Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:9]1([OH:22])[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)#[N:8]>C1COCC1>[NH2:8][CH2:7][C:9]1([OH:22])[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(C#N)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(CN)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 59.2 %

Procedure:
To a suspension of lithium aluminum hydride (84 mg, 2.2 mmol) in THF (5 mL), a solution of tert-butyl 4-cyano-4-hydroxypiperidine-1-carboxylate (200 mg, 0.88 mmol, step 1 of Example 22) in THF (1 mL) was added dropwise at 0° C. The mixture was stirred for 1 h at that temperature and Na2SO4.10H2O (400 mg) was added slowly, and the mixture was stirred for 5 h at room temperature. The mixture was filtered though a pad of Celite, washed with CH2Cl2 (20 mL×2), the filtrate was concentrated to give clear colorless oil. The residue was chromatographed on a column of silica gel eluting with CH2Cl2/MeOH/NH4OH (14:1:0.1) to give 120 mg (59%) of the title compound as white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[C:12]([CH3:17])=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:10].[CH:18]([O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:20])[CH3:19]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:28]([C:25]2[CH:24]=[CH:23][C:22]([O:21][CH:18]([CH3:20])[CH3:19])=[CH:27][CH:26]=2)(=[O:30])=[O:29])=[C:3]([C:9]([C:11]2[C:12]([CH3:17])=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:4]=1
Reactant: CC(C)Oc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ncccc1C(=O)c1cc(Cl)ccc1N
Product: Cc1ncccc1C(=O)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(OC(C)C)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-amino-5-chloro-phenyl)-(2-methyl-pyridin-3-yl)-methanone and 4-isopropoxy-benzenesulfonyl chloride and purified by HPLC. 1H NMR (CDCl3) δ 10.63 (br s, 1H, NH), 8.63 (dd, 1H, J=4.8 Hz, J=1.8 Hz), 7.79 (d, 1H, J=8.8 Hz), 7.71 (d, 1H, J=8.8 Hz), 7.48 (dd, 1H, J=9.0 Hz, J=2.2 Hz), 7.27 (dd, 1H, J=7.7 Hz, J=1.8 Hz), 7.19 (dd, 1H, J=7.7 Hz, J=4.8 Hz), 7.14 (d, 1H, J=2.2 Hz), 4.55 (septet, 1H, J=6 Hz), 2.35 (s, 3H), 1.35 (d, 3H, J=6 Hz). MS: m/z 445 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:9][C@@H:10]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:11]([NH:13][CH2:14][C:15]#[N:16])=[O:12])=[N:6][CH:7]=1.[N:27]1([C:33]2[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=2)[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.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:15]([CH2:14][NH:13][C:11](=[O:12])[C@@H:10]([O:9][CH:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:5]1[CH:4]=[CH:3][C:2]([C:36]2[CH:35]=[CH:34][C:33]([N:27]3[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]3)=[CH:38][CH:37]=2)=[CH:7][N:6]=1)[CH2:17][CH:18]([CH3:20])[CH3:19])#[N:16]
Reactant: CC(C)C[C@H](OC(c1ccccc1)c1ccc(Br)cn1)C(=O)NCC#N
Reactant: OB(O)c1ccc(N2CCNCC2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)C[C@H](OC(c1ccccc1)c1ccc(-c2ccc(N3CCNCC3)cc2)cn1)C(=O)NCC#N
Temperature: 90 °C

Procedure:
(2S)-2-[(5-bromopyridin-2-yl)(phenyl)methoxy]-N-(cyanomethyl)-4-methylpentanamide from example 53 step 3 (156 mg, 0.375 mmol), 4-piperazine-1-ylphenyl boronic acid (100 mg, 0.413 mmol, 1.1 eg), [1,1′-Bis(diphenylphosphino)-ferrocene dichloropalladium II complex with CH2Cl2 (13.7 mg, 0.0187 mmol, 0.05 eg), sodium carbonate (2M soln, 750 uL, 1.5 mmol, 4 eg) were mixed together in DMF (5 mL). The reaction mixture was degased 3× with N2, then heated to 90° C. for 5 hours. After cooling, the mixture was evaporated under high vacuum and residue was chromatographed with a mixture of dichloromethane/methanol/ammonium hydroxide (90:9:1) to give the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[CH:4][C:5]([NH:8]C(=O)C(C)(C)C)=[N:6][CH:7]=1.Cl>>[Br:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: CN1CCC(Nc2cc(NC(=O)C(C)(C)C)ncc2Br)CC1
Agent: Cl
Product: CN1CCC(Nc2cc(N)ncc2Br)CC1
Yield: 99.4 %

Procedure:
N-(5-Bromo-4-(1-methylpiperidin-4-ylamino)pyridin-2-yl)pivalamide (526 mg, 1.075 mmol) in 6M HCl (10 mL, 60.0 mmol) was heated by microwave irradiation to 105° C. for 1.5 hr. After cooling the volatiles were removed in vacuo. The residue was purified by ion exchange on Isolute SCX II acidic resin, washing with MeOH and then with 2M NH3 in MeOH. The basic fractions were concentrated to give crude 5-bromo-N4-(1-methylpiperidin-4-yl)pyridine-2,4-diamine (290 mg, 1.069 mmol, 100% yield) as a cream powder. LCMS (4) Rt=0.56 min; m/z (ESI+) 271/273 (MW). Di-tert-butyl dicarbonate (73.6 μl, 0.317 mmol) dissolved in the minimum amount of dichloromethane was slowly added to an ice-cooled solution of 5-bromo-N4-(piperidin-4-yl)pyridine-2,4-diamine (86 mg, 0.317 mmol) in triethylamine (134 μL, 0.951 mmol) and dichloromethane (2.44 mL). The mixture was stirred at 0° C. for 30 min followed by 1 hr at r.t. Solvents were removed in vacuo and the crude material was purified by preparative thin layer chromatography, eluting with 7% MeOH, 1% NH3 in dichloromethane, to give tert-butyl 4-(2-amino-5-bromopyridin-4-ylamino)piperidine-1-carboxylate (91 mg, 0.245 mmol, 77%) as a colourless foam.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH2:8])=[CH:3][CH:2]=1.[Cl:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][C:15](Cl)=[O:16]>>[Cl:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][C:15]([NH:8][CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)=[O:16]
Reactant: O=C(Cl)CCOCCCl
Reactant: NCc1ccncc1
Product: O=C(CCOCCCl)NCc1ccncc1

Procedure:
Title compound was prepared starting from (4-pyridyl)methanamine and 3-(2-chloroethoxy)propanoyl chloride following the procedure outlined for Example 27A. 1H NMR (CDCl3): δ 2.38-2.41 (m, 2H), 2.60-2.63 (m, 2H), 3.54-3.60 (m, 2H), 3.66-3.69 (m, 2H), 4.45 (d, 2H, J=6.1 Hz), 6.12 (br t, 1H, D2O exchanged), 7.09-7.11 (m, 2H), 8.40-8.42 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[O:5][C:6]1[C:11]([F:12])=[CH:10][C:9]([CH2:13][OH:14])=[CH:8][C:7]=1[F:15].Cl[C:21]1[CH:22]=[C:23]2[N:30]([CH3:31])[C@@H:29]([CH3:32])[CH2:28][N:24]2[C:25](=[O:27])[N:26]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[O:5][C:6]1[C:7]([F:15])=[CH:8][C:9]([CH2:13][O:14][C:21]2[CH:22]=[C:23]3[N:30]([CH3:31])[C@@H:29]([CH3:32])[CH2:28][N:24]3[C:25](=[O:27])[N:26]=2)=[CH:10][C:11]=1[F:12]
Reactant: OCc1cc(F)c(Oc2ccc(F)c(F)c2)c(F)c1
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C
Product: C[C@H]1Cn2c(cc(OCc3cc(F)c(Oc4ccc(F)c(F)c4)c(F)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (4-(3,4-difluorophenoxy)-3,5-difluorophenyl)methanol and (S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[C:15]2([F:19])[CH2:18][CH2:17][CH2:16]2)[CH2:3][CH2:2]1.Cl.[F:21][C:22]1([F:30])[CH2:26][NH:25][C@H:24]([C:27]([NH2:29])=[O:28])[CH2:23]1>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:25]3[CH2:26][C:22]([F:30])([F:21])[CH2:23][C@H:24]3[C:27]([NH2:29])=[O:28])=[O:14])[CH:9]=[CH:8][C:7]=2[C:15]2([F:19])[CH2:18][CH2:17][CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(C2(F)CCC2)c(OCC2CC2)n1
Reactant: NC(=O)[C@@H]1CC(F)(F)CN1
Agent: Cl
Product: NC(=O)[C@@H]1CC(F)(F)CN1C(=O)c1ccc(C2(F)CCC2)c(OCC2CC2)n1
Yield: 91 %

Procedure:
In analogy to the procedure described in Example 127 e), 6-(cyclopropylmethoxy)-5-(1-fluorocyclobutyl)pyridine-2-carboxylic acid (Example 130 f, 20 mg, 49.8 μmol) was reacted with (S)-4,4-difluoropyrrolidine-2-carboxamide hydrochloride (CAN 426844-51-1, 11.1 mg, 59.7 μmol) to give the title compound (18 mg, 91%) as off-white solid, MS (EI): m/e=398.4 [MH+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([NH2:15])=[O:14])[CH2:6][CH2:5]2.BrC1C=C2C(=C([N+:30]([O-:32])=[O:31])C=1)N(C1(C=CC=CC1)C(N)=O)CC2>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:30]([O-:32])=[O:31])[CH:10]=1)[N:7]([C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([NH2:15])=[O:14])[CH2:6][CH2:5]2
Reactant: NC(=O)c1ccccc1N1CCc2cc(Br)ccc21
Reactant: NC(=O)C1(N2CCc3cc(Br)cc([N+](=O)[O-])c32)C=CC=CC1
Product: NC(=O)c1ccccc1N1CCc2cc(Br)cc([N+](=O)[O-])c21

Procedure:
It is predicted that if the 2-(5-bromo-indolin-1-yl)-benzamide of Example 13a is treated in the manner of Example 1b that 1-(5-bromo-7-nitro-1-indolinyl)benzamide will be obtained.
Reaction SMILES: [CH3:1][N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:3].F[P-](F)(F)(F)(F)F.[NH2:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][C:27]=1[O:35][CH3:36].CCN(C(C)C)C(C)C.CNC>C1COCC1>[NH2:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([N:2]([CH3:3])[CH3:1])=[O:31])=[CH:28][C:27]=1[O:35][CH3:36]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1cc(C(=O)O)ccc1N
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)N(C)C)ccc1N
Reaction time: 18 h
Yield: 59.4 %

Procedure:
HATU (0.296 g, 0.778 mmol) was added to a solution of 4-amino-3-methoxybenzoic acid (0.1 g, 0.598 mmol), DIPEA (0.156 mL, 0.897 mmol) and dimethylamine (2M in THF, 0.598 mL, 1.196 mmol) in THF (1.617 ml). The reaction mixture was stirred for 18 hours. The reaction was partitioned between EtOAc and water, the organic layers were washed with water, dried over Na2SO4 and concentrated in vacuo. The residue was purified by Biotage silica gel column chromatography eluting with DCM/EtOAc 60/40 to 40/60 followed by filtration through an SCX-2 column eluting with 2M NH3/MeOH to afford the title compound as a colourless oil (69 mg, 59%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH3:12].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.[NH2:32][CH2:33][CH2:34][OH:35]>C(Cl)Cl.C(O)(C)C.C(Cl)(Cl)Cl>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:32][CH2:33][CH2:34][OH:35])=[O:8])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: NCCO
Reactant: COc1cc(C(=O)O)ccc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: COc1cc(C(=O)NCCO)ccc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 17 %

Procedure:
To a solution of 4-amino-3-methoxybenzoic acid (1 equiv) in anhydrous DCM (0.6 M) was added triethylamine (4 equiv), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.2 equiv) and 2-amino-ethanol (2 equiv) portionwise. The mixture was stirred at room temperature overnight. After the reaction was complete, as monitored by LCMS, the mixture was diluted with a mixture of isopropanol in chloroform (30%), washed with water and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by silica column to give the title compound as a white solid (17% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.05-8.02 (t, J=5.6 Hz, 1H), 7.32-7.27 (m, 1H), 6.60 (d, J=8.0 Hz, 1H), 5.21 (brs, 2H), 4.69 (t, J=5.6 Hz, 1H), 3.80 (s, 3H), 3.50-3.46 (m, 2H), 2.34-3.27 (m, 2H). MS (ESI) m/z 211.1 [M+1]+.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCCCCCCCCCCC.NC(N)=[O:23].C(=O)(O)[O-].[Na+].OO>O>[CH2:1]1[O:23][CH:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: NC(N)=O
Agent: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: CCCCCCCCCCCC
Solvent: O
Product: c1ccc(C2CO2)cc1

Procedure:
To a mechanically stirred solution of styrene (0.1 mol), dodecane (0.01 mol), urea (2.08 mol), sodium bicarbonate (0.03 mol) in 50.0 ml of water at 20° C. is added 30% aqueous hydrogen peroxide (0.22 mol) drop-wise over a period of 5 h. After 5 h the organic layer of the reaction mixture was separated by a separating funnel. The aqueous layer was extracted with 4×20 mL diethyl ether. The combined organic layer was distilled to yield styrene oxide. The conversion to epoxide is 99% with selectivity 95%.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=O)[C:10]([OH:12])=[O:11])[N:8]=1)=[O:2].[NH2:14][O:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22]>CO>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:14][O:15][CH2:16][CH2:17][NH:18][C:19]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:25])[C:10]([OH:12])=[O:11])[N:8]=1)=[O:2]
Reactant: O=CNc1nc(C(=O)C(=O)O)cs1
Reactant: CC(C)(C)OC(=O)NCCON
Solvent: CO
Product: CC(C)(C)OC(=O)NCCON=C(C(=O)O)c1csc(NC=O)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 77.6 %

Procedure:
A mixture of 2-(2-formamidothiazol-4-yl)-glyoxylic acid (1.59 g.), tert-butyl N-aminooxyethylcarbamate (1.40 g.) and methanol (25 ml.) was stirred at room temperature for 6 hours. After removal of methanol from the resultant solution under reduced pressure, the residue was pulverized with diethyl ether. The precipitates were collected by filtration to give 2-(2-formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetic acid (syn isomer, 2.21 g.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](#[N:21])[CH2:18][C:19]#[N:20].C(O)C.[BH4-].[Na+]>O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][CH:18]([C:17]#[N:21])[C:19]#[N:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(OCc2ccccc2)c1
Reactant: N#CCC#N
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CC(C#N)Cc1cccc(OCc2ccccc2)c1
Yield: 91.6 %

Procedure:
Using 1.06 g of 3-(benzyloxy)benzaldehyde, 0.33 g of malononitrile, 8 ml of ethanol, 1.5 ml of water and 57 mg of sodium borohydride, and according to the process described in the REFERENCE PRODUCTION EXAMPLE 19, there was obtained 1.20 g of (3-(benzyloxy)benzyl)malononitrile (the intermediate (31)).
Reaction SMILES: [N:1]1[C:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[S:3][C:2]=1[NH:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:24](=O)[CH3:25])[CH2:19][CH2:18]1.Cl.[OH-].[Na+]>C1COCC1>[CH2:24]([NH:23][CH:20]1[CH2:21][CH2:22][CH:17]([CH2:16][NH:15][C:2]2[S:3][C:4]3[CH2:10][CH2:9][O:8][C:7]4[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=4[C:5]=3[N:1]=2)[CH2:18][CH2:19]1)[CH3:25]
Reactant: CC(=O)NC1CCC(CNc2nc3c(s2)CCOc2ccccc2-3)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCNC1CCC(CNc2nc3c(s2)CCOc2ccccc2-3)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
To a stirred solution of N1-{4-[(4,5-dihydro-benzo[2,3]oxepino[4,5-d][1,3]thiazol-2-ylamino)-methyl]cyclohexyl}acetamide (0.380 g, 1.02 mmol) in anhydrous THF (4 ml) was added 1M BH3 in THF (5.0 ml, 5.0 mmol). The solution was stirred at room temperature overnight. 4N HCl (12 ml) was added slowly and stirring continued for 15 minutes. The resulting solution was made basic (pH˜9) with 2N NaOH. The cloudy solution was extracted with EtOAc and the organic layer washed with water. Removal of the solvent in vacuo, gave 69% (252 mg) of the product as a solid which was used without further purification: 1H-NMR (CDCl3) δ 0.96 (4H, m), 1.08 (3H, t, J=7.1 Hz), 1.47 (1H, m), 1.76 (2H, d, J=12.1 Hz), 1.90 (2H, m), 2.37 (2H, m), 2.63 (2H, q, J=7.0 Hz), 3.05 (2H, t, J=5.7 Hz), 3.11 (2H, t, J=5.1 Hz), 4.28 (2H, t, J=5.2 Hz), 5.73 (1H, broad t), 6.96 (1H, dd, J=0.9 Hz, 7.7 Hz), 7.10 (2H, m), 8.22 (1H, dd, J=1.3 Hz, 7.6 Hz); 358 (ESMS, MH+).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[CH2:26]([C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)[CH3:27]>C(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][C:28]([CH2:26][CH3:27])=[CH:29][CH:30]=2)[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: CCc1ccc(C(=O)Cl)cc1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1ccc(C(=O)N[C@@H]2CCc3cccc(N4CCN(C)CC4)c3C2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (110 mg, 0.46 mmol) and triethylamine (95 μL, 0.68 mmol) in methylene chloride (20 mL) was added dropwise 4-ethylbenzoyl chloride (81 mg, 0.48 mmol) in methylene chloride (5 mL). After the addition the reaction was allowed to stir at ambient temperature for 15 min and then washed with water. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:4) as the eluent. Yield: 120 mg (66%) of the title compound as white crystals: mp 177-178° C.; [α]21D −43° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 377 (27, M+).
Reaction SMILES: [CH2:1]([N:8]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:9][C:10]([F:17])([F:16])[C:11]([O:13]CC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[NH4+].[Cl-]>CN1C(=O)CCC1>[CH2:1]([N:8]1[CH2:9][C:10]([F:16])([F:17])[C:11](=[O:13])[CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCN(Cc1ccccc1)CC(F)(F)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)C1CN(Cc2ccccc2)CC(F)(F)C1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 59.6 %

Procedure:
To a solution of ethyl 3-(benzyl(3-ethoxy-3-oxopropyl)amino)-2,2-difluoropropanoate (10.78 g, 31.4 mmol) in NMP (100 mL) at 0° C. was added potassium tert-butoxide (5.64 g, 50.2 mmol) and the reaction mixture stirred at room temperature for 2 days. The reaction mixture was cooled to 0° C. and aqueous NH4Cl solution was added. The aqueous phase was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and the solvent was evaporated. The residue was purified by flash chromatography using a gradient EtOAc/Heptane 0-70% over 40 minutes to give the title compound as white solid (5.56 g, 60%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[N:17]=[C:18]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)[O:19][C:20]=3[CH3:21])=[CH:12][CH:11]=2)[CH:5]=[C:6]([Br:9])[C:7]=1[OH:8].Br[CH2:33][C:34]([O:36]C)=[O:35]>>[Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13]([C:16]3[N:17]=[C:18]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:24][CH:23]=4)[O:19][C:20]=3[CH3:21])=[CH:14][CH:15]=2)[CH:5]=[C:6]([Br:9])[C:7]=1[O:8][CH2:33][C:34]([OH:36])=[O:35]
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1-c1ccc(-c2cc(Br)c(O)c(Br)c2)cc1
Reactant: COC(=O)CBr
Product: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1-c1ccc(-c2cc(Br)c(OCC(=O)O)c(Br)c2)cc1

Procedure:
The title compound was prepared from 3,5-dibromo-4′-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-ol, and methyl bromoacetate in substantially the same manner, as described in Example 5, and was obtained as an off-white solid, mp 165–166° C.; MS m/e 609 (M+);
Reaction SMILES: Br[C:2]1[C:3]2[CH2:10][CH2:9][CH:8]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])[C:4]=2[CH:5]=[N:6][CH:7]=1.[F:16][C:17]1[CH:26]=[C:25]2[C:20]([CH2:21][CH2:22][C:23](=[O:28])[N:24]2[CH3:27])=[CH:19][C:18]=1B1OC(C)(C)C(C)(C)O1>>[F:16][C:17]1[CH:26]=[C:25]2[C:20]([CH2:21][CH2:22][C:23](=[O:28])[N:24]2[CH3:27])=[CH:19][C:18]=1[C:2]1[C:3]2[CH2:10][CH2:9][CH:8]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])[C:4]=2[CH:5]=[N:6][CH:7]=1
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)c(F)cc21
Reactant: CCC(=O)NC1CCc2c(Br)cncc21
Product: CCC(=O)NC1CCc2c(-c3cc4c(cc3F)N(C)C(=O)CC4)cncc21
Yield: 72 %

Procedure:
In analogy to the procedure described for the preparation of intermediate A-2 [E], (rac)-N-(4-bromo-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)propionamide (intermediate A-3) was reacted with 7-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-9) to give the title compound as a light brown solid in 72% yield. MS: 368.2 (M+H+).
Reaction SMILES: [C:1]([NH:5][C@@H:6]1[CH2:11][CH2:10][C@H:9]([NH:12]C(=O)OCC2C=CC=CC=2)[C@H:8]([CH2:23][S:24]([CH:27]([CH3:29])[CH3:28])(=[O:26])=[O:25])[CH2:7]1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([NH:5][C@@H:6]1[CH2:11][CH2:10][C@H:9]([NH2:12])[C@H:8]([CH2:23][S:24]([CH:27]([CH3:29])[CH3:28])(=[O:25])=[O:26])[CH2:7]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)S(=O)(=O)C[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)S(=O)(=O)C[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N
Yield: 95.6 %

Procedure:
A solution of benzyl (1S,2R,4R)-4-(tert-butylamino)-2-(isopropylsulfonylmethyl)-cyclohexylcarbamate (230 mg, 0.54 mmol), in 50 mL of MeOH was treated with 50 mg of 10% Pd/C and hydrogenated overnight at 55 psi. The mixture was filtered through Celite and concentrated on a rotary evaporator to give 150 mg of (1R,3R,4S)-N1-tert-butyl-3-(isopropylsulfonylmethyl)cyclohexane-1,4-diamine. This was used without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:18][CH:17]2[N:19]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH:10]([CH2:11][C:12]3[NH:13][N:14]=[CH:15][C:16]=32)[CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([S:20]([N:19]2[CH:10]3[CH2:9][NH:8][CH2:18][CH:17]2[C:16]2[CH:15]=[N:14][NH:13][C:12]=2[CH2:11]3)(=[O:21])=[O:22])=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CC2Cc3[nH]ncc3C(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: C1COCCO1
Product: O=S(=O)(c1ccc(Cl)cc1)N1C2CNCC1c1cn[nH]c1C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
12-(4-Chloro-benzenesulfonyl)-4,5,10,12-tetraaza-tricyclo[6.3.1.02,6]dodeca-2(6),3-diene-10-carboxylic acid tert-butyl ester (207 mg, 0.471 mmol) was covered with HCl in dioxane (4 N, 2 mL). The reaction mixture was stirred at room temperature for 2 h after which it was concentrated under vacuum and purified by preparative HPLC to give 12-(4-chloro-benzenesulfonyl)-4,5,10,12-tetraaza-tricyclo[6.3.1.02,6]dodeca-2(6),3-diene as a white solid. Retention time (min)=1.125, method [1], MS (ESI) 339.1 (M+H); 1H NMR (300 MHz, CDCl3) δ 7.59 (d, J=8.2 Hz, 2H), 7.30-7.25 (m, 3H), 5.09 (s, 1H), 4.35-4.14 (m, 1H), 3.25-3.18 (m, 2H), 2.98 (d, J=13.7 Hz, 1H), 2.77 (dd, J=17.0, 7.1 Hz, 2H), 2.55 (d, J=17.0 Hz, 1H)
Reaction SMILES: [CH3:1][C:2]([CH3:13])([C:5](=O)[N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[C:3]#[N:4].[H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl-].[NH4+].C(OCC)C>C1COCC1>[CH3:1][C:2]([CH3:13])([CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH2:3][NH2:4]
Reactant: CC(C)(C#N)C(=O)N1CCCCC1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(CN)CN1CCCCC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of Example 393A (0.9 g, 5 mmol) in 10 mL of THF was treated with a 1M solution of LAH in THF (10 mL, 10 mmol), stirred at room temperature for 6 hours, cooled to 0° C., and treated with 10 mL of saturated ammonium chloride and 30 mL of diethyl ether. The organic layer was washed with saturated ammonium chloride solution (3×), dried (Na2SO4), filtered, and concentrated to provide the desired product. MS (ESI(+)) m/e 171 (M+H)+.