Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=3[C:24]#[N:25])=[CH:13][CH:12]=2)[C:8]2[CH:26]=[C:27]([NH:30][C:31]([NH:33][CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[O:32])[CH:28]=[CH:29][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[N-:40]=[N+:41]=[N-:42].[Na+].[Cl-].[NH4+]>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=3[C:24]3[NH:42][N:41]=[N:40][N:25]=3)=[CH:13][CH:12]=2)[C:8]2[CH:26]=[C:27]([NH:30][C:31]([NH:33][CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[O:32])[CH:28]=[CH:29][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCc1nc2ccc(NC(=O)NC3CCCCC3)cc2n1Cc1ccc(-c2cc(Cl)ccc2C#N)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: CCCCc1nc2ccc(NC(=O)NC3CCCCC3)cc2n1Cc1ccc(-c2cc(Cl)ccc2-c2nnn[nH]2)cc1

Procedure:
Prepared in analogous manner to Example 59 from 4'-[(2-n-butyl-6-(N-cyclohexylaminocarbonylamino)-benzimidazol-1-yl)-methyl]-5-chloro-2-cyano-biphenyl and sodium azide/ammonium chloride.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:19](=[O:20])[N:18]([CH3:21])[C:11]3[N:12]=[C:13](SC)[N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:6][C:5]([NH:22][C:23]([NH:25][C:26]2[CH:30]=[C:29]([CH:31]([CH3:33])[CH3:32])[O:28][N:27]=2)=[O:24])=[C:4]([F:34])[CH:3]=1.[CH3:35][NH2:36].C1COCC1>>[Cl:1][C:2]1[C:7]([C:8]2[C:19](=[O:20])[N:18]([CH3:21])[C:11]3[N:12]=[C:13]([NH:36][CH3:35])[N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:6][C:5]([NH:22][C:23]([NH:25][C:26]2[CH:30]=[C:29]([CH:31]([CH3:33])[CH3:32])[O:28][N:27]=2)=[O:24])=[C:4]([F:34])[CH:3]=1
Reactant: CN
Reactant: CSc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(C)C)on4)c(F)cc3Cl)c(=O)n(C)c2n1
Solvent: C1CCOC1
Product: CNc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(C)C)on4)c(F)cc3Cl)c(=O)n(C)c2n1
Yield: 47.6 %

Procedure:
Using a procedure analogous to Example A1, 1-(4-chloro-2-fluoro-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(5-isopropylisoxazol-3-yl)urea (0.113 g, 0.225 mmol) and 2.0M MeNH2/THF (1.12 ml, 2.25 mmol) were combined to afford 1-(4-chloro-2-fluoro-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(5-isopropylisoxazol-3-yl)urea (52 mg, 48% yield) as a faintly yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 9.85 (s, 1H), 8.94 (brs, 1H), 8.62 (s, 1H), 8.15 (d, J=8.8 Hz, 1H), 7.88 (brq, J=4.8 Hz, 1H), 7.77 (s, 1H), 7.58 (d, J=10.8 Hz, 1H), 6.46 (s, 1H), 3.59 (s, 3H), 3.00 (septet, J=6.8 Hz, 1H), 2.91 (d, J=4.8 Hz, 3H), 1.20 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 486.2 (M+H+), 488.3 (M+2+H+).
Reaction SMILES: C(=O)=O.[Na].[CH3:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[CH2:7].CO.O1[CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH:9]1[C:10]2[C:11](=[CH:17][C:18]3[C:8]([CH:9]=2)=[CH:6][CH:5]=[CH:20][CH:19]=3)[CH:12]=[CH:13][C:8]=1[C:6]([CH3:5])=[CH2:7]
Reactant: C1CCOC1
Reactant: C=C(C)c1ccccc1
Agent: O=C=O
Agent: [Na]
Solvent: CO
Product: C=C(C)c1ccc2cc3ccccc3cc2c1
Temperature: -40 °C
Reaction time: 24 h

Procedure:
About 100 milliliters of tetrahydrofuran is vacuum distilled into a light tight ampule containing the above monomer, the ampule chilled to the temperature of dry ice (approximately -40° C) and about 5 milliliters of initiator solution (5 × 10-5 moles of the sodium salt of alphamethyl styrene tetramer in tetrahydrofuran) injected into the ampule through a side arm on the ampule. Polymerization of the monomer commences upon the introduction of the initiator into the ampule. After about 24 hours of continuous stirring at -40° C, the contents of the ampule are emptied into a flask containing methanol thereby quenching the polymerization reaction and precipitating the polymer. The polymer solids are recovered from the methanol solution by filtration, dried and reprecipitated from benzene with methanol. Yield: 8.0 grams of white polymer, Mw 280,000, Mw /Mn 1.74.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C([Li])CCC.[Cl:12][CH2:13][CH2:14][CH2:15]I.O>O1CCCC1>[Cl:12][CH2:13][CH2:14][CH2:15][C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1]
Reactant: C#C[Si](C)(C)C
Reactant: ClCCCI
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)C#CCCCCl
Reaction time: 0.5 h

Procedure:
A solution of trimethylsilylacetylene (12.0 g., Aldrich) in dry tetrahydrofuran (100 ml.) was stirred at 0°, under a current of nitrogen and n-butyllithium (76.5 ml. of 1.6M solution in hexane) was added dropwise. The solution was stirred for 30 minutes and a solution of 1-chloro-3-iodopropane (25.0 g.) in dry tetrahydrofuran (75 ml.) was added. The reaction mixture was allowed to warm to 20° and stirred for 18 hours. The mixture was poured into water and the aqueous mixture was extracted with diethyl ether. The ethereal extracts were washed with water and dried over anhydrous magnesium sulphate. The solvent was removed in vacuo and the residue distilled. 5-Chloro-1-trimethylsilylpent-1-yne was obtained as a colourless oil (12.7 g., b.p. 67°-27°, 15 mm. Hg.).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:18][CH:19]([CH3:23])[CH2:20][O:21][CH3:22])=[C:12]([NH2:17])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:24][CH3:25])=[C:5]([CH3:26])[O:4][N:3]=1.[N:27]([CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=[C:28]=S>>[CH3:1][C:2]1[C:6]([C:7]2[C:8]([O:24][CH3:25])=[CH:9][C:10]3[C:11]4[N:18]([CH:19]([CH3:23])[CH2:20][O:21][CH3:22])[C:28]([NH:27][CH2:30][CH2:31][N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)=[N:17][C:12]=4[CH:13]=[N:14][C:15]=3[CH:16]=2)=[C:5]([CH3:26])[O:4][N:3]=1
Reactant: S=C=NCCN1CCOCC1
Reactant: COCC(C)Nc1c(N)cnc2cc(-c3c(C)noc3C)c(OC)cc12
Product: COCC(C)n1c(NCCN2CCOCC2)nc2cnc3cc(-c4c(C)noc4C)c(OC)cc3c21
Yield: 46 %

Procedure:
From 7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-N4-(1-methoxypropan-2-yl)quinoline-3,4-diamine (for a preparation see Intermediate 19) (70 mg) and 4-(2-isothiocyanatoethyl)morpholine (50 mg) to give the title compound as beige solid (45 mg, 46%). LCMS (formate) Rt 0.56 min, MH+ 495
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:8][CH:9]=[CH:10][CH2:11]Cl>C(#N)C>[Cl:8][CH:9]=[CH:10][CH2:11][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC=CCCl
Reactant: Nc1ccccc1
Solvent: CC#N
Product: ClC=CCNc1ccccc1

Procedure:
1 mole of aniline was dissolved in 200 mL acetonitrile, and 0.7 mole 1,3-dichloropropene was added. The reaction was heated to reflux overnight with mechanical stirring. The reaction was then filtered and concentrated. Upon distillation, N-(3-chloro-2-propenyl)aniline was obtained as a yellow solid. The main distillation cut contained 65% N-(3-chloro-2-propenyl)aniline by weight.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7](C1C=CC=C(O)C=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].S([O:39][CH2:40][CH:41]1[CH2:46][CH2:45][N:44]([C:47]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[O:48])[CH2:43][CH2:42]1)(C1C=CC(C)=CC=1)(=O)=O>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:7][CH:8]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[O:39][CH2:40][CH:41]1[CH2:42][CH2:43][N:44]([C:47]([O:49][CH2:50][C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)=[O:48])[CH2:45][CH2:46]1)=[O:22])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OCc3ccccc3)CC2)cc1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(c1ccccc1)c1cccc(OCC2CCN(C(=O)OCc3ccccc3)CC2)c1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
To a stirred solution of tert-butyl(3-hydroxyphenyl)(phenyl)methylcarbamate. (the second eluting isomer from Chiral Example 1 Step 4, 1.00 g, 3.34 mmol) in DMF (15 mL), was added potassium carbonate (0.554 g, 4.01 mmol). The reaction mixture was stirred for 10 minutes, and benzyl 4-((tosyloxy)methyl)piperidine-1-carboxylate (prepared according to Bioorganic & Medicinal Chemistry Letters, 20(1), 380-382; 2010, which is incorporated herein by reference in its entirety, 1.48 g, 3.67 mmol) added. The reaction mixture was heated at 60° C. for 2 days followed by 80° C. for 5 days. The reaction mixture was diluted with ethyl acetate and washed with water and saturated brine (×2). The organic phase was dried with anhydrous magnesium sulfate, and the solvent evaporated at reduced pressure. The crude material was purified by silica gel chromatography eluting with 100% iso-hexane to 50% ethyl acetate in iso-hexane to afford the title compound (1.12 g, 63%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH2:9])[CH2:3][CH2:2]1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1>C(Cl)Cl.N1C=CC=CC=1>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([S:18]([NH:9][CH2:8][CH2:7][N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1
Reactant: NCCN1CCOCC1
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cccc(S(=O)(=O)NCCN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
2-Morpholinoethylamine (1.75 mL, 13.3 mmol) was added over 10 min to a solution of 3-(methyloxy)benzenesulfonyl chloride (2.5 g, 12.1 mmol) in CH2Cl2 (10 mL) and pyridine (4 mL) and the resulting solution was stirred at rt for 1 h. The mixture was concentrated, dissolved in EtOAc and the organic phase was washed with H2O and brine, dried (MgSO4), filtered and the filtrate was concentrated to give an orange oil (3.3 g, 92%) which was used directly in the next step. MS (ES+) m/e 301 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([O:13][CH3:14])[C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:28]=[CH:29][CH:30]=2)[CH2:21][CH2:20]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([O:13][CH3:14])[C:10]([NH:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25]3[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:34])[CH3:35])[CH:28]=[CH:29][CH:30]=3)[CH2:21][CH2:20]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(C(=O)O)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: COC(C(=O)NCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccc(Cl)c(Cl)c1

Procedure:
Example 39 was prepared from (3,4-dichlorophenyl)(methoxy)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 8.02–7.94 (m, 1H), 7.54 (d, 2H, J=10.1 Hz), 7.41 (d, 1H, J=8.5 Hz), 7.34–7.19 (m, 4H), 6.97 (d, 1H, J=7.0 Hz), 4.56 (s, 1H), 3.83 (s, 3H), 3.09–3.01 (m, 2H), 2.55–2.39 (m, 4H), 2.17 (s, 1H), 2.08–1.95 (m, 3H), 1.91–1.77 (m, 4H), 1.74–165 (m, 2H), 1.22 (d, 6H, J=6.6 Hz); ESMS m/e: 520.2 (M+H)+.
Reaction SMILES: [CH:1]1[C:18]2[C:19]3[C:4]([C:5]4[CH:6]=[CH:7][CH:8]=[C:9]5[C:24]=4[C:13]([C:14]=3[C:15]3[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=3[CH:17]=2)=[C:12]2[CH:25]=[CH:26][CH:27]=[CH:28][C:11]2=[CH:10]5)=[CH:3][CH:2]=1.[Br:29]Br>C(Cl)(Cl)(Cl)Cl>[Br:29][C:10]1[C:9]2[C:24]3[C:13]([C:14]4[C:15]5[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=5[CH:17]=[C:18]5[C:19]=4[C:4]([C:5]=3[CH:6]=[CH:7][CH:8]=2)=[CH:3][CH:2]=[CH:1]5)=[C:12]2[CH:25]=[CH:26][CH:27]=[CH:28][C:11]=12
Reactant: c1ccc2c(c1)cc1cccc3c4cccc5cc6ccccc6c(c54)c2c13
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: Brc1c2ccccc2c2c3c1cccc3c1cccc3cc4ccccc4c2c31

Procedure:
After dibenzo[a,o]perylene dissolved in carbon tetrachloride was brominated with cooling for four hours by adding one molar equivalent of bromine, the reaction product was refined in accordance with an ordinary method to obtain 7-bromodibenzo[a,o]perylene. Di-p-tolylamine, potassium carbonate and copper powder were added to the thus obtained 7-bromodibenzo[a,o]perylene and were allowed to react for 30 hours at 200° C. After the reaction solution was diluted with water, the reaction product was extracted with chloroform. Thereafter, it was refined in accordance with an ordinary method to obtain a target compound expressed in Formula 32.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[CH:27]=3)(=[O:25])=[O:24])=[CH:16][CH:15]=2)=[O:13])[S:9][CH:10]=1)C.[OH-].[K+].O>C(O)C>[CH3:32][C:30]1[CH:31]=[C:26]([S:23]([N:20]2[C:21]3[C:17](=[CH:16][CH:15]=[C:14]([C:12]([NH:11][C:8]4[S:9][CH:10]=[C:6]([CH2:5][C:4]([OH:34])=[O:3])[N:7]=4)=[O:13])[CH:22]=3)[CH2:18][CH2:19]2)(=[O:25])=[O:24])[CH:27]=[C:28]([CH3:33])[CH:29]=1
Reactant: CCOC(=O)Cc1csc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(C)cc(C)c2)CC3)n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(C)cc(S(=O)(=O)N2CCc3ccc(C(=O)Nc4nc(CC(=O)O)cs4)cc32)c1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
(2-{[1-(3,5-Dimethyl-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-thiazol-4-yl)-acetic acid ethyl ester (0.10 g, 0.20 mmol) was suspended in ethanol (1.00 mL) and treated at room temperature with 3N KOH in water (0.20 mL, 0.60 mmol). The mixture was warmed to 50° C. and stirred for 18 hours, then cooled to room temperature and evaporated. The residue was dissolved in water (1.00 mL) and set to pH 1 with HCl 1N. The resulting suspension was filtered, washing with water and the filtrate dried under vacuum to yield (2-{[1-(3,5-dimethyl-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-thiazol-4-yl)-acetic acid as a white solid, 0.09 g (99%), MS (ISP): m/e=470.2 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH2:15])[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:16]([C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1)=O.C(O)(=O)C.Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH:15][CH2:16][C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=3)[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: Nc1nc(Nc2cc(Cl)cc(Cl)c2)n[nH]1
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Product: N#Cc1ccc(CNc2nc(Nc3cc(Cl)cc(Cl)c3)n[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67 %

Procedure:
To a solution of N3-(3,5-dichlorophenyl)-1H-1,2,4-triazole-3,5-diamine Intermediate 2 (100 mg, 410 μmol) in MeOH (3.5 mL) was added 4-formylbenzonitrile (53.7 mg, 410 μmol) followed by acetic acid (36.7 mg, 35 μl, 611 μmol). The reaction was stirred at room temperature for 15 minutes, 2-picoline borane complex (52.6 mg, 492 μmol) was added and the stirring was continued overnight. The reaction mixture was poured into 0.1N HCl solution (25 ml). The volume was reduced and the resulting suspension was filtered to give an off white solid as desired product (109 mg, 67% yield). MS +m/z: 358 (M+H)+
Reaction SMILES: [C:1]([O:6][CH:7]([O:9][C:10]([NH:12][CH2:13][C:14]1([CH2:20][C:21]([O:23]CC2C=CC=CC=2)=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:11])[CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([O:6][CH:7]([O:9][C:10]([NH:12][CH2:13][C:14]1([CH2:20][C:21]([OH:23])=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:11])[CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: [H][H]
Reactant: CC(OC(=O)NCC1(CC(=O)OCc2ccccc2)CCCCC1)OC(=O)C(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(OC(=O)NCC1(CC(=O)O)CCCCC1)OC(=O)C(C)C

Procedure:
Compound (10) (113 g) was dissolved in ethyl acetate (700 mL) and 10 g of 10% Pd-C was added. The reaction mixture was subjected to 50 psi of hydrogen gas in a Parr reactor for 40 min. Filtration through a sintered glass funnel and a hydrophobic membrane filtration cartridge (Millipore Opticap) removed the catalyst. The supernatant was concentrated to afford the product (11) as a white, crystalline solid (78 g, quantitative yield). Crystals formed in the freezer, then at room temperature over several days. 1H NMR (CDCl3, 400 MHz): 1.15 (d, 6H), 1.40–1.55 (m, 10H), 1.45 (d, 3H), 2.32 (s, 2H), 2.49–2.56 (m, 1H), 3.23 (d, 2H), 5.41 (t, 1H), 6.75 (q, 1H). MS(ESI) m/z 330.29 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][O:20][CH2:21][CH2:22][NH:23][CH:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:23]([CH2:22][CH2:21][O:20][CH3:19])[CH:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: COCCNC1CCN(C)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COCCN(Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1)C1CCN(C)CC1
Yield: 41.7 %

Procedure:
2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (150 mg) and (2-methoxy-ethyl)-(1-methyl-piperidin-4-yl)-amine (128 mg) were stirred together in 1,2-dichloroethane (8 ml) and acetic acid (32 mg) with sodium triacetoxyborohydride (146 mg) at room temperature overnight. Dichloromethane/aqueous sodium hydrogen carbonate extraction and purification on silica yielded (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-(2-methoxy-ethyl)-(1-methyl-piperidin-4-yl)-amine (97 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9][NH2:10])=[CH:4][CH:3]=1.[CH:17]1([C:23]([N:25]2[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]2)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>ClCCCl>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9][NH:10][CH:28]2[CH2:29][CH2:30][N:25]([C:23]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:24])[CH2:26][CH2:27]2)=[CH:4][CH:3]=1
Reactant: O=C1CCN(C(=O)C2CCCCC2)CC1
Reactant: NCc1ccccc1Oc1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: O=C(C1CCCCC1)N1CCC(NCc2ccccc2Oc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Yield: 63.5 %

Procedure:
A solution of 2-(4-chlorophenoxy)benzylamine (AMR01076, 100 mg, 0.428 mmol) and 1-cyclohexanecarbonylpiperidin-4-one (89.5 mg, 0.428 mmol) in DCE (5 mL) was treated with NaBH(OAc)3 (127 mg, 0.60 mmol) and acetic acid (26 mg, 0.428 mmol). The mixture was stirred at room temperature under a N2 atmosphere until TLC showed that the reactants were consumed (30 min). Then, it was quenched with saturated NaHCO3 solution, the aqueous layer was washed with DCM (2×20 mL), and the combined organic layers were dried (MgSO4), filtered and evaporated to dryness. Column chromatography on silica gel of the crude product using DCM to DCM/MeOH 95:5 gradient as eluent gave {4-[2-(4-chlorophenoxy)benzylamino]piperidin-1-yl}cyclohexylmethanone (116 mg, 63%) as a colorless oil. Rf: 0.4 (DCM/MeOH 9:1) LC/MS (APCI) tr=10.18 min, m/z 429.46 (36), 427.44 (M++H, 100). HPLC tr=4.43 min (93.94%) 1H NMR (270 MHz, CDCl3) δ 1.12-1.79 (15H, m, 7CH2+NH), 2.44 (1H, m, CHCO), 2.64 (2H, m, CH2), 2.99 (1H, m, CHNH), 3.80 (2H, m, CH2NH), 3.82 (1H, m, ½CH2), 4.39 (1H, br d, J=13.3 Hz, ½CH2), 6.84 (2H, AA′BB′, ArH), 6.86 (1H, m, ArH), 7.12 (1H, td, ArH), 7.22 (1H, m, ArH), 7.25 (2H, AA′BB′, ArH) and 7.39 (1H, dd, J=7.3, 1.7 Hz, ArH). 13C NMR (270 MHz, CDCl3) δ 25.97, 29.40, 29.59, 32.29, 33.40, 40.32 (CH2), 40.54 (CH), 43.91, 45.65 (CH2), 54.00 (CH), 118.94, 119.61, 124.54, 127.96, 128.70, 129.84, 130.57, 131.84, 154.35, 156.38 (ArC), and 174.48 (C═O).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]=O)[C:3]=1[CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.[CH3:23][C:24]([CH3:29])([CH3:28])[CH2:25][CH2:26][NH2:27]>C1(C)C=CC=CC=1>[CH3:23][C:24]([CH3:29])([CH3:28])[CH2:25][CH2:26]/[N:27]=[CH:8]/[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c(F)cccc2C=O)CC1
Reactant: CC(C)(C)CCN
Solvent: Cc1ccccc1
Product: CC(C)(C)CC/N=C/c1cccc(F)c1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
To a solution of tert-butyl 4-(2-fluoro-6-formylphenyl)piperidine-1-carboxylate (1.0 g, 4.23 mmol) in toluene (14 mL) was added 3,3 dimethylbutylamine (428.0 mg, 569.1 μL, 4.230 mmol) and 4 Å molecular sieves. The resulting solution was stirred at rt overnight. The molecular sieves were filtered off and the mixture concentrated in vacuo to give 1.5 g of tert-butyl 4-(2-((E)-(3,3-dimethylbutylimino)methyl)-6-fluorophenyl)piperidine-1-carboxylate as an off-white solid (1.5 g). The material was used without further purification for the next step. 1H-NMR in CD3CN of the crude was consistent for the product with a diagnostic peak of the imine proton @ 8.74 ppm.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][CH:8]1[CH2:12][C:11]2([CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[O:10][CH:9]1[CH3:19].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1>[CH2:5]([O:4][C:2](=[O:3])[NH:7][CH:8]1[CH2:12][C:11]2([CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[O:10][CH:9]1[CH3:19])[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: CC1OC2(CCN(C)CC2)CC1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)NC1CC2(CCN(C)CC2)OC1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl chloroformate was added to 3-Amino-2,8-dimethyl-1-oxa-8-azaspiro[4.5]decane (1 g 5.4 mmol) in THF (20 ml). An additional 20 ml of THF were added and the reaction was stirred for 2 hours at room temperature. The THF solution was mixed with saturated sodium carbonate solution and the THF layer was separated, dried and evaporated to give a product which was purified by chromatography on silica gel and eluting with 5-10% ammoniated MeOH/CHCl3. The major fraction was converted to the fumaric acid salt in ether but a solid could not be obtained. The salt was neutralized with aqueous alkali and the base was extracted into methylene chloride. Concentration of the methylene chloride afforded the title carbamate compound as an oil.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:29]([C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=1)[CH:39]=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:39][C:38]3[CH:41]=[CH:42][CH:43]=[C:36]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:37]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4cccc(Oc5ccccc5)c4)c3)c(Cc3ccccc3)cnc12

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 3-phenoxy-benzaldehyde according to the procedure of Example 66. MS (ES) m/z 561.1.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[C:10]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[N:9]=[CH:8]1)=[N+]=[N-].[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOC(C)=O>C1COCC1>[NH2:1][CH2:4][CH2:5][CH2:6][N:7]1[C:11]([C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)=[C:10]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[N:9]=[CH:8]1
Reactant: [N-]=[N+]=NCCCn1cnc(-c2ccc(F)cc2)c1-c1ccncc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NCCCn1cnc(-c2ccc(F)cc2)c1-c1ccncc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The compound of example 3, described above (254 mg, 0.79 mmol), was dissolved in THF (2 mL) an added dropwise to a 0° solution of 1 N LiAlH4 in THF (1.2 mL, 1.2 mmol), stirred at 0° for 15 min, EtOAc (4 mL) was carefully added and the mixture was added to ice cold 10% NaOH (15 mL) and the product was extracted with EtOAc (4×25 mL), dried (K2CO3) and concentrated to a waxy solid, (175 mg, 75%). mp=81°-82°.