Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.FC(F)(F)C(O)=O.[NH2:17][C@H:18]1[C@H:24]([CH3:25])[O:23][C:22]2[CH:26]=[CH:27][C:28]([C:30]([F:33])([F:32])[F:31])=[CH:29][C:21]=2[NH:20][C:19]1=[O:34].[C:35]([O:39][C:40]([N:42]([CH3:48])[C@@H:43]([CH3:47])[C:44](O)=[O:45])=[O:41])([CH3:38])([CH3:37])[CH3:36]>>[C:35]([O:39][C:40](=[O:41])[N:42]([CH3:48])[C@H:43]([C:44](=[O:45])[NH:17][C@@H:18]1[C:19](=[O:34])[NH:20][C:21]2[CH:29]=[C:28]([C:30]([F:31])([F:33])[F:32])[CH:27]=[CH:26][C:22]=2[O:23][C@H:24]1[CH3:25])[CH3:47])([CH3:36])([CH3:38])[CH3:37]
Reactant: C[C@@H]1Oc2ccc(C(F)(F)F)cc2NC(=O)[C@H]1N
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1Oc2ccc(C(F)(F)F)cc2NC(=O)[C@H]1NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C
Yield: 75.3 %

Procedure:
In a similar manner to that described for Example 36 Step 1 except 4 equivalents of DIEA were used, (2S,3S)-3-amino-2-methyl-7-(trifluoromethyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one trifluoroacetate (58 mg, 0.155 mmol) and (S)-2-(tert-butoxycarbonyl(methyl)amino)propanoic acid (31.5 mg, 155 μmol) were converted to a material which was purified by silica gel chromatography to afford methyl-[(S)-1-((6S,7S)-6-methyl-8-oxo-2-trifluoromethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-ylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester (52 mg, 75%)
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[OH:5][CH2:6][C:7]1([C:22](O)=[O:23])[CH2:11][CH2:10][N:9]([C:12](=[O:21])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH2:8]1.O>C(O)C>[CH2:1]([O:3][C:6]([C:7]1([CH2:22][OH:23])[CH2:11][CH2:10][N:9]([C:12](=[O:21])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH2:8]1)=[O:5])[CH3:2]
Reactant: CC(=O)Cl
Reactant: COc1ccc(C(=O)N2CCC(CO)(C(=O)O)C2)cc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1(CO)CCN(C(=O)c2ccc(OC)cc2)C1
Temperature: 80 °C
Yield: 60.9 %

Procedure:
Acetyl chloride (80.2 mL, 1130 mmol) was added to a suspension of 3-hydroxymethyl-1-(4-methoxy-benzoyl)-pyrrolidine-3-carboxylic acid (210.0 g, 751.9 mmol) (see Preparation 9) in ethanol (2100 mL) and the reaction mixture was heated at 80° C. for 4 hours. Water (200 mL) was added then ethanol was removed by concentration under reduced pressure. The aqueous residue was partitioned between ethyl acetate (2 L) and saturated aqueous NaHCO3 (1500 mL). The organic layer was separated, washed with water (1500 mL) then concentrated under reduced pressure to afford the title compound as a colourless oil (140.7 g, 61%). (99.3:0.7 ratio of isomers)
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][C@@H:5]1[CH2:11][OH:12].[C:13]1([N:19]2[CH2:24][CH2:23][N:22]([C:25](OC3C=CC([N+]([O-])=O)=CC=3)=[O:26])[CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CCCCCCC.C1COCC1>[C:13]1([N:19]2[CH2:20][CH2:21][N:22]([C:25]([O:12][CH2:11][C@H:5]3[CH2:6][N:7]([CH3:10])[CH2:8][CH2:9][N:4]3[CH3:3])=[O:26])[CH2:23][CH2:24]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCN(c2ccccc2)CC1
Reactant: CN1CCN(C)[C@@H](CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CN1CCN(C)[C@@H](COC(=O)N2CCN(c3ccccc3)CC2)C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 61.1 %

Procedure:
Sodium hydride (1.14 g, 60% dispersion in mineral oil, 28.6 mmol) was suspended in heptane (10 mL) under an argon atmosphere. The heptane was decanted off, and the flask was charged with THF (20 mL) and cooled to 0° C. A solution of 1,4-dimethyl-(R)-2-hydroxymethyl piperazine (Intermediate 4; 1.38 g, 9.5 mmol) in THF (20 mL) was added drop-wise, followed by a solution of the 4-nitrophenyl 4-phenylpiperazine-1-carboxylate (Intermediate 2; 4.06 g, 12.4 mmol) in THF (20 mL). The reaction mixture was allowed to warm to room temperature, stirred for 16 hours, the reaction mixture was cooled to 0° C. then quenched with the drop-wise addition of sat aq NaHCO3 solution and concentrated in vacuo. The residue was dissolved in EtOAc (200 mL), washed with sat aq NaHCO3 solution (4×50 mL), dried (MgSO4) and concentrated in vacuo. The residue was suspended in water:formic acid solution [1:1] (20 mL), filtered and the filtrate was purified by reverse phase column chromatography (gradient eluting with methanol in water, with 1% formic acid in each solvent, 0-15%). The resulting residue was dissolved in DCM (50 mL) and stirred with solid K2CO3 for 20 minutes, filtered and concentrated in vacuo to give [(2R)-1,4-dimethylpiperazin-2-yl]methyl 4-phenylpiperazine-1-carboxylate (1.93 g, 61%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([N:23]3[CH2:28][CH2:27][C:26]([NH:35]C(=O)OC(C)(C)C)([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:25][CH2:24]3)=[O:22])[C:9]=2[CH3:43])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([N:23]3[CH2:24][CH2:25][C:26]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)([NH2:35])[CH2:27][CH2:28]3)=[O:22])[C:9]=2[CH3:43])=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)N2CCC(NC(=O)OC(C)(C)C)(c3ccccc3)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C(=O)N2CCC(N)(c3ccccc3)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Yield: 86.8 %

Procedure:
tert-Butyl N-(1-{[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}-4-phenylpiperidin-4-yl)carbamate (1 eq, 243 mg, 0.380 mmol) was stirred in dichloromethane (7 mL) and trifluoroacetic acid (3 mL) for 16 h. The reaction was concentrated in vacuo. The crude reaction material was then purified by silica gel column chromatography using 0-50% CMA 80/ethyl acetate to yield pure 1-{[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}-4-phenylpiperidin-4-amine (178 mg, 87%). 1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.64-1.95 (m, 2H) 2.10-2.29 (m, 5H) 3.50-3.66 (m, 1H) 3.70-3.88 (m, 1H) 4.03-4.19 (m, 1H) 4.42 (d, J=13.28 Hz, 1H) 7.04-7.10 (m, 2H) 7.13-7.20 (m, 1H) 7.20-7.40 (m, 6H) 7.40-7.50 (m, 3H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]23[CH2:23][CH:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=42)[C:15]2[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:4][CH2:3]1.[C:24](Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26]>>[CH:21]1[C:22]2[C:9]3([CH2:8][N:5]4[CH2:6][CH2:7][CH:2]([NH:1][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:3][CH2:4]4)[CH2:23][CH:16]([C:15]4[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:17]=2[CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: NC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Product: CC(C)(C)C(=O)NC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1

Procedure:
Using a procedure similar to that described in Example 27 except starting with 4-amino-1-[9,10-dihydro-9,10-methanoanthracen-9-ylmethyl]piperidine and pivaloyl chloride, the title compound was obtained as a white solid (87%), mp 181.5°-2.5° C.; MS(CI): 389 (M+H); NMR (300 MHz,DMSO-d6): 1.05(s, 9H), 1.37-1.66(m, 4H), 2.24(m, 2H), 2.45(s, 2H), 2.97(m, 2H), 3.31(s, 2H), 3.56(m, 1H), 4.30(s, 1H), 6.91(m, 4H), 7.06(d, 1H, J=8.1 Hz), 7.17-7.27(m, 4H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[CH:3]=1.[CH2:13]([Sn](CCCC)(CCCC)C=C)[CH2:14]CC>CN(C)C=O.C(OCC)(=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>[CH:13]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[CH:3]=1)=[CH2:14]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1ccc(Br)cc1C
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: CCOC(C)=O
Product: C=Cc1ccc(C(=O)OC)c(C)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a round-bottom flask, which was purged and maintained with a nitrogen atmosphere, was added a solution of methyl 4-bromo-2-methylbenzoate (compound 152.1, 14.0 g, 61.1 mmol, 1.00 equiv) in N,N-dimethylformamide (150 mL). Tributyl(ethenyl)stannane (29.3 g, 92.4 mmol, 2.00 equiv) and Pd(PPh3)4 (7.10 g, 6.14 mmol, 0.10 equiv) were added to the reaction. The resulting mixture was stirred overnight at 100° C. in an oil bath. After cooling to room temperature, the mixture was diluted with 400 mL of ethyl acetate. The organic layer was washed with 2×400 mL of NH4Cl (aq.) and 2×400 mL of brine, dried over anhydrous sodium sulfate, then concentrated in vacuo. The crude product was purified by CombiFlash with the following conditions (IntelFlash-1): mobile phase, petroleum ether/ethyl acetate=1:0 increasing to petroleum ether/ethyl acetate=100:1 within 20 min; Detector, UV 254 nm. This resulted in 6.81 g (63%) of methyl 4-ethenyl-2-methylbenzoate as a colorless oil.
Reaction SMILES: [I-].[Na+].[H-].[Na+].[CH2:5]([O:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl[CH2:22][CH2:23][CH2:24][CH2:25][C:26]#[N:27]>CN(C=O)C>[C:17]([O:16][C:14]([N:13]([CH2:22][CH2:23][CH2:24][CH2:25][C:26]#[N:27])[O:12][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)NOCc1ccccc1
Reactant: N#CCCCCCl
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCCCC#N)OCc1ccccc1
Reaction time: 0.25 h

Procedure:
N-(tert-Butoxycarbonyl)-N-(4-cyanobutyl)-O-benzylhydroxylamine (4) was synthesized by adding sodium iodide (84 mg, 0.56 mmol) and then sodium hydride (80% oil dispersion, 0.49 g, 16.3 mmol) to O-benzyl-N-tert-butoxycarbonyl hydroxylamine (2.68 g, 12.0 mmol) in dry DMF (40 ml). After stirring for 15 minutes, 5-chlorovaleronitrile (1.5 mL, 13.3 mmol) was added and the suspension heated at 80°-85° C. for 4 hours under argon. After cooling, the reaction was quenched with H2O (100 mL), then extracted with ether (4×75 mL). The combined organic layers were washed with 100 mL each of 1% aqueous Na2SO3, H2O and brine and then concentrated to give 4.39 g crude product. Column chromatography with 4.5% EtOAc/CHCl3 produced 3.17 g of O-benzyl-N-(tert-butoxycarbonyl)-N-(4-cyanobutyl)hydroxylamine (4) (87% yield): NMR δ 1.5-1.75 (s+m, 13 H), 2.3 (t, 2 H), 3.4 (t, 2 H), 4.77 (s, 2 H), 7.3 (s, 5 H). Anal. calcd. for C17H24N2O3 : C, 67.08; H, 7.95; N, 9.20. Found: C, 67.19; H, 7.99; N, 9.11.
Reaction SMILES: Cl.CN(C)[CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7].[C:15]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[O-]CC.[Na+]>C(O)C>[C:15]([CH:23]([CH2:4][CH2:5][C:6](=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CN(C)CCC(=O)c1ccccc1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(CCC(=O)c1ccccc1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
To a stirred mixture of 2.14 g of β-dimethylaminopropiophenone hydrochloride and 1.92 g of ethyl benzoylacetate in 30 cc of ethanol was added in small portions 1.36 g of sodium ethoxide at room temperature. The resulting mixture was stirred at room temperature for 30 minutes and then heated under reflux for 1 hour. After cooling, the solvent was distilled off and water was added to the residue. The aqueous layer was acidified with 1N HCl, and extracted twice with chloroform. The combined organic layer was washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off and the crude product thus obtained was purified by a silica gel column chromatography (eluent: ethyl acetate/hexane=1/5) to obtain 2.45 g of compound G. Yield: 75.5%.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4]([NH:10][C:11](=[O:19])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[SH:18])[CH2:3]1.[N:20]#[C:21]Cl>O1CCCC1>[CH3:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4]([NH:10][C:11](=[O:19])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[S:18][C:21]#[N:20])[CH2:3]1
Reactant: N#CCl
Reactant: CC1CC(NC(=O)c2ccccc2S)CC(C)(C)C1
Solvent: C1CCOC1
Product: CC1CC(NC(=O)c2ccccc2SC#N)CC(C)(C)C1
Temperature: -15 °C
Reaction time: 2 h
Yield: 86.3 %

Procedure:
49.9 g (0.18 mol) of 2-mercaptobenzoic acid N-(3,5,5-trimethyl-cyclohexyl)-amide are initially introduced into 200 ml of tetrahydrofuran. The solution is cooled to -15° C. and 33.3 g (0.54 mol) of cyanogen chloride, dissolved in 50 ml of tetrahydrofuran, are added dropwise in the course of 30 minutes such that the internal temperature does not exceed -5° C. When the dropwise addition has ended, the mixture is allowed to come to room temperature in the course of 1 hour and stirring is then continued at this temperature for a further 2 hours. Excess cyanogen chloride and some of the solvent are distilled off under reduced pressure. The solution is poured into water, with vigorous stirring, and the solid which has precipitated is filtered off with suction and dried in a desiccator. 47 g (86.5% of theory) of 2-thiocyanato-benzoic acid N-(3,5,5-trimethylcyclohexyl)-amide are obtained as a colorless powder of melting point 117° C.
Reaction SMILES: [CH2:1]([N:8]([CH3:12])[CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:15][S:16](Cl)(=[O:18])=[O:17].[Na+].[Cl-]>O.C1(C)C=CC=CC=1>[CH3:15][S:16]([O:11][CH2:10][CH2:9][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:12])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: CN(CCO)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CN(CCOS(C)(=O)=O)Cc1ccccc1

Procedure:
N-Benzyl-N-methyl-ethanolamine (20.73 g), 61.94 g of toluene and 83.41 g of a 30% aqueous solution of NaOH were respectively weighed and placed in a 300-mL four-necked flask. While the mixture was stirred, the flask inside temperature was lowered to 6.8° C. Then, 31.68 g of methanesulfonyl chloride was added dropwise over 3 hours and 17 minutes at a flask inside temperature of 5 to 10° C. Water (33 mL) was added to dissolve the NaCl which had precipitated out in the aqueous phase, and the mixture was separated into the toluene phase and aqueous phase. A toluene solution of N-benzyl-N-methyl-ethanolamine methanesulfonate was thus obtained in a yield of 68.8 mole percent.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[N:7][CH:8]=2)[N:3]=1.[Cl:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Cl:12][CH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[N:7][CH:8]=2)[N:3]=1
Reactant: Cc1ccc2cnccc2n1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: ClCc1ccc2cnccc2n1
Temperature: 25 °C

Procedure:
To a solution of 2-methyl-1,6-naphthyridine (E. M. Hawes, J. Heteroc. Chem. 11(2), 151 (1974)) (3.8 g) in CCl4 (230 mL) were added N-chlorosuccinimide (4.2 g) and benzoylperoxide (320 mg). The mixture was brought to reflux with two 150-watt spotlights and irradiated for 4 hr. The mixture was then cooled to room temperature, evaporated to dryness, and chromatographed on flash silica gel using ethyl acetate:toluene (1:1) as eluant to give the title compound, 80% pure and used as is for the next step.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH2:10])[CH2:5][CH2:4]1.[S:11]1[C:15]([C:16]2[CH:21]=[CH:20][N:19]=[C:18](Cl)[N:17]=2)=[CH:14][C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]1=2>C(O)(C)C.ClCCl>[NH2:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][NH:10][C:18]2[N:17]=[C:16]([C:15]3[S:11][C:12]4[CH:26]=[CH:25][CH:24]=[CH:23][C:13]=4[CH:14]=3)[CH:21]=[CH:20][N:19]=2)[CH2:5][CH2:4]1
Reactant: NCC1CCC(CN)CC1
Reactant: Clc1nccc(-c2cc3ccccc3s2)n1
Solvent: CC(C)O
Solvent: ClCCl
Product: NC[C@H]1CC[C@@H](CNc2nccc(-c3cc4ccccc4s3)n2)CC1
Yield: 88 %

Procedure:
4-Aminomethyl-cyclohexylmethyl-amine (cis/trans-mixture, ca. 2:1) (1.28 g, 9.00 mmol) is added to a stirred suspension of 4-benzo[b]thiophen-2-yl-2-chloro-pyrimidine (986 mg, 4.00 mmol) in isopropanol (13 mL) at ambient temperature under nitrogen. The resultant mixture is heated at 110° C. for 20 hours. At ambient temperature the mixture is diluted with dichloromethane (40 mL), washed with 1N NaOH (13 mL), and dried (MgSO4). After concentration and subsequent chromatographic purification on silica gel, eluting with 2 M NH3/MeOH in dichloromethane 0-20%, the title compound is obtained as a 2:1 cis/trans-mixture (1.24 g, 88% yield). ES+(m/z) 353 [M+H].
Reaction SMILES: [CH3:1][N:2]([C:18]1[CH:19]=[CH:20][C:21]([C:24]([O:26][C:27]2[C:32]([F:33])=[C:31]([F:34])[C:30]([F:35])=[C:29]([F:36])[C:28]=2[F:37])=[O:25])=[N:22][CH:23]=1)[CH:3]1[C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][C:6]=2[CH2:5][CH2:4]1)[N:13]=[C:12]([CH3:16])[NH:11][C:10]3=[O:17].F[C:39](F)(F)[C:40](OC1C(F)=C(F)C(F)=C(F)C=1F)=O>>[CH3:16][C:12]1[NH:11][C:10](=[O:17])[C:9]2[C:14](=[CH:15][C:6]3[CH2:5][CH2:4][CH:3]([N:2]([C:18]4[CH:19]=[CH:20][C:21]([C:24]([O:26][C:27]5[C:32]([F:33])=[C:31]([F:34])[C:30]([F:35])=[C:29]([F:36])[C:28]=5[F:37])=[O:25])=[N:22][CH:23]=4)[CH2:1][C:39]#[CH:40])[C:7]=3[CH:8]=2)[N:13]=1
Reactant: Cc1nc2cc3c(cc2c(=O)[nH]1)C(N(C)c1ccc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)nc1)CC3
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Product: C#CCN(c1ccc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)nc1)C1CCc2cc3nc(C)[nH]c(=O)c3cc21

Procedure:
Using an analogous procedure to that described in section (5) of Example 6, 5-[N-((6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)]pyridine-2-carboxylic acid was reacted with pentafluorophenyl trifluoroacetate to give pentafluorophenyl 5-[N-((6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]-pyridine-2-carboxylate as a foam.
Reaction SMILES: Br.Br.[CH2:3]([N:10]1[C@@H:15]2[CH2:16][C@@H:12]([NH:13][CH2:14]2)[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:18]1[CH:19]=[CH:20][C:21]2[N:22]([C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][N:26]=2)[N:23]=1>>[CH2:3]([N:10]1[CH2:11][CH:12]2[CH2:16][CH:15]1[CH2:14][N:13]2[C:18]1[CH:19]=[CH:20][C:21]2[N:22]([C:24]([C:27]([F:28])([F:30])[F:29])=[N:25][N:26]=2)[N:23]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: c1ccc(CN2C[C@H]3C[C@@H]2CN3)cc1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Agent: Br
Product: FC(F)(F)c1nnc2ccc(N3CC4CC3CN4Cc3ccccc3)nn12

Procedure:
A mixture of (1R,4R)-6-benzyl-3,6-diazabicyclo[2.2.1]heptane dihydrobromide and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 4. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.2% aqueous ammonia) and acetonitrile as eluents to give 6-(5-benzyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([CH3:5])=O.[CH2:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[CH:3]([NH:15][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:5]
Reactant: NCc1ccccc1
Reactant: CC(=O)C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(NCc1ccccc1)C(F)(F)F
Yield: 98.4 %

Procedure:
After briskly stirring a mixture of 1,1,1-trifluoroacetone (1.0 ml; 11.2 mmol), benzylamine (1.1 ml; 10 mmol), AcOH (2 ml) and 3 Å molecular sieves (5 g) in 30 ml of CH2Cl2 for 2 hour at room temperature, sodium triacetoxyborohydride (4.25 g; 20 mmol) was added. After stirring 48 hours at room temperature, the reaction mixture was filtered through celite. After removing the volatiles in vacuo the residue was partitioned between ether (100 ml) and 1N NaOH (100 ml). The organic layer was washed with brine (50 ml), dried (MgSO4) and filtered through a 5×5 cm pad of silica gel. The pad was rinsed with ether and the filtrate was concentrated to afford 2.0 g (99%) of the title compound of this step as a colorless liquid.
Reaction SMILES: S(Cl)([Cl:3])=O.[ClH:5].O[CH:7]([CH3:29])[CH2:8][N:9]1[CH2:14][CH2:13][C:12]([N:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:19](=[O:22])[CH2:20][CH3:21])([CH2:15][O:16][CH3:17])[CH2:11][CH2:10]1>ClCCl>[ClH:3].[Cl:5][CH:7]([CH3:29])[CH2:8][N:9]1[CH2:14][CH2:13][C:12]([N:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:19](=[O:22])[CH2:20][CH3:21])([CH2:15][O:16][CH3:17])[CH2:11][CH2:10]1
Reactant: O=S(Cl)Cl
Reactant: CCC(=O)N(c1ccccc1)C1(COC)CCN(CC(C)O)CC1
Agent: Cl
Solvent: ClCCl
Product: CCC(=O)N(c1ccccc1)C1(COC)CCN(CC(C)Cl)CC1
Reaction time: 8 h
Yield: 85 %

Procedure:
14 Parts of sulfinyl chloride are stirred and there is added dropwise a solution of 37 parts of N-[1-(2-hydroxypropyl)-4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide monohydrochloride in 360 parts of dichloromethane. Upon completion, stirring is continued overnight at reflux temperature. The reaction mixture is evaporated and the residue is suspended in 2-propanone. The product is filtered off and dried, yielding 31.5 parts (85%) of N-[1-(2-chloropropyl)-4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide monohydrochloride.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([F:28])=[C:13]([CH:27]=2)[O:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23]([O:25][CH3:26])=[O:24])[CH2:19][CH2:18]2)=[N:6][CH:7]=1.[F:29][CH:30]([F:47])[O:31][C:32]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:33]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[F:29][CH:30]([F:47])[O:31][C:32]1[CH:37]=[CH:36][C:35]([C:2]2[CH:3]=[N:4][C:5]([NH:8][C:9]3[CH:10]=[CH:11][C:12]([F:28])=[C:13]([CH:27]=3)[O:14][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][CH:20]([C:23]([O:25][CH3:26])=[O:24])[CH2:19][CH2:18]3)=[N:6][CH:7]=2)=[CH:34][CH:33]=1
Reactant: CC1(C)OB(c2ccc(OC(F)F)cc2)OC1(C)C
Reactant: COC(=O)C1CCN(CCOc2cc(Nc3ncc(Br)cn3)ccc2F)CC1
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: C1COCCO1
Product: COC(=O)C1CCN(CCOc2cc(Nc3ncc(-c4ccc(OC(F)F)cc4)cn3)ccc2F)CC1
Temperature: 90 °C

Procedure:
To a solution of methyl 1-(2-(5-(5-bromopyrimidin-2-ylamino)-2-fluorophenoxy)ethyl)piperidine-4-carboxylate 47 (0.24 mmol) in 1,4-dioxane (2.0 mL) is added 2-(4-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 7 (0.28 mmol), 1.8M K2CO3 (0.5 mmol) and Pd(PPh3)4 (0.017 mmol). The reaction is evacuated and backfilled with nitrogen twice then heated at 90° C. for 12 h. The reaction mixture is cooled to rt, diluted with water (10 mL) and extracted with DCM (2×20 mL). The organic layer is separated, dried over Na2SO4 and concentrated. Purification by preparative HPLC (ACN gradient 20-70%) affords methyl 1-(2-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-fluorophenoxy)ethyl)piperidine-4-carboxylate 48 as white solid. MS (m/z) (M+1)+: 517.1.