Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][NH:2]/[C:3](=[N:14]\[H])/[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[N:6][CH:5]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:27][CH2:26][N:25]([CH2:28][C:29](O)=O)[C:24]2=[O:32])=[CH:19][CH:18]=1.Cl.C(N=C=NCCCN(C)C)C>ClC(Cl)C>[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:27][CH2:26][N:25]([CH2:28][C:29]3[O:1][N:2]=[C:3]([C:4]4[CH:5]=[N:6][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:9]=4)[N:14]=3)[C:24]2=[O:32])=[CH:19][CH:18]=1
Reactant: [H]/N=C(\NO)c1ccc(C(F)(F)F)nc1
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(Cl)Cl
Product: O=C1C(c2ccc(F)cc2)CCN1Cc1nc(-c2ccc(C(F)(F)F)nc2)no1
Temperature: 85 °C

Procedure:
(Z)—N-Hydroxy-6-(trifluoromethyl)nicotinimidamide (0.082 g, 0.399 mmol), 2-(3-(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid (0.086 g, 0.363 mmol; Example 216A) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.104 g, 0.544 mmol) were stirred together in dichloroethane (1 mL) at room temperature for 4 hours. The reaction was heated to 85° C. and heated overnight. The reaction was cooled, loaded onto a GraceResolv™ 12 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 5% ethyl acetate/hexanes to 50% ethyl acetate/hexanes (Flow=36 mL/minute) over 30 minutes to give the title compound. 1H NMR (300 MHz, CDCl3) δ 9.41 (d, J=1.7, 1H), 8.58-8.50 (m, 1H), 7.84 (dd, J=0.5, 8.1, 1H), 7.33-7.26 (m, 2H), 7.11-7.01 (m, 2H), 4.98 (d, J=17.0, 1H), 4.87 (d, J=17.0, 1H), 3.78 (t, J=9.0, 1H), 3.74-3.61 (m, 2H), 2.67 (dddd, J=4.3, 7.0, 9.1, 13.2, 1H), 2.26 (ddd, J=8.5, 13.0, 16.5, 1H); MS (ESI+) m/z 407.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([C:21](O)=[O:22])=[N:19][CH:20]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:4][CH:3]=1.O.ON1[C:32]2C=C[CH:35]=[CH:36][C:31]=2[N:30]=N1.C(N(C(C)C)C(C)C)C.Cl.CN(C)CCCN=C=NCC.C[C@H]([OH:62])CN>C1COCC1>[OH:62][CH2:32][C@@H:31]([NH:30][C:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9][O:10][C:11]=2[CH2:24][OH:25])=[CH:20][N:19]=1)=[O:22])[CH2:36][CH3:35]
Reactant: On1nnc2ccccc21
Reactant: C[C@H](O)CN
Reactant: O=C(O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H](CO)NC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.7 %

Procedure:
To a solution of 5-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-pyridine-2-carboxylic acid (75 mg, 0.22 mmol) in THF (2 mL) was added 1-hydroxy-benzotriazole hydrate (34.1 mg, 0.22 mmol), N-ethyldiisopropylamine (95.2 μL, 0.55 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (42.6 mg, 0.22 mmol) and S-(+)-1-amino-2-propanol (16.7 mg, 0.22 mmol). The reaction mixture was stirred overnight at room temperature. Evaporation of the mixture followed by chromatography (silica, dichloro-methane:methanol=1:0 to 9:1) afforded the title compound (50 mg, 55%) as a colourless gum. MS: m/e=416.2 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]([CH2:20][CH3:21])[C:12]2=[O:22])=[O:10])[CH2:3][CH2:2]1.[CH2:23]([O:27][C:28]1[CH:33]=[CH:32][C:31](Cl)=[CH:30][CH:29]=1)[CH:24]1[O:26][CH2:25]1>>[NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]([CH:20]([CH3:23])[CH3:21])[C:12]2=[O:22])=[O:10])[CH2:3][CH2:2]1.[O:26]1[CH:24]([CH2:23][O:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:25]1
Reactant: Clc1ccc(OCC2CO2)cc1
Reactant: CCn1c(=O)n(C(=O)NCC2CCNCC2)c2ccccc21
Product: CC(C)n1c(=O)n(C(=O)NCC2CCNCC2)c2ccccc21
Product: c1ccc(OCC2CO2)cc1

Procedure:
The procedure given in Example 104 was followed using 3-ethyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-ylmethyl)-amide and 4-chlorophenyl glycidyl ether as a reactant, instead of 3-isopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-ylmethyl)-amide and 1,2-epoxy-3-phenoxypropane, to give the title compound.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:7][C:8]1[N:9]=[CH:10][C:11]2[CH:17]=[C:16]([C:18]3[C:23]([Cl:24])=[C:22]([O:25][CH3:26])[CH:21]=[C:20]([O:27][CH3:28])[C:19]=3[Cl:29])[C:15](=[O:30])[N:14]([CH2:31][CH3:32])[C:12]=2[N:13]=1.CCN(C(C)C)C(C)C.[C:42](Cl)(=[O:45])[CH:43]=[CH2:44]>ClCCl>[Cl:24][C:23]1[C:22]([O:25][CH3:26])=[CH:21][C:20]([O:27][CH3:28])=[C:19]([Cl:29])[C:18]=1[C:16]1[C:15](=[O:30])[N:14]([CH2:31][CH3:32])[C:12]2[N:13]=[C:8]([NH:7][C@@H:3]3[CH2:4][CH2:5][CH2:6][C@@H:2]3[NH:1][C:42](=[O:45])[CH:43]=[CH2:44])[N:9]=[CH:10][C:11]=2[CH:17]=1
Reactant: CCn1c(=O)c(-c2c(Cl)c(OC)cc(OC)c2Cl)cc2cnc(N[C@@H]3CCC[C@@H]3N)nc21
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)N[C@H]1CCC[C@H]1Nc1ncc2cc(-c3c(Cl)c(OC)cc(OC)c3Cl)c(=O)n(CC)c2n1
Reaction time: 1 h
Yield: 64.4 %

Procedure:
To a solution of 2-(((1R,2S)-2-aminocyclopentyl)amino)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-ethylpyrido[2,3-d]pyrimidin-7(8H)-one (0.105 mmol) in dichloromethane (2.1 mL) at −20° C. was added DIEA (0.018 mL, 0.105 mmol) and acryloyl chloride (0.008 mL, 0.105 mmol) and the reaction was stirred for 1 h. LC-MS indicated complete consumption of SM. The reaction mixture was purified by silica gel chromatography to yield N-((1S,2R)-2-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-ethyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)cyclopentyl)acrylamide (36 mg, 65%). MS (ES+) C25H27Cl2N5O4 requires: 531, found: 532.
Reaction SMILES: FC1C(O[C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=C(F)C(F)=C(F)C=1F.[CH3:29][C:30]1[O:34][N:33]=[C:32]([CH2:35][O:36][NH2:37])[CH:31]=1>>[CH3:29][C:30]1[O:34][N:33]=[C:32]([CH2:35][O:36][NH:37][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)[CH:31]=1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1ccccc1NCc1ccncc1
Reactant: Cc1cc(CON)no1
Product: Cc1cc(CONC(=O)c2ccccc2NCc2ccncc2)no1

Procedure:
Prepared by the same method as described for example 415. Starting materials: 2-[(Pyridin-4-ylmethyl)-amino]-benzoic acid pentafluorophenyl ester (preparation 7C) and O-(5-Methyl-isoxazol-3-ylmethyl)-hydroxylamine (see preparation 61)
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)=[O:19])=[CH:11][CH:10]=2)O1.[Cl:32][C:33]1[CH:38]=[CH:37][N:36]2[C:39](I)=[CH:40][N:41]=[C:35]2[CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.ClCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:32][C:33]1[CH:38]=[CH:37][N:36]2[C:39]([C:9]3[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][C:18]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=4)=[O:19])=[CH:13][CH:14]=3)=[CH:40][N:41]=[C:35]2[CH:34]=1
Reactant: CC1(C)OB(c2ccc(CCCC(=O)Nc3cccc(C(F)(F)F)c3)cc2)OC1(C)C
Reactant: Clc1ccn2c(I)cnc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(CCCc1ccc(-c2cnc3cc(Cl)ccn23)cc1)Nc1cccc(C(F)(F)F)c1
Yield: 62.6 %

Procedure:
Suspend 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-N-(3-trifluoromethyl-phenyl)-butyramide (0.47 g, 1.15 mmol), 7-chloro-3-iodo-imidazo[1,2-a]pyridine (0.29 g, 1.05 mmol) and solid potassium carbonate (0.48 g, 3.45 mmol) in dioxane (4 mL) and water (2 mL). Deoxygenate the reaction contents with nitrogen for 10 minutes at room temperature. Add trans-dichlorobis(triphenylphosphine)palladium (II) (22 mg, 0.03 mmol) to the reaction. Fit a reflux condenser and heat the reaction to 105° C. over the weekend. Cool the reaction, dilute with dichloromethane and filter through Celite®. Concentrate the filtrate and then chromatograph on silica, using 0-3% methanol/ethyl acetate, to yield the product (301 mg, 57%). MS(ES), m/z 458 (M+1).
Reaction SMILES: I[C:2]1[C:11]2[N:10]([CH:12]3[CH2:17][CH2:16][CH2:15][CH:14]([CH2:18][NH:19][C:20](=[O:27])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:13]3)[C:9](=[O:28])[C:8]3=[C:29]([CH3:32])[O:30][N:31]=[C:7]3[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(#N)C.[CH3:36][OH:37].CCN(CC)CC.C[C:46](C)=[O:47].ClCCl>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]>[CH3:36][O:37][C:46]([C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([CH2:18][NH:19][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:13]1)[C:9](=[O:28])[C:8]1=[C:29]([CH3:32])[O:30][N:31]=[C:7]21)=[O:47]
Reactant: CC(C)=O
Reactant: CO
Reactant: Cc1onc2c1c(=O)n(C1CCCC(CNC(=O)c3ccccc3)C1)c1c(I)cccc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc2c3noc(C)c3c(=O)n(C3CCCC(CNC(=O)c4ccccc4)C3)c12
Yield: 83 %

Procedure:
In a fashion similar to that described for Example 592, N-[3-(6-Iodo-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylmethyl]-benzamide (0.048 g, 0.089 mmol), acetonitrile (10 ml), MeOH (5 ml), Et3N (0.04 ml, 0.267 mmol), and PdCl2(dppf) (0.004 g, 0.004 mmol) gave the title compound (0.035 g, 83%) after column chromatography (silica gel, acetone/dichloromethane gradient). MS(FIA) (m/z) 472.3 [M−1].
Reaction SMILES: [CH2:1]([N:8]([CH2:12][Si](C)(C)C)[CH2:9]OC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:23][CH2:24][CH3:25])(=[O:22])/[CH:18]=[CH:19]\[CH2:20][CH3:21]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:1]([N:8]1[CH2:9][C@H:19]([CH2:20][CH3:21])[C@H:18]([C:17]([O:23][CH2:24][CH3:25])=[O:22])[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CC/C=C\C(=O)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@@H]1CC
Reaction time: 48 h
Yield: 96.1 %

Procedure:
To a solution of N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (9.98 mL, 39.0 mmol) and (Z)-ethyl pent-2-enoate (5 g, 39.0 mmol) in DCM (50 mL) was added TFA (0.030 mL, 0.390 mmol) at rt. After about 2 days, the reaction mixture was concd in vacuo to provide crude (cis)-ethyl 1-benzyl-4-ethylpyrrolidine-3-carboxylate (9.8 g, 96%) as an oil. LC/MS (Table 1, Method a) Rt=1.62 min; MS m/z: 262 (M+H)+.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[N:20]1([CH2:26][CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][NH2:37])[CH2:31][CH2:30]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(#N)C>[N:20]1([CH2:26][CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][NH:37][C:2]([N:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[C:8](=[O:15])[NH:7][C:6]4[CH:16]=[CH:17][CH:18]=[N:19][C:5]3=4)=[O:3])[CH2:31][CH2:30]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NCCN1CCC(CCCN2CCCCC2)CC1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Solvent: CC#N
Product: O=C1Nc2cccnc2N(C(=O)NCCN2CCC(CCCN3CCCCC3)CC2)c2ccccc21
Yield: 16 %

Procedure:
Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[4-[3-(piperidin-1-yl)propyl)-piperidin-1-yl]ethanamine in a yield of 16% of theory. Colourless crystals, m.p. 192°-193° C. (acetonitrile).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]#[N:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:25]CCN1CCCC1C.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:25][CH:2]1[CH2:3][CH2:4][CH2:5][N:1]1[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2([C:22]#[N:23])[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)=[CH:12][CH:11]=1
Reactant: N#CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: CC1CCCN1CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1CCCN1CCCOc1ccc(C2(C#N)CCOCC2)cc1
Yield: 88.4 %

Procedure:
4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbonitrile (315 mg, 1.55 mmol), 1-(3-chloro-propyl)-2-methyl-pyrrolidine (400 mg, 2.48 mmol), DMF (6 ml) and K2CO3 (833 mg, 6.03 mmol) were reacted together according to general procedure E. Purification by chromatography on silica, eluant DCM:MeOH:NH3 (92:6:2) provided the title compound (450 mg, 88%) as an orange oil. 1H NMR (400 MHz, CDCl3), δ 7.37 (d, 2H), 6.93 (d, 2H), 4.12-3.99 (m, 4H), 3.89 (td, 2H), 2.35-1.62 (m, 14H), 1.42 (m, 1H), 1.09 (d, 3H).
Reaction SMILES: C(OP([CH2:9][S:10]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[C:21]([CH3:29])[CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])(OCC)=O)C.[Br-].[Li+].C(=O)CC.[CH2:36]1[CH2:46]CN2C(=NCCC2)[CH2:38][CH2:37]1>C1COCC1.ClCCl>[CH3:29][C:21]1[CH:20]=[C:19]([N:16]2[CH2:15][CH2:14][N:13]([S:10](/[CH:9]=[CH:46]/[CH2:36][CH2:37][CH3:38])(=[O:12])=[O:11])[CH2:18][CH2:17]2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1
Reactant: CCOP(=O)(CS(=O)(=O)N1CCN(c2cc(C)nc3ccccc23)CC1)OCC
Reactant: C1CCC2=NCCCN2CC1
Agent: [Br-]
Agent: [Li+]
Solvent: CCC=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCC/C=C/S(=O)(=O)N1CCN(c2cc(C)nc3ccccc23)CC1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 13.6 %

Procedure:
4-[4-(Diethoxyphosphorylmethylsulfonyl)piperazin-1-yl]-2-methyl-quinoline (47 mg, 0.106 mmol) was dissolved in anhydrous THF (1 ml), lithium bromide (11.1 mg, 0.128 mmol) and propionaldehyde (9.2 μl, 0.128 mmol) were added with stirring and the mixture was cooled to −10° C. DBU (15.2 μl, 0.102 mmol) was added, and the temperature was raised to room temperature. Stirring was continued for 30 minutes, the reaction mixture was diluted with dichloromethane, washed with 5% sodium bicarbonate solution (2×), water and evaporated to dryness. The residue was purified with preparative HPLC (gradient of water containing 0.1% ammonia and acetonitrile). 5 mg of a solid were obtained (0.014 mmol, 14%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]=1[CH2:23][CH2:24][NH2:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]1(=O)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:17])([CH3:16])[CH3:18])[CH:12]=[C:11]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]=1[CH2:23][CH2:24][NH:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)c1cc(OCc2ccccc2)c(CCN)c(C(C)(C)C)c1
Reactant: O=C1CCCCC1
Product: CC(C)(C)c1cc(OCc2ccccc2)c(CCNC2CCCCC2)c(C(C)(C)C)c1

Procedure:
The product from Step A (0.227 g) was treated with 0.070 g (0.71 mmol) of cyclohexanone according to the procedure described in Example 3. The product was purified on a silica gel flash chromatography column eluted with 5-10% isopropanol in hexane. Evaporation of the purified fractions and drying in vacuo afforded the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][CH2:13][N:14]3[C:17](=[O:34])[C@@H:18]([NH:26]C(=O)OC(C)(C)C)[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.[ClH:42]>ClCCl.CCOCC>[ClH:42].[NH2:26][C@@H:18]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17]([N:14]1[C:15]2[C:11](=[CH:10][CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH:16]=2)[CH2:12][CH2:13]1)=[O:34]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCc2ccc(-c3ccc(F)cc3)cc21
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: N[C@@H](Cc1ccccc1)C(=O)N1CCc2ccc(-c3ccc(F)cc3)cc21
Reaction time: 3 h
Yield: 89 %

Procedure:
The (S)-tert-butyl 1-(6-(4-fluorophenyl)indolin-1-yl)-1-oxo-3-phenylpropan-2-ylcarbamate (93.0 mg, 202 μmol) was dissolved in dichloromethane and TFA (1.0 mL, 13 mmol) was added. The resulting solution was stirred for three hours. The mixture was then concentrated and the residue was dissolved in ethyl acetate and extracted with saturated sodium bicarbonate (1×30 mL). The organic layer was then dried over magnesium sulfate and concentrated to dryness and the residue was again dissolved in ethyl acetate and 2.0 equivalents of 1M HCl in ether solution was added. A precipitate formed and the slurry was filtered and washed with hexanes to give (2S)-2-amino-1-(6-(4-fluorophenyl)indolin-1-yl)-3-phenylpropan-1-one hydrochloride (65 mg, 89% yield). MS ESI (pos.) m/e: 361.1 (M+H).
Reaction SMILES: CS(C)=O.[H-].[Na+].[Br-].[C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:10])=[O:9].[C:35]([C:43]1[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=1)(=O)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>O.O1CCCC1>[N:45]1[CH:46]=[CH:47][CH:48]=[C:43](/[C:35](/[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:15]\[CH2:14][CH2:13][CH2:12][CH2:11][C:8]([OH:10])=[O:9])[CH:44]=1
Reactant: O=C(O)CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(c1ccccc1)c1cccnc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCCC/C=C(/c1ccccc1)c1cccnc1
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 80 %

Procedure:
To dimethylsulfoxide (40 ml) was added dropwise sodium hydride (1.0 g), and the mixture was heated at 80° C. for 30 minutes. The reaction mixture was cooled to room temperature, to which was added 5-carboxypentyltriphenyl phosphonium bromide (9.5 g, 21 mmole), and the mixture was stirred for 5 minutes. To the reaction mixture was added a tetrahydrofuran solution (10 ml) of 3.7 g (0.02 mole) of 3-benzoylpyridine. The mixture was stirred for 30 minutes at room temperature, followed by addition of water (100 ml), which was subjected to extraction twice with ethylacetate (50 ml). The aqueous layers were combined and adjusted to pH 6 with 2N HCl, which was subjected to extraction with ethyl acetate. The organic layers were combined and washed with water and dried (magnesium sulfate). The solvent was then evaporated and the residue was subjected to a silica-gel chromatography using ethanol-ethyl acetate (1:5) as the eluent to yield (E)+(Z)-7-(3-pyridyl)-7-phenyl-6-heptenoic acid (A-3, I-4 in Table 10) (4.5 g 79%).
Reaction SMILES: [NH2:1][S:2]([C:5]1[C:10]([NH:11][C:12]([CH:14]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:25][C:26]3[S:30][C:29]([CH3:31])=[N:28][CH:27]=3)[C:15]2=[O:32])=O)=[CH:9][CH:8]=[CH:7][N:6]=1)(=[O:4])=[O:3].NS(C1C=C(Br)C=CC=1NC(C1C(=O)N(CC2C=CC=CC=2)C2C(C=1O)=CC=CN=2)=O)(=O)=O>>[O:3]=[S:2]1(=[O:4])[C:5]2[N:6]=[CH:7][CH:8]=[CH:9][C:10]=2[NH:11][C:12]([C:14]2[C:15](=[O:32])[N:16]([CH2:25][C:26]3[S:30][C:29]([CH3:31])=[N:28][CH:27]=3)[C:17]3[C:22]([C:23]=2[OH:24])=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:1]1
Reactant: Cc1ncc(CN2C(=O)C(C(=O)Nc3cccnc3S(N)(=O)=O)C(=O)c3ccccc32)s1
Agent: NS(=O)(=O)c1cc(Br)ccc1NC(=O)c1c(O)c2cccnc2n(Cc2ccccc2)c1=O
Product: Cc1ncc(Cn2c(=O)c(C3=NS(=O)(=O)c4ncccc4N3)c(O)c3ccccc32)s1

Procedure:
The title compound was prepared according to the procedure of Example 84D substituting the product of Example 103C for the product of Example 84C (0.033 g, 68%). MS (APCI) m/z 454 (M+H)+. 1H NMR (300 MHz, DMSO-d6) δ 2.56 (s, 3H), 5.74 (s, 2H), 7.48 (t, J=6.80 Hz, 1H), 7.82 (s, 1H), 7.88 (m, 4H), 8.24 (m, 2H), 8.71 (dd, J=4.41, 1.47 Hz, 1H), 14.01 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](CC#N)=[N:5][CH:6]=[CH:7][CH:8]=1>C(O)C.[Pt]=O.Cl>[CH3:3][CH2:4][NH2:5].[CH3:1][O:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccnc1CC#N
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Product: CCN
Product: COc1cccnc1
Reaction time: 24 h
Yield: 149.6 %

Procedure:
2-[(3-methoxy)pyridyl]acetonitrile (2.0 g, 13 mmol) in 25 ml ethanol was reduced at room temperature under 60 p.s.i. for 24 h using platinum oxide (0.5 g) and 5N HCl (0.2 ml) as catalyst. The organics were concentrated and then taken up in ethyl acetate and water. 1N NaOH was added to pH 12 and the amine was extracted out (2×300 ml ethyl acetate). The organics were then washed with brine and saturated sodium bicarbonate and then dried over sodium sulfate. The solution is filtered and concentrated giving 1.5 g of oily material. This is used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[F:22][C:23]1[CH:35]=[CH:34][C:26]([O:27][CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:25][CH:24]=1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][N:31]4[CH2:30][CH2:29][CH:28]([O:27][C:26]5[CH:34]=[CH:35][C:23]([F:22])=[CH:24][CH:25]=5)[CH2:33][CH2:32]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc(OC2CCNCC2)cc1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Solvent: CN(C)C=O
Solvent: CCO
Product: O[C@@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCC(Oc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 4-(4-fluoro-phenoxy)-piperidine (Table No.1, SM 5) in ethanol essentially as described above in Example 21. Purity by LC/MS=86%, [M+H]+=481 and 8%, [M+H]+=573.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].O=[C:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CC(O)=O.CCOC(C)=O>[CH2:13]([O:12][C:9]1[CH:10]=[CH:11][C:2]([NH:1][CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)=[C:3]([C:4]([O:6][CH3:7])=[O:5])[CH:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COC(=O)c1cc(OCc2ccccc2)ccc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(OCc2ccccc2)ccc1NC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 297.9 %

Procedure:
A mixture of 2 g of methyl 2-amino-5-(benzyloxy)benzoate, 3.1 g of 1,1-dimethylethyl 4-oxopiperidine-1-carboxylate and 3.29 g of NaBH(OAc)3 in 10 ml of AcOH is irradiated under a microwave field (Biotage Initiator Sixty) at 110° C. for 20 min. The same reaction is repeated with two other lots of 2 g of methyl 2-amino-5-(benzyloxy)benzoate. The three reaction media are combined. The combined product is taken up in AcOEt. The organic phase is washed with water, with a saturated NH4Cl solution and with a saturated NaHCO3 solution, dried over Na2SO4 and filtered, and the solvent is evaporated under reduced pressure. The residue is chromatographed on silica gel, elution being carried out with an AcOEt/heptane mixture, (5/95, v/v) as far as (30170, v/v), to give 10.2 g of the expected product.