloride (606 mg, 14.3 mmol) and sodium carbonate (4.35 g, 40.95 mmol) were added successively to abs. dimethylformamide (60 ml) under argon. Pd(dppf)Cl2 (1.116 g, 1.365 mmol) was added to this mixture and the reaction mixture was heated at 100° C. with exclusion of moisture for 6 h and then stirred at room temperature for 16 h. For working up of the mixture, water (150 ml) and ethyl acetate (300 ml) was added and the mixture was stirred for 10 min. After separation of the phases, the aqueous phase was extracted with ethyl acetate (3×100 ml). The combined organic phases were washed with saturated sodium chloride solution (3×100 ml), dried and concentrated. The residue was a brown oil (5.5 g) which, apart from 3-methyl-2-trimethylsilanyl-1H-indole-5-carbonitrile, contained traces of the isomer 2-methyl-3-trimethylsilanyl-1H-indole-5-carbonitrile and DMF.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:20](O)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.CN1CCOCC1.[NH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>CN(C=O)C.CCCCCC.C(OCC)(=O)C>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:20](=[O:21])[N:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[CH2:23][C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: C1CCNCC1
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N1CCCCC1
Reaction time: 0.17 h
Yield: 102.9 %

Procedure:
(S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-4-(tert-butoxy)-4-oxobutanoic acid (Compound SP404, Fmoc-Asp(OtBu)-OH) (30 g, 72.9 mmol) was dissolved in DMF (243 mL). N-methylmorpholine (9.6 ml, 87 mmol) and then O-(7-aza-1H-benzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (HATU) (33.3 g, 87 mmol) were added at 0° C., and the mixture was stirred for 10 minutes. Piperidine (7.1 ml, 71.5 mmol) was further added dropwise, and the mixture was stirred for 30 minutes. The reaction mixture was diluted with hexane/ethyl acetate=1/1 (1500 ml), and the organic layer was sequentially washed with a saturated aqueous ammonium chloride solution, a saturated aqueous sodium bicarbonate solution, water and brine. The organic extract was dried over sodium sulfate and then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to afford tert-butyl (S)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-oxo-4-(piperidin-1-yl)butanoate (Compound SP403) (35.2 g, 99%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21]CC3C=CC=CC=3C(F)(F)F)[N:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].O[C:34]1[CH:39]=[CH:38][C:37]([C:40]([NH2:42])=[O:41])=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][C:34]3[CH:39]=[CH:38][C:37]([C:40](=[O:41])[NH2:42])=[CH:36][CH:35]=3)[N:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: NC(=O)c1ccc(O)cc1
Reactant: CCOC(=O)C1CCN(c2ncnc(OCc3ccccc3C(F)(F)F)c2[N+](=O)[O-])CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(c2ncnc(Oc3ccc(C(N)=O)cc3)c2[N+](=O)[O-])CC1
Temperature: 80 °C
Yield: 65 %

Procedure:
A mixture of compound 7 (63 mg, 0.2 mmol), 4-hydroxybenzene carboxamide (35 mg, 0.26 mmol) and potassium carbonate (36 mg, 0.26 mmol) in DMF (1 ml) was heated in microwave for 2 minutes at 80° C. Following the general procedure, compound A34 was obtained as a yellow solid (65%). 1HNMR (CDCl3, 400 MHz) δ 1.19 (t, 3H), 1.70-1.80 (m, 2H), 1.98-2.03 (m, 2H), 2.65-2.80 (m, 1H), 3.22 (t, 2H), 3.82-3.96 (m, 2H), 4.07 (q, 2H), 7.25 (d, 2H), 7.40 (s, 1H), 7.92 (d, 2H), 8.00 (s, 1H), 8.20 (s, 1H). Exact mass calculated for C19H21N5O6 415.15, found 416.2 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:11][C:12]([F:27])([F:26])[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1B(O)O.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:14]1[CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=[CH:18][C:13]=1[C:12]([F:11])([F:26])[F:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(N)C(=O)OC(C)(C)C
Reactant: OB(O)c1cc(C(F)(F)F)ccc1C(F)(F)F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CN(Nc1cc(C(F)(F)F)ccc1C(F)(F)F)C(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 39.4 %

Procedure:
A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 600 mg, 3.4 mmol), 2,5-bis(trifluoromethyl)phenylboronic acid (ChemFocus, LLC, East Brunswick, N.J., USA; 953 mg, 3.7 mmol), copper(II) acetate (746 mg, 4.1 mmol) and triethylamine (575 μL, 4.1 mmol) in 1,2-dichloroethane (18 mL) was heated in an oil bath at 50° C. for 2 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluting with 10% ethyl acetate/hexanes, to give N′-(2,5-bis-trifluoromethyl-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (480 mg, 33%) as a colorless oil that solidified.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][N:6]([CH3:8])[CH3:7])C.Cl.[OH-].[K+].[Cl:15][C:16]1[CH:17]=[C:18]([NH:31][C:32]2[C:33]3[CH:41]=[C:40]([NH:42][C:43](=[O:53])[CH2:44]P(=O)(OCC)OCC)[N:39]=[CH:38][C:34]=3[N:35]=[CH:36][N:37]=2)[CH:19]=[CH:20][C:21]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=1.[Li+].[Cl-]>O.C(Cl)Cl.CO.CC(N(C)C)=O.C1COCC1>[Cl:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][C:21]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=1)[NH:31][C:32]1[C:33]2[CH:41]=[C:40]([NH:42][C:43](=[O:53])/[CH:44]=[CH:4]/[CH2:5][N:6]([CH3:8])[CH3:7])[N:39]=[CH:38][C:34]=2[N:35]=[CH:36][N:37]=1
Reactant: CCOP(=O)(CC(=O)Nc1cc2c(Nc3ccc(OCc4cccc(Cl)c4)c(Cl)c3)ncnc2cn1)OCC
Reactant: CCOC(CN(C)C)OCC
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)C/C=C/C(=O)Nc1cc2c(Nc3ccc(OCc4cccc(Cl)c4)c(Cl)c3)ncnc2cn1
Temperature: 40 °C
Reaction time: 24 h
Yield: 84.9 %

Procedure:
To a stirred mixture of 2,2-diethoxy-N,N-dimethylethanamine (1.16 g, 7.20 mmol) and water (1.2 mL) at room temperature and under a nitrogen atmosphere was added an aq. 37% HCl (1.21 mL, 14.4 mmol). After addition the mixture was stirred at 40° C. (bath) for 24 h. It was cooled to 0° C. (bath). This is called solution A. KOH (1.03 g, 18.4 mmol) was dissolved in water (5.5 mL) at room temperature under a nitrogen atmosphere. It was cooled to 0° C. (bath). This is called solution B. To a stirred heterogeneous mixture of compound 228 (1.70 g, 2.88 mmol) and THF (5.5 mL) at room temperature and under a nitrogen atmosphere was added minimum amount of DMA (3 mL) to give a homogeneous solution. LiCl (122 mg, 2.88 mmol) was added and stirred at 0° C. (bath) for 15 min. The cold solution B was added and stirred at 0° C. for 2 min. Then the cold solution A was added and the final reaction mixture was continued to stir at 0° C. under a nitrogen atmosphere. The reaction was monitored by TLC (DCM-MeOH=20:1). After 25 min more KOH (s) (0.34 g, 6.13 mmol) was added and stirred further at 0° C. for another 35 min. It was poured into water (200 mL). Petroleum ether (200 mL) was added and stirred at room temperature for 15 min. Petroleum ether layer was decanted. More petroleum ether (200 mL) was added and stirred for 15 min. The solid was collected by suction filtration; washed with water (4×20 mL); dried under reduced pressure over silica gel/KOH to give (2E)-N-(4-{3-chloro-4-[(3-chlorobenzyl)oxy]anilino}pyrido[3,4-d]pyrimidin-6-yl)-4-(dimethylamino)-2-butenamide (1) (1.28 g, 85%) as a pale yellow solid, mp 195-198; HPLC: 96.8% pure; 1H NMR δ [(CD3)2SO] 10.88 (s, 1H), 10.19 (s, 1H), 8.99 (s, 1H), 8.97 (s, 1 H), 8.58 (s, 1H), 7.99 (d, J=2.6 Hz, 1H), 7.73 (dd, J=9.0, 2.6 Hz, 1H), 7.56 (br s, 1H), 7.49-7.38 (m, 3H), 7.27 (d, J=9.0 Hz, 1H), 6.87 (dt, J=15.4, 6.0 Hz, 1H), 6.51 (br d, J=15.4 Hz, 1H), 5.26 (s, 2H), 3.09 (br d, J=6.0 Hz, 2H), 2.19 (s, 6H). Anal. Calcd for C26H24Cl2N6O2.0.3H2O: C, 59.05; H, 4.69; N, 15.89. Found C, 58.96; H, 4.62; N, 15.73.
Reaction SMILES: [NH2:1][C:2](=[N:43][OH:44])[C:3]1[CH:8]=[CH:7][C:6]([C@@:9]2([CH3:42])[C:13](=[O:14])[N:12]([CH2:15][C:16]([O:18]CC3C=CC4C(=CC=CC=4)C=3)=[O:17])[C:11](=[O:30])[N:10]2[CH2:31][C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=2)=[CH:5][CH:4]=1>CO.[OH-].[Pd+2].[OH-].S([O-])([O-])(=O)=O.[Ba+2]>[NH2:1][C:2](=[N:43][OH:44])[C:3]1[CH:4]=[CH:5][C:6]([C@@:9]2([CH3:42])[C:13](=[O:14])[N:12]([CH2:15][C:16]([OH:18])=[O:17])[C:11](=[O:30])[N:10]2[CH2:31][C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=2)=[CH:7][CH:8]=1
Reactant: C[C@]1(c2ccc(C(N)=NO)cc2)C(=O)N(CC(=O)OCc2ccc3ccccc3c2)C(=O)N1Cc1ccc2ccccc2c1
Agent: [Pd+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CO
Product: C[C@]1(c2ccc(C(N)=NO)cc2)C(=O)N(CC(=O)O)C(=O)N1Cc1ccc2ccccc2c1
Yield: 36.9 %

Procedure:
2 g (3.4 mmol) of 2-naphthylmethyl ((S)-4-(4-(amino-hydroximino-methyl)phenyl)-3-(2-naphthylmethyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetate in 200 ml of absolute methanol were hydrogenated over palladium hydroxide/barium sulfate for 4 h. The catalyst was filtered off, the filtrate was concentrated in vacuo and the residue was stirred with ethyl acetate. The product was filtered off with suction and dried in a high vacuum. 0.56 g (37%) of the title compound was obtained.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]1[CH:7]=[N:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:14][CH:13]=2)=[N:10][CH:11]=1)C.O.C(O)(=O)C>C(O)COCCO>[OH:5][C:6]1[CH:7]=[N:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:14][CH:13]=2)=[N:10][CH:11]=1
Reactant: CCCCCCCCOc1ccc(-c2ncc(OCC)cn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: OCCOCCO
Solvent: O
Product: CCCCCCCCOc1ccc(-c2ncc(O)cn2)cc1
Yield: 66.1 %

Procedure:
NaOH (58.4 g) was added to a solution of 5-ethoxy-2-(4-octyloxyphenyl)pyrimidine (48 g) dissolved in diethylene glycol (300 ml), followed by keeping the mixture at 220° C. for 3 hours, allowing the resulting material to cool down, adding water and acetic acid, filtering off deposited crystals, and recrystallizing from ethanol to obtain 5-hydroxy-2-(4-octyloxyphenyl)pyrimidine (29 g, m.p.: 131.2°-132.5° C.)
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][C:4](=O)[CH:3]=1.S(O)(O)(=O)=O.[NH2:15][OH:16].S(=O)(=O)(O)O.S([O-])([O-])(=O)=O.[NH4+].[NH4+].[Cl-].[Na+]>>[CH3:1][C:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][C:4](=[N:15][OH:16])[CH:3]=1
Reactant: NO
Reactant: CC1=CC(=O)CC(C)C1
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Product: CC1=CC(=NO)CC(C)C1
Temperature: 70 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
375 g of 3,5-dimethylcyclohexenone, 99% pure, (= 372 g of 100% pure product = 3 moles) are added to 1,080 g (= 923 ml) of a 25% strength technical grade hydroxylamine sulphate solution (d = 1.17) which additionally contains about 20 g of sulphuric acid and 20 g of ammonium sulphate, the mixture is heated to 70° C. and stirred at this temperature for one hour. The resulting solution can be worked up as follows: (a) 300 g of sodium chloride are added to the hot solution at 70° C. and the mixture is stirred without cooling until the temperature has reached 20° C. 3,5-Dimethylcyclohexenone oxime hydrochloride thus precipitates. It is filtered off and washed with 20% strength sodium chloride solution. After drying, this gives 600 g of hydrochloride with a content of pure compound of 85.1%, corresponding to 97% of theory. (b) After cooling the hot solution from 70° C. to 20° C., the latter is exhaustively extracted with an extracting agent, for example methylene chloride. The solvent is distilled off. A brown oil remains which consists of a mixture of oxime and oxime sulphate in a ratio of 2:1; yield 95%. (c) After cooling the hot solution from 70° C. to +10° C., the pH value is adjusted at this temperature to 5-5.5 with sodium hydroxide solution. This gives a thick white precipitate of 3,5-dimethylcyclohexenone oxime. It is filtered off and washed with water. This gives 510.4 g of oxime with a content of pure compound of 98%, corresponding to 95% of theory.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=O.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[C:14]1([NH:13][CH2:1][C:3]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: Nc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ccc(CNc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 55.3 %

Procedure:
Methyl 4-formylbenzoate (1 g, 6 mmol) and aniline (837 mg, 9 mmol) were dissolved in methanol (30 mL). The mixture was heated to 50° C., and acetic acid (two or three drop) was added to the reaction mixture. The resultant mixture was stirred at 50° C. for 1 hour. After the mixture was cooled to room temperature, sodium cyanoborohydride (1.13 g, 18 mmol) was added. The mixture was stirred at room temperature for 18 hours. The reaction was quenched with water (10 mL) and the mixture was extracted with dichloromethane (10 mL×3). The combined organic phase was separated, dried by sodium sulfate and then filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=8:1) to give methyl 4-((phenylamino)methyl)benzoate (0.8 g, 55%). LRMS (M+H+) m/z: cald. 241.08. found 241. LRMS (M+H+) m/z: calcd 241.08. found 241. 1H NMR (300 MHz, CD3OD): δ 7.95 (dd, J=7.2 Hz, J=2.1 Hz, 2H), 7.44 (d, J=7.8 Hz, 2H), 7.05 (t, J=6.0 Hz, 2H), 6.60-6.56 (m, 3H), 4.37 (s, 2H), 3.86 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](Br)=[CH:8][C:9]=1[NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].C(N(CC)CC)C.[C:26]([C:30]#[CH:31])([CH3:29])([CH3:28])[CH3:27].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.C(Cl)Cl.[Cu]I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:31]#[C:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:8][C:9]=1[NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: COC(=O)c1sc(Br)cc1NC(=O)OC(C)(C)C
Reactant: C#CC(C)(C)C
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1NC(=O)OC(C)(C)C
Temperature: 60 °C

Procedure:
To a solution of 3-(tert-butoxycarbonyl)amino-5-bromo-thiophene-2-carboxylic acid methyl ester (4.566 g, 13.58 mmol) in dry DMF (40 mL) are added copper (I) iodide (52 mg, 0.27 mmol), Pd2 dba3 (622 mg, 0.68 mmol) and triethylamine (9.46 mL, 67.9 mmol), and the mixture is deoxygenated by bubbling nitrogen through solution for 10 min. Then tert-butylacetylene (6.62 mL, 54.32 mmol) and BINAP (676 mg, 1.09 mmol) are added to the mixture, and it is heated at 60° C. overnight under nitrogen. The mixture is diluted with CH2Cl2 and filtered through celite washing with CH2Cl2. Filtrate is washed with brine, organic fraction is separated, dried over Na2SO4, concentrated, and the residue is purified by column chromatography on silica gel eluting with gradient of EtOAc in hexane to give of 5-(3,3-dimethyl-but-1-ynyl)-3-(tert-butoxycarbonyl)amino-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5][C:6]1[CH:17]=[CH:16][C:9]([CH2:10][NH:11][C:12](=[S:15])[NH:13][NH2:14])=[CH:8][CH:7]=1.[C:18](OCC)(=[O:22])[C:19]([NH2:21])=[O:20]>CO>[C:18]([NH:14][NH:13][C:12]([NH:11][CH2:10][C:9]1[CH:8]=[CH:7][C:6]([O:5][CH3:4])=[CH:17][CH:16]=1)=[S:15])(=[O:22])[C:19]([NH2:21])=[O:20]
Reactant: COc1ccc(CNC(=S)NN)cc1
Reactant: CCOC(=O)C(N)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CNC(=S)NNC(=O)C(N)=O)cc1
Yield: 91 %

Procedure:
Sodium methoxide (5.4 g., 0.1 mole) and 4-(p-methoxybenzyl)thiosemicarbazide (2.1 g., 0.1 mole) were stirred in methanol (200 ml.) for a period of five minutes. Ethyl oxamate (11.7 g., 0.1 mole) was then added to the mixture and the resulting mixture was refluxed for a period of three hours. At this point, most of the solvent was evaporated under reduced pressure, water (200 ml.) was added to the residue and the pH adjusted to 2.0 with dilute hydrochloric acid. The resulting solid was then filtered and subsequently dried in vacuo at 50° C. to yield pure 1-oxamoyl-4-(p-methoxybenzyl)-3-thiosemicarbazide (25.7 g., 91% yield), m.p. 185°-190° C.
Reaction SMILES: C(O[C:4]1[CH2:10][C:9](=[O:11])[NH:8][C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[N:5]=1)C.[CH:16]1([C:22]([NH:24][NH2:25])=O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.CCOC(C)=O.C([O-])(O)=O.[Na+]>C(O)(=O)C.CCOCC.O>[CH:16]1([C:22]2[N:5]3[C:4]([CH2:10][C:9](=[O:11])[NH:8][C:7]4[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=43)=[N:25][N:24]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: NNC(=O)C1CCCCC1
Reactant: CCOC1=Nc2ccccc2NC(=O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=C1Cc2nnc(C3CCCCC3)n2-c2ccccc2N1
Temperature: 120 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4-ethoxy-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Preparation 3(A) (5 g, 24.5 mmol) in glacial acetic acid (75 mL) was added cyclohexanecarboxylic acid hydrazide (Preparation 14) (3.5 g, 24.5 mmol). The reaction was heated at 120° C. for 2.5 hours, was cooled to room temperature, and EtOAc (50 mL), water (50 mL) and aqueous NaHCO3 (50 mL) were added. The mixture was stirred for 5 minutes and Et2O was added (125 mL). The suspension was stirred for 15 minutes and the solids were removed by filtration with the aid of Et2O to provide 5.92 g of 1-cyclohexyl-4H,6H-2,3,6,10b-tetraaza-benzo[e]azulen-5-one.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9]Cl)=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[N:5]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:3]=1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][N:28]=1>>[CH3:18][O:17][C:13]1[CH:12]=[C:11]([C:6]2[C:7]3[CH2:8][CH2:9][N:33]([C:30]4[CH:29]=[N:28][C:27]([O:26][CH3:25])=[CH:32][CH:31]=4)[C:2]=3[N:3]=[C:4]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[N:5]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccc(N)cn1
Reactant: COc1cccc(-c2nc(N3CCOCC3)nc(Cl)c2CCCl)c1
Product: COc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccc(OC)nc2)c1

Procedure:
In the same manner as Example 1-A-01, from 4-[4-chloro-5-(2-chloroethyl)-6-(3-methoxyphenyl)-pyrimidin-2-yl]-morpholine and 2-methoxy-pyridin-5-ylamine, the desired compound was obtained.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][CH2:6][C@:7]1([C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][N:22]=3)[CH2:17][CH2:16]2)=[O:14])[CH2:11][CH2:10][C@@H:9]([NH2:12])[CH2:8]1)[CH3:4].[CH3:31][CH:32]1[C:37](=O)[CH2:36][CH2:35][O:34][CH2:33]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:3]([O:5][CH2:6][C@:7]1([C:13]([N:15]2[CH2:16][CH2:17][N:18]([C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][N:22]=3)[CH2:19][CH2:20]2)=[O:14])[CH2:11][CH2:10][C@@H:9]([NH:12][C@@H:37]2[CH2:36][CH2:35][O:34][CH2:33][CH:32]2[CH3:31])[CH2:8]1)[CH3:4]
Reactant: CCOC[C@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)CC[C@@H](N)C1
Reactant: CC1COCCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC[C@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)CC[C@@H](N[C@@H]2CCOCC2C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.3 %

Procedure:
To a solution of (1R,3S)-3-(ethoxymethyl)-3-(4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentanamine dihydrochloride (100.0 mg, 0.211 mmol), 3-methyltetrahydro-4H-pyran-4-one (72.3 mg, 0.634 mmol) and triethylamine (0.118 mL, 0.845 mmol) in dry methylene chloride (5 mL) was added sodium triacetoxyborohydride (134.3 mg, 0.634 mmol). After being stirred at room temperature under N2 overnight, the reaction was quenched with aqueous NaHCO3 and diluted with methylene chloride. The organic layer was separated and the aqueous layer was extracted with methylene chloride three times. The organics were combined, dried over MgSO4, filtered, purified by silica gel Combi-Flash system (gradient, 0 to 40% MeOH in EtOAc, 12 gram column) to give the desired product (34 mg, 34%). MS calculated for C25H37F3N4O3: (M+H) 499.3; found 499.3.
Reaction SMILES: [Cl:1][C:2]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[CH3:15][Mg]Cl>O1CCCC1>[Cl:1][C:2]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4](=[O:5])[CH3:15]
Reactant: C[Mg]Cl
Reactant: CON(C)C(=O)c1cccc(F)c1Cl
Solvent: C1CCOC1
Product: CC(=O)c1cccc(F)c1Cl
Temperature: 0 °C
Yield: 95 %

Procedure:
To a 2L flask was added 2-chloro-3-fluoro-N-methoxy-N-methylbenzamide (41.49 g, 191 mmol) and tetrahydrofuran (800 mL). The solution was cooled to 0° C., then methylmagnesium chloride, 3.0M solution in THF (254 mL, 763 mmol) was added dropwise through addition funnel. The mixture was gradually warmed to 5° C. The reaction was quenched with 5N HCl (190 mL) until it is acidic and extracted with EtOAc twice. The organic solution was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude was purified by flash chromatography on silica gel (330 g, 0-50% EtOAc/hexane in 20 min) to give 1-(2-chloro-3-fluorophenyl)ethanone as a colorless oil (31.3 g, 95% yield). MS m/z=173 [M+H]+. Calculated for C8H6ClFO: 172.6.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C([Li])CCC.Cl[Si:15]([CH3:18])([CH3:17])[CH3:16]>O1CCCC1>[CH3:16][Si:15]([CH3:18])([CH3:17])[N:6]([Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: Nc1ccc(Br)cc1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)N(c1ccc(Br)cc1)[Si](C)(C)C
Temperature: 0 °C

Procedure:
The general procedure described by J. R. Pratt et al, in the publication entitled "Organosilicon Compounds. XX. Synthesis of Aromatic Diamines via Trimethylsilyl-Protecting Aniline Intermediates," J. Org. Chem, Vol. 40, No. 8, 1975, pages 1090 to 1094, was followed with some modifications as described herein To a tetrahydrofuran (500 ml) solution of p-bromoaniline (106.0g, 0.62 mol) cooled to 0° C. there was added over a period of one hour n-butyllithium (825 ml, 1.3 mol). The reaction mixture turned brown but remained homogeneous The reaction mixture was refluxed for 2 hours to complete the metallation, cooled to ice temperature, and then chlorotrimethylsilane (180 ml, 1 4 mol) was added so as to not let the reaction temperature exceed 15° C.. The reaction mixture was allowed to warm to room temperature and was refluxed overnight Filtration was accomplished by the Schlenk technique, and a gas chromatogram (GC) was taken. The solvent was evaporated and the residue was distilled to give three fractions Fraction 1 - b.p. 25°-89° C./0.5 torr, 22.0g (this forerun was discarded); Fraction 2 - b.p. 90°-108° C./0 5 torr, 32g, 95% pure by