Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:19]=[CH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.[Li]CCCC.[CH:32](=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[C:33]1([CH:32]([C:2]2[CH:10]=[C:9]3[C:5]([C:6]([CH:19]=[CH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:7][N:8]3[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=2)[OH:39])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=Cc1ccccc1
Reactant: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc(I)cc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc(C(O)c3ccccc3)cc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a solution of 6-iodo-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole, prepared in Example 14, step (i), (143 mg, 0.3 mmol) in THF (1 mL) cooled to −78° C. under an atmosphere of argon was added n-BuLi (0.2 mL, 0.315 mmol) dropwise. The resulting mixture was stirred at −78° C. for 30 min, then a solution of benzaldehyde (0.035 mL, 0.33 mmol) in THF (0.5 mL) was added rapidly via a cannula. After 0.5 h the reaction was quenched with saturated NH4Cl (aq) and diluted with EtOAc (10 mL) and H2O (3 mL). The phases were separated and the aqueous was extracted 2×10 mL EtOAc. The pooled EtOAc was washed with brine (5 mL), dried with Na2SO4, decanted and concentrated under reduced pressure. The crude mixture was purified by silica gel chromatography (eluting with hexane:EtOAc 4:1) to give phenyl-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-methanol (68 mg, 50% yield). Rf sm=0.72; Rf p =0.39 (7:3 hexane:EtOAc); FTIR (thin film) 3368, 2952, 2893, 1621, 1478, 1449, 1374, 1307, 1249, 1216, 1078, 960, 859, 835 cm−1. MS (ESI) [M+H]/z Calc'd 457, found 457.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+].CCCCCCC>C(OCC)(=O)C>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][N:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]1=[O:1])[CH3:15]
Reactant: Cc1ccnc(O)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1ccc(C)cc1=O
Yield: 77 %

Procedure:
As described for example 320a, 2-hydroxy-4-methyl-pyridine was reacted with ethyl bromoacetate and potassium carbonate. Extractive workup followed by chromatography (SiO2, heptane:ethyl acetate=100:0 to 40:60) afforded the title compound as a colorless liquid (yield: 77%). MS: m/e=196.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[OH:13].[Cl:14]N1C(=O)CCC1=O.P(Br)(Br)Br.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.CN(C=O)C.O>[Cl:14][C:7]1[CH:8]=[N:9][C:10]2[C:5]([C:6]=1[OH:13])=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2
Reactant: COc1ccc2nccc(O)c2c1
Reactant: O=C1CCC(=O)N1Cl
Agent: BrP(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2ncc(Cl)c(O)c2c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
3-Chloro-6-methoxy-quinolin-4-ol was prepared as described in WO 02\40474 by heating 6-methoxy-quinolin-4-ol with N-chloro-succinimide in acetic acid at 65° C. (96%) and (11 g) in dry DMF (80 mL) cooled in ice, was treated with phosphorus tribromide (15.6 g) and stirred at room temperature for 3.5 h. It was treated with iced-water, basified with sodium carbonate solution, and the solid collected and washed with water and dried in vacuo to afford a yellow solid (13.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21](=[O:32])[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.[N:33]([CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=C=O>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21](=[O:32])[NH:33][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38]
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccccc2NC(=O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO)C1
Reactant: CCOC(=O)CN=C=O
Product: CCOC(=O)CNC(=O)Nc1ccccc1C1CN(C)Cc2c(Cl)cc(Cl)cc21
Product: Cl

Procedure:
In a similar manner to example 34, 2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)phenylamine (example 3, intermediate 5) and ethyl isocyanatoacetate were reacted.
Reaction SMILES: BrC1N=C2CCCN(CCCCCCC([O-])=O)C2=NC=1Cl.[Br:22][C:23]1[N:24]=[C:25]2[CH2:33][CH2:32][C:31](=O)[N:30]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[C:26]2=[N:27][C:28]=1[Cl:29].CO>C1COCC1>[Br:22][C:23]1[N:24]=[C:25]2[CH2:33][CH2:32][CH2:31][N:30]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[C:26]2=[N:27][C:28]=1[Cl:29]
Reactant: CCOC(=O)CCCCCCN1C(=O)CCc2nc(Br)c(Cl)nc21
Agent: O=C([O-])CCCCCCN1CCCc2nc(Br)c(Cl)nc21
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)CCCCCCN1CCCc2nc(Br)c(Cl)nc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
7-(2-bromo-3-chloro-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoate A cooled (0° C.) solution of ethyl 7-(2-bromo-3-chloro-6-oxo-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoate (step 1)(1.0 g, 2.388 mmol) in THF (10 ml) under a nitrogen atmosphere was treated with borane-methyl sulfide complex over 30 mins. The resulting mixture was stirred at 0° C. for 2 h 30 minutes and stored in a fridge overnight. The mixture was cooled in an ice bath and cautiously treated with MeOH (5 ml). The yellow solution was stirred at 0° C. for 1 hour and concentrated under reduced pressure. The crude material was purified by chromatography on silica eluting with 0-100% EtOAc in iso-hexane to afford ethyl 7-(2-bromo-3-chloro-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoate
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([Cl:34])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O.C(Cl)Cl>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([Cl:34])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(Cl)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(Cl)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-chloro-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid/methylene chloride.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7]([S:19]C1C=CC=C(Cl)C=1)=[C:8]([CH3:18])[N:9]2[CH2:14][C:15]([OH:17])=[O:16])(=[O:3])[CH3:2].[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1S>>[C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7]([S:19][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[Cl:27])=[C:8]([CH3:18])[N:9]2[CH2:14][C:15]([OH:17])=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc2c1c(Sc1cccc(Cl)c1)c(C)n2CC(=O)O
Reactant: Sc1ccccc1Cl
Product: CC(=O)Nc1cccc2c1c(Sc1ccccc1Cl)c(C)n2CC(=O)O

Procedure:
The title compound was prepared by the method of Example 5 parts (iv) and using the product from Example 17 part (i) and 2-chlorothiophenol, and purified by column chromatography (33% EtOAc/hexane as eluent). The resulting product was treated as outlined in example 1 part (v) to give the title compound.
Reaction SMILES: C(OC([N:8]([CH2:21][C@@H:22]1[C@@H:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][N:24]([C:33](=[O:41])[CH2:34][CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=O)(C)(C)C.CO.[ClH:44].O1CCOCC1>>[ClH:44].[C:11]1([C@H:9]([NH:8][CH2:21][C@@H:22]2[C@@H:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:25][N:24]([C:33](=[O:41])[CH2:34][CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])[CH2:23]2)[CH3:10])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: C[C@H](c1cccc2ccccc12)N(C[C@H]1CN(C(=O)CCCCC(=O)O)C[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C[C@@H](NC[C@H]1CN(C(=O)CCCCC(=O)O)C[C@@H]1c1ccccc1)c1cccc2ccccc12

Procedure:
A 237 mg portion of 6-[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]-6-oxohexanoic acid was dissolved in 2.0 ml of 4 M hydrogen chloride/1,4-dioxane solution and 2.0 ml of methanol at room temperature and stirred for 62Hours. The reaction solution was concentrated under a reduced pressure, and the thus obtained residue was purified by a silica gel column chromatography (chloroform-methanol) and then dissolved in 2.0 ml of ethyl acetate, mixed with 1.0 ml of 4 M hydrogen chloride/ethyl acetate solution and concentrated under a reduced pressure. The residue was dissolved in ethanol and mixed with ethyl acetate, and the thus obtained precipitate was collected by filtration and dried under a reduced pressure to obtain 40 mg of 6-[(3S,4S)-3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]-6-oxohexanoic acid hydrochloride as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:10])=[CH2:9])=[CH:4][CH:3]=1.[Br-].C1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Li]CCCC.BrC1C=CC(C(=O)C)=C([Cl:46])C=1>CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:10])=[CH2:9])=[C:4]([Cl:46])[CH:3]=1
Reactant: C=C(C)c1ccc(Br)cc1
Reactant: CC(=O)c1ccc(Br)cc1Cl
Agent: [Br-]
Agent: [Li]CCCC
Agent: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Product: C=C(C)c1ccc(Br)cc1Cl
Yield: 50 %

Procedure:
The title compound was synthesized in analogy to 1-bromo-4-isopropenylbenzene (described in example S87) using triphenylphosphonium bromide (2.32 g, 6.51 mmol), nBuLi (5.09 ml, 1.6M solution in hexane, 8.14 mmol) and 1-(4-bromo-2-chlorophenyl)-ethanone (1.52 g, 6.51 mmol) in DMSO (7 ml). The residue which was isolated was purified by filtration through a short pad of silica using pentane as eluant to give 4-bromo-2-chloro-1-isopropenylbenzene (750 mg, 50%) as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ 7.51 (d, J=2.0 Hz, 1H), 7.34 (dd, J=2.0, 8.0 Hz, 1H), 7.07 (d, J=8.0 Hz, 1H), 5.24 (m, 1H), 4.96 (m, 1H), 2.07 (m, 3H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][C:16](=[O:18])[CH:15]=[C:14]([O:19]CCCNC)[C:13]=2[CH:25]=1.C(N(C(C)C)CC)(C)C.C(OC([NH:42][C:43]([N:52]1[CH:56]=[CH:55][CH:54]=N1)=[N:44]C(OC(C)(C)C)=O)=O)(C)(C)C>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][C:16](=[O:18])[CH:15]=[C:14]([O:19][CH2:54][CH2:55][CH2:56][NH:52][C:43]([NH2:42])=[NH:44])[C:13]=2[CH:25]=1
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Reactant: CNCCCOc1cc(=O)oc2ccc(Cl)cc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)NCCCOc1cc(=O)oc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-Chloro-4-(3-methylamino-propoxy)-1-benzopyran-2-one trifluoroacetic acid salt (200 mg, 0.543 mmol) is suspended in 7 mL of DCM. Diisopropylethylamine is added dropwise until pH=9 by pH paper. N,N′-Bis(tert-butoxycarbonyl)-1-H-pyrazole-1-carboxamidine (169 mg, 0.543 mmol) is added and is stirred at ambient temperature overnight. The reaction mixture is concentrated in vacuo and Et2O is added to form a white precipitate, which is filtered and is washed with Et2O. The crude material is treated with neat TFA (10 mL) for 30 min at ambient temperature. The TFA is removed under reduced pressure. Et2O is added to precipitate the product, which is filtered, is washed with Et2O, and is dried. The crude material is further purified by reversed-phase HPLC to afford the title compound as the trifluoroacetic acid salt. (108 mg, 48.6%). %). 1H NMR (DMSO-d6, 300 MHz) δ 7.86 (1H, d, J=2.5 Hz), 7.72 (1H, dd, J=2.5, 8.75 Hz), 7.64 (1H, t, J=5.5 Hz), 7.47 (1H, d, J=8.75 Hz), 7.12 (3H, br s), 6.00 (1H, s), 4.26 (2H, t, J=5.75 Hz), 3.36 (2H, m, J=6.25 Hz), 2.04 (2H, m, J=6.25 Hz); MS (ESI, Pos.) calcd for C13H14ClN3O3 m/z [M+H]=296.1, found 296.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:12][N:11]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C1C(=O)N([Cl:24])C(=O)C1>CC#N>[Cl:24][C:9]1[C:10]([C:13]([F:14])([F:15])[F:16])=[N:11][NH:12][C:8]=1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: Fc1cccc(-c2cc(C(F)(F)F)n[nH]2)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: Fc1cccc(-c2[nH]nc(C(F)(F)F)c2Cl)c1

Procedure:
Following protocol L, 5-(3-fluorophenyl)-3-trifluoromethyl-1H-pyrazole was treated with NCS in CH3CN to yield the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:9]2[NH:8][CH2:7][C@@H:6]3[CH2:12][C@@H:13]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[CH2:14][C:4]=1[C:5]=23)#[N:2].CCN(CC)CC.[C:29]1([C:35](Cl)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[C:35]([N:8]1[C:9]2[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[C:4]3[CH2:14][C@H:13]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[CH2:12][C@H:6]([C:5]=23)[CH2:7]1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCN(CCC)[C@H]1Cc2c(C#N)ccc3c2[C@H](CN3)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCN(CCC)[C@H]1Cc2c(C#N)ccc3c2[C@@H](C1)CN3C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.5 %

Procedure:
To a sol of (2aR,4R)-6-cyano-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole (1 g, 3.5 mmol) and Et3N (354 mg, 3.5 mmol) in 50 mL of methylene chloride was added a sol of triphenylmethyl chloride (trityl chloride) (0.98 g, 3.5 mmol) in 10 mL of methylene chloride dropwise at RT. The reaction mixture was stirred for 16 hr at RT. The reaction mixture was extracted with water and cold 1 N HCl. The organic sol was washed with sat'd NaHCO3 sol and with sat'd brine sol. The organic sol was dried (MgSO4) and conc to dryness in vacuo to give a residue. The residue was slurried with warm hexanes, cooled and filtered to remove insolubles. The filtrate was conc to an oil. The oil was chromatographed (silica gel, 20% EtOAc in hexanes) to provide 1.5 g of (2aR,4R)-1-trityl-6-cyano-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole.
Reaction SMILES: ClC(Cl)(Cl)C(=N)O[CH:5]([C:7]1[C:15]2[N:14]=[CH:13][N:12]([CH2:16][CH3:17])[C:11]=2[CH:10]=[C:9]([C:18]([F:21])([F:20])[F:19])[CH:8]=1)[CH3:6].[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2([CH2:45][OH:46])[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]2)=[CH:28][CH:27]=1.ClC(Cl)C.C1CCCCC1>>[CH2:16]([N:12]1[C:11]2[CH:10]=[C:9]([C:18]([F:21])([F:19])[F:20])[CH:8]=[C:7]([CH:5]([O:46][CH2:45][C:32]3([C:29]4[CH:28]=[CH:27][C:26]([F:25])=[CH:31][CH:30]=4)[CH2:33][CH2:34][N:35]([C:38]([O:40][C:41]([CH3:42])([CH3:43])[CH3:44])=[O:39])[CH2:36][CH2:37]3)[CH3:6])[C:15]=2[N:14]=[CH:13]1)[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccc(F)cc2)CC1
Reactant: CCn1cnc2c(C(C)OC(=N)C(Cl)(Cl)Cl)cc(C(F)(F)F)cc21
Solvent: CC(Cl)Cl
Solvent: C1CCCCC1
Product: CCn1cnc2c(C(C)OCC3(c4ccc(F)cc4)CCN(C(=O)OC(C)(C)C)CC3)cc(C(F)(F)F)cc21
Temperature: 0 °C

Procedure:
(±)-(1-(1-Ethyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-4-yl)ethyl 2,2,2-trichloroacetimidate (670 mg, 1.7 mmol) and tert-butyl 4-(4-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (772 mg, 2.5 mmol) were combined in a dichloroethane/cyclohexane mixture (4:2, 6 mL) and cooled to 0° C. The reaction mixture was treated with tetrafluoroboric acid-diethyl ether complex (91 μL, 0.67 mmol), and subsequent processing including extractive work up and purification were carried out as described in example 8 to give 281 mg (30.7%) as white foam-like solid. 1H-NMR (500 MHz, CHLOROFORM-D) δ ppm 7.97 (s, 1 H), 7.54 (s, 1 H), 7.20-7.33 (m, 3 H), 7.00 (t, J=8.7 Hz, 2 H), 5.10 (q, J=6.6 Hz, 1 H), 4.17-4.30 (m, 2 H), 3.56-3.78 (m, 2 H), 3.24-3.40 (m, 2 H), 2.93-3.12 (m, 2 H), 2.02-2.21 (m, 2 H), 1.80-1.99 (m, 2 H), 1.56 (t, 3 H), 1.37-1.47 (m, 12 H). 550.40 (MH)+.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([CH:17]=[C:18]([CH3:20])[CH3:19])=[C:15]([C:21]([OH:23])=O)[N:14]=[N:13]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].C1C=C[C:27]2N(O)N=[N:30][C:28]=2[CH:29]=1.C1(N)CC1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C>[CH:28]1([NH:30][C:21]([C:15]2[N:14]=[N:13][N:12]([C:9]3[CH:8]=[CH:7][C:6]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:11][CH:10]=3)[C:16]=2[CH:17]=[C:18]([CH3:20])[CH3:19])=[O:23])[CH2:29][CH2:27]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2C=C(C)C)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2C=C(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 191.3 %

Procedure:
1-{4-[(Ethylamino)carbonyl]phenyl}-5-(2-methylprop-1-en-1-yl)-1H-1,2,3-triazole-4-carboxylic acid (490 mg, 1.56 mmol) obtained in Example 95b), HOBt (106 mg, 0.779 mmol, 0.5 eq.) and cyclopropylamine (0.145 ml, 2.03 mmol, 1.3 eq.) were dissolved in acetonitrile-DMF (2:1, 8.0 ml), WSC (366 mg, 1.87 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate-hexane (5:1, 48 ml) and washed with 2% aqueous sodium carbonate solution, 10% aqueous ammonium chloride solution and saturated brine. The aqueous layers were each extracted with ethyl acetate-hexane-THF (4:1:1, 48 ml). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated, and ethyl acetate was added to the residue. The precipitate was collected by filtration, washed with ethyl acetate and diethyl ether and dried to give the title compound as a white powder (526 mg, 1.49 mmol, 95.4%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([N:7]=[C:8]=[O:9])=[N:4][CH:3]=1.C1C=CC=CC=1.[CH2:16]([NH:18][CH2:19][CH:20]=[O:21])[CH3:17]>C(O)C.O>[CH2:16]([N:18]([CH2:19][CH:20]=[O:21])[C:8]([NH:7][C:5]1[S:6][C:2]([Cl:1])=[CH:3][N:4]=1)=[O:9])[CH3:17]
Reactant: O=C=Nc1ncc(Cl)s1
Reactant: CCNCC=O
Solvent: CCO
Solvent: c1ccccc1
Solvent: O
Product: CCN(CC=O)C(=O)Nc1ncc(Cl)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Chlorothiazol-2-yl isocyanate dimer (17.0 grams), benzene (70 ml) and the dimethyl acetal of 2-ethylaminoacetaldehyde (13.5 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is then stirred at room temperature for a period of about one hour. After this time the reaction mixture is filtered, and the filtrate is stripped of solvent under reduced pressure, leaving an oil. This oil is dissolved in an ethanol-water mixture, and the solution is filtered. The filtrate is then stripped of solvents under vacuum to yield the desired product the dimethyl acetal of 2-[1-ethyl-3-(5-chlorothiazol-2-yl)ureido]acetaldehyde.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([NH2:13])=[N:8][C:9]([NH2:12])=[CH:10][CH:11]=2)[CH:3]=[N:2]1.[H-].[Na+].Cl[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:22][CH:23]=1>CN(C)C=O>[O:24]([C:21]1[N:22]=[CH:23][C:18]([CH2:17][N:1]2[CH:5]=[C:4]([C:6]3[C:7]([NH2:13])=[N:8][C:9]([NH2:12])=[CH:10][CH:11]=3)[CH:3]=[N:2]2)=[CH:19][CH:20]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: ClCc1ccc(Oc2ccccc2)nc1
Reactant: Nc1ccc(-c2cn[nH]c2)c(N)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ccc(-c2cnn(Cc3ccc(Oc4ccccc4)nc3)c2)c(N)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 25.1 %

Procedure:
To an N,N-dimethylformamide (5.00 mL) solution of 3-(1H-pyrazol-4-yl)-pyridine-2,6-diamine (30.0 mg, 0.171 mmol) described in Manufacturing Example 36-1-2 was added sodium hydride (7.52 mg, 0.188 mmol, 60% in oil) on an ice bath (0° C.) under nitrogen atmosphere, which was stirred for 10 minutes at room temperature. Thereafter, 5-chloromethyl-2-phenoxy-pyridine (59.9 mg, 0.273 mmol) described in Manufacturing Example 193-1-2 was added to the above mixture, which was stirred for 30 minutes at room temperature. The reaction mixture was partitioned into ethyl acetate and water at room temperature. The organic layer was washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound (15.4 mg, 25.2%).
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.Cl.[CH3:30][O:31][C:32](=[O:38])[C@@H:33]1[CH2:37][CH2:36][CH2:35][NH:34]1.CCN(C(C)C)C(C)C.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH3:30][O:31][C:32](=[O:38])[C@@H:33]1[CH2:37][CH2:36][CH2:35][N:34]1[C:11](=[O:13])[C:10]1[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=1[C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1CCCN1C(=O)c1ccccc1C(=O)c1ccccc1
Temperature: 10 °C
Reaction time: 12 h
Yield: 69 %

Procedure:
6.20 g (27.5 mmol) of o-benzoylbenzoic acid was dissolved in 150 ml of methylene chloride at 25° C. under a nitrogen atmosphere. The solution was cooled to 10° C. and 4.08 g (30.2 mmol) of 1-hydroxybenzotriazole hydrate was added, followed by 5.0 g (30.2 mmol) of L-proline methyl ester HCl and followed by 6.22 g (30.2 mmol) of N,N'-diisopropylethylamine. Lastly, 6.22 g (30.2 mmol) N,N'-dicyclohexylcarbodiimide (DCC) was added which produced a slight exothermic reaction and the mixture was then stirred for 12 hours, after which time tlc analysis indicated complete consumption of starting material. A standard work-up was performed which involved removing precipitated urea by filtration and washing the filtrate with 5% sodium bicarbonate solution, 1N sodium hydroxide solution, 1N hydrochloric acid and brine. The organic phase was dried over magnesium sulfate and evaporated in vacuo to afford a yellow residue. Purification by flash chromatography on silica gel (40:1/methylene chloride:methanol) gave a yield of 6.4 g (69%) of the title compound as a cloudy gum which crystallized on standing. TLC (90:10/CH2Cl2 :MeOH): Rf =0.80. mp=128-130. 1H NMR (CDCl3) δ: 7.40-7.85(m,9H); 4.25-4.55(m,1H); 3.40-3.75(m,5H); 1.85-2.40(m,4H). I.R. (KBr): 1622, 1661, 1739, 1745 cm-1. Standard Combustion Analysis: C,71.20; H,5.68; N,4.15. Found: C,70.63; H,5.53; N=4.36. High Resolution Mass Spectrum: m/e=338.1384±0.8 ppm (calculated for C20H20NO).