Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7](Br)=[CH:6][C:3]=1[C:4]#[N:5].[CH3:11][N:12](C=O)C>[C-]#N.[Zn+2].[C-]#N>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([C:11]#[N:12])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(Br)ccc1N
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc(N)c(C#N)c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Using a literature procedure described in the following literature reference which is herein incorporated by reference in its entirety for all purposes as if fully set forth herein, a dry round bottom flask was charged with 2-amino-5-bromo benzonitrile (1 equivalent) and zinc cyanide (2 equivalents), and DMF was added: J. Med. Chem. 2000, 43, 4063. Nitrogen was bubbled through the solution for 5 minutes, and Pd[P(Ph)3]4 was added in one portion. The reaction mixture was stirred at 90° C. overnight. After cooling to room temperature, saturated NaHCO3 was added, and the mixture was extracted with EtOAc. The organic extracts were collected and dried (Na2SO4). Evaporation of the solvent under reduced pressure and purification by column chromatography on silicagel (2% methanol in methylene chloride) afforded the desired 4-aminobenzene-1,3-dicarbonitrile as a white solid. GC/MS m/z: 143 (M+, 100%), Rt 14.7 minutes
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[S:10][C:11]=2[CH2:12][NH2:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:19]1[N:27]=[CH:26][N:25]=[C:24]2[C:20]=1[N:21]=[CH:22][NH:23]2.CCN(C(C)C)C(C)C>C(O)CCC>[C:1]1([C:7]2[C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[S:10][C:11]=2[CH2:12][NH:13][C:19]2[N:27]=[CH:26][N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][NH:23]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCc1sc2ccccc2c1-c1ccccc1
Reactant: Clc1ncnc2[nH]cnc12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(-c2c(CNc3ncnc4[nH]cnc34)sc3ccccc23)cc1
Temperature: 100 °C
Yield: 38.4 %

Procedure:
A mixture of C-(3-phenylbenzo[b]thiophen-2-yl)methylamine from Example 26 (230 mg, 0.961 mmol), 6-chloro-9H-purine (278 mg, 1.80 mmol) and DIPEA (0.34 mL, 1.92 mmol) in n-butanol (10 mL) was heated at 100° C. for 20 h. After cooling to RT, volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) and then sonicated in diethyl ether. Further purification by column chromatography (Si—PCC, gradient 0-5% MeOH in DCM) afforded 165 as a white solid (132 mg, 38%). LCMS: RT 4.22 min [M+H]+ 358.1. 1H NMR (DMSO, 400 MHz): δ 12.96 (1H, s), 8.40 (1H, s), 8.23 (1H, s), 8.14 (1H, s), 7.94-7.85 (1H, m), 7.63-7.54 (4H, m), 7.51-7.43 (2H, m), 7.38-7.29 (2H, m), 4.94 (2H, s)
Reaction SMILES: [C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH:20]=O>>[C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:20][C:19]3[CH:22]=[CH:23][C:24]([Cl:25])=[C:17]([Cl:16])[CH:18]=3)[CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Nc1ccccc1)N1CCNCC1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Product: O=C(Nc1ccccc1)N1CCN(Cc2ccc(Cl)c(Cl)c2)CC1

Procedure:
The title compound was prepared from piperazine-1-carboxylic acid phenylamide and 3,4-dichlorobenzaldehyde in analogy to Example 18. 1H NMR (400 MHz, CDCl3): 8.82-8.81 (m, 2H), 7.98-7.96 (m, 2H), 7.65-7.57 (m, 3H), 7.16-7.13 (m, 1H), 3.88-3.81 (m, 4H), 3.50 (s, 2H), 2.60-2.53 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](S(O)(=O)=O)=[CH:6][CH:7]=1.[C:12]1(=[O:18])CC[CH2:15][CH2:14][CH2:13]1.CC(CCO)=C>C1(C)C=CC=CC=1>[CH3:15][C:14]1[CH2:1][C:2]2([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)[O:18][CH2:12][CH:13]=1
Reactant: O=C1CCCCC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=C(C)CCO
Solvent: Cc1ccccc1
Product: CC1=CCOC2(CCCCC2)C1
Temperature: 115 °C
Yield: 80 %

Procedure:
A mixture of p-TSA (20 g, 0.105 mol) and toluene (2 L) was heated to 115° C. To this mixture were added cyclohexanone (980 g, 10 mols) and isoprenol (946 g, 11 mols) and heated further for 3-6 h. Water was removed from the reaction azeotropically. The reaction mixture was then cooled to room temperature. The organic phase was washed with a 5% Na2CO3 solution, washed with water dried and concentrated and distilled further to provideto 4-methyl-1-oxaspiro [5.5] undec-3-ene (1.32 kg) having a purity of 98% (sum of the isomers) for a total yield of 80%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[CH2:26][C:27](O)=[O:28]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:27](=[O:28])[CH2:26][C:20]2[C:19]([Cl:18])=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:25])[CH2:7]1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: O=C(O)Cc1c(Cl)cccc1Cl
Product: O=C(Cc1c(Cl)cccc1Cl)NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Yield: 11.9 %

Procedure:
Example 20 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 1 (0.055 g) and (2,6-dichlorophenyl)acetic acid (0.041 g) to give the title compound (0.011 g).
Reaction SMILES: [O:1]=[C:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:4][CH2:5]C.CON(C)C(=O)[C@@H](NC(=O)OC(C)(C)C)CC>>[O:1]=[C:2]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:12])([CH3:13])[CH3:11])[CH2:4][CH3:5]
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)c1ccccc1
Agent: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)OC
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)c1ccccc1

Procedure:
was synthesised in the same way as (91c) from (S)-tert-butyl 1-(methoxy(methyl)amino)-1-oxobutan-2-ylcarbamate (95d, 250 mg, 1.02 mmol).
Reaction SMILES: [C:1]([C:6](=[CH:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30])[C:7]([O:9]CC)=O)(=[O:5])[CH2:2][CH2:3][CH3:4].C1(OC2C=CC=CC=2)C=CC=CC=1>CCCCCC>[C:1]([C:6]1[C:7](=[O:9])[C:19]2[C:14](=[C:15]([N:20]3[C:24](=[O:25])[C:23]4=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]4[C:21]3=[O:30])[CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)C(=CNc1ccccc1N1C(=O)c2ccccc2C1=O)C(=O)OCC
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCCC(=O)c1c[nH]c2c(N3C(=O)c4ccccc4C3=O)cccc2c1=O

Procedure:
Ethyl 2-butyryl-3-(2-phthalimidophenylamino)acrylate (83 g, 0.2 mol) was added portionwise to boiling diphenyl ether and heated under reflux for 45 mins. The mixture was cooled, diluted with hexane and the 3-butyryl-8-phthalimido-4(1H)quinolone (50 g, 67.5%) filtered off, washed with hexane and dried, m.p. 318°-20° C.
Reaction SMILES: [CH:1]1([N:4]([CH:26]2[CH2:28][CH2:27]2)[C:5]([C:7]2[N:23]([CH2:24][CH3:25])[C:10]3=[N:11][C:12]([NH:19][C:20]([NH2:22])=[S:21])=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.Cl[CH2:30][C:31](=O)[C:32]([CH3:35])([CH3:34])[CH3:33]>>[C:32]([C:31]1[N:22]=[C:20]([NH:19][C:12]2[N:11]=[C:10]3[N:23]([CH2:24][CH3:25])[C:7]([C:5]([N:4]([CH:1]4[CH2:2][CH2:3]4)[CH:26]4[CH2:27][CH2:28]4)=[O:6])=[CH:8][C:9]3=[C:14]3[N:15]([CH3:18])[CH:16]=[N:17][C:13]=23)[S:21][CH:30]=1)([CH3:35])([CH3:34])[CH3:33]
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(NC(N)=S)nc21
Reactant: CC(C)(C)C(=O)CCl
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3nc(C(C)(C)C)cs3)nc21

Procedure:
Prepared from N,N-dicyclopropyl-6-ethyl-1-methyl-4-thioureido-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 2B) and 1-chloro-3,3-dimethylbutan-2-one using the same procedure as reported for 2.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=2)=[N:6][CH:7]=1.[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[C:20]#[CH:21])[CH3:17].C(N(CC)CC)C>C(OCC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]Br>[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[C:20]#[C:21][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=2)=[N:6][CH:7]=1)[CH3:17]
Reactant: C#CC(OCC)OCC
Reactant: Fc1ccc(-c2ccc(Br)cn2)cc1F
Agent: [Cu]Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(C#Cc1ccc(-c2ccc(F)c(F)c2)nc1)OCC
Reaction time: 2 h

Procedure:
A mixture of 2.00 g of crude 5-bromo-2-(3,4-difluorophenyl)pyridine (GC purity 81%), 1.12 ml of 3,3-diethoxy-1-propine, 0.138 g of tetrakis(triphenylphosphine)palladium, 0.052 g of copper(I) bromide and 36 ml of triethylamine was heated to boiling for 2 hours. After cooling the reaction mixture was diluted with 100 ml of diethyl ether, washed twice with 40 ml of water each time, dried over sodium sulphate, filtered, the filtrate was boiled briefly with active charcoal, filtered and concentrated. The crude 5-(3,3-diethoxy-1-propynyl)-2-(3,4-difluorophenyl)pyridine, (2.58 g; GC purity 72%), obtained as a brown-black oil, was used directly in the next step.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[CH:8][C:9](/[CH:13]=[CH:14]/[C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])=[CH:19][CH:18]=3)=[O:16])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1.[N:29]1[CH:34]=[CH:33][C:32]([CH:35]=[O:36])=[CH:31][CH:30]=1>>[CH3:27][N:26]([CH3:28])[CH2:25][CH2:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([C:15](=[O:16])[CH2:14][CH:13]([C:9]2[CH:8]=[C:7]3[C:12](=[CH:11][CH:10]=2)[C:4](=[N:3][O:2][CH3:1])[CH2:5][CH2:6]3)[C:35]([C:32]2[CH:33]=[CH:34][N:29]=[CH:30][CH:31]=2)=[O:36])=[CH:22][CH:21]=1
Reactant: CON=C1CCc2cc(/C=C/C(=O)c3ccc(OCCN(C)C)cc3)ccc21
Reactant: O=Cc1ccncc1
Product: CON=C1CCc2cc(C(CC(=O)c3ccc(OCCN(C)C)cc3)C(=O)c3ccncc3)ccc21

Procedure:
The title compound was prepared from the product of Step 1 and pyridine-4-carboxaldehyde using the method described in Example 1 Step 4; MS(ES+) m/e 486 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:12])[C:9]=2[Cl:11])[NH:4][C:3]1=[O:13].[CH2:20]([N:22]([CH2:36][CH3:37])[C:23](=[O:35])[NH:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1)[CH3:21]>C(Cl)Cl.CCOC(C)=O>[NH2:1][C:2]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:12])[C:9]=2[Cl:11])[N:4]([S:31]([C:28]2[CH:27]=[CH:26][C:25]([NH:24][C:23]([N:22]([CH2:36][CH3:37])[CH2:20][CH3:21])=[O:35])=[CH:30][CH:29]=2)(=[O:33])=[O:32])[C:3]1=[O:13]
Reactant: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: NC1(c2ccccc2)C(=O)Nc2ccc(Cl)c(Cl)c21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)N2C(=O)C(N)(c3ccccc3)c3c2ccc(Cl)c3Cl)cc1

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 1 from 0.4 g of 3-amino-4,5-dichloro-1,3-dihydro-3-phenylindol-2-one and 0.4 g of 4-(N',N'-diethylureido)benzenesulfonyl chloride. Chromatography on silica using a DCM/AcOEt mixture (85/15; v/v) as the eluent gives the expected product after crystallization from a DCM/iso ether mixture. m=0.46 g. M.p.=161°-163° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[N:16]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=4)[CH:14]=[C:13]([C:27]([NH2:29])=[O:28])[C:9]=3[NH:10][C:11]=2[CH:12]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[N:16]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=4)[CH:14]=[C:13]([C:27]([NH2:29])=[O:28])[C:9]=3[NH:10][C:11]=2[CH:12]=1
Reactant: NC(=O)c1cc(-c2cccc(C(F)(F)F)c2)nc2c1[nH]c1cc([N+](=O)[O-])ccc12
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1cc(-c2cccc(C(F)(F)F)c2)nc2c1[nH]c1cc(N)ccc12
Reaction time: 3 h
Yield: 42 %

Procedure:
A mixture of 7-nitro-2-(3-(trifluoromethyl)phenyl)-5H-pyrido[3,2-b]indole-4-carboxamide (200 mg, 0.500 mmol) and Pd-C (200 mg, 0.188 mmol)in MeOH (5 mL) under a H2 balloon was stirred for 3 hr. Filtration followed by preparative HPLC (100×30 mm Luna C18 column, Solvent A=10% Methanol, 90% H2O, 0.1% TFA; Solvent B=90% Methanol, 10% H2O, 0.1% TFA, 10-60% B at 42 mL/min over 20 min) and SCX capture and release with 2 N NH3 in MeOH afforded 7-amino-2-(3-(trifluoromethyl)phenyl)-5H-pyrido[3,2-b]indole-4-carboxamide (80 mg, 0.21 mmol, 41% yield). MS (ESI) m/z 371.09 (M+H). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.16 (1H, d, J=4.58 Hz), 8.58 (2H, br. s.), 8.51 (1H, br. s.), 8.25-8.37 (1H, m), 7.86-7.99 (1H, m), 7.75 (3H, d, J=6.10 Hz), 6.82 (1H, d, J=3.36 Hz), 6.48-6.67 (1H, m), 5.61 (2H, br. s.).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=12.[CH3:10][C:11]([CH3:31])([O:13][C:14]([NH:16][C@H:17]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=1)[CH2:18][C:19](O)=[O:20])=[O:15])[CH3:12].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>ClCCl>[CH3:12][C:11]([CH3:31])([O:13][C:14]([NH:16][C@H:17]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=1)[CH2:18][C:19]([N:7]1[CH2:8][CH2:9][N:4]2[CH:3]=[CH:2][N:1]=[C:5]2[CH2:6]1)=[O:20])=[O:15])[CH3:10]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc(F)c(F)c1
Reactant: c1cn2c(n1)CNCC2
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2ccnc2C1)Cc1ccc(F)c(F)c1
Yield: 70.3 %

Procedure:
The title compound was prepared from 5,6,7,8-tetrahydroimidazo[1,2-α]pyrazine (31.3 mg, 0.254 mmol, from Step B), (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(3,4-difluorophenyl)butanoic acid (80 mg, mmol), DIPEA (32.8 mg, 0.254 mmol), HOBT (41.2 mg, 0.305 mmol) and EDC (73 mg, 0.381 mmol) in 5 mL of dichloromethane, using a procedure analogous to that described in Example 1, Step C. Purification by HPLC (Gilson; YMC-Pack Pro C18 column, 100×20 mm I.D.; solvent gradient system from 10% acetonitrile, 90% water, and 0.1% trifluoroacetic acid to 90% acetonitrile, 10% water, and 0.1% trifluoroacetic acid) gave 75 mg of the title compound as a viscous oil. 1H NMR (500 Mz, CDCl3) δ 1.38 (s, 9H), 2.05 (bs, 1H), 2.62 (m, 2H), 2.89 (m, 2H) 3.81–4.04 (m, 5H), 4.64–4.88 (m, 2H). 5.38 (m, 1H) 6.88 (m, 2H), 7.0 5(m, 3H). ESI-MS 421 (M+1).
Reaction SMILES: [CH2:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[C:5]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:2]=C.ClCCl.[BH4-].[Na+].C[OH:28]>>[C:16]1([C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=3)=[N:7][NH:8][C:4]=2[CH2:1][CH2:2][OH:28])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CO
Reactant: C=CCc1[nH]nc(-c2ccc(C)cc2)c1-c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(-c2n[nH]c(CCO)c2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Allyl-4-phenyl-3-p-tolyl-1H-pyrazole (1.0 g, 3.64 mmol) was dissolved in methanol (40 mL) and dichloromethane (10 mL) and cooled to −78° C. on a dry-ice/acetone bath. Ozone was bubbled through the solution for h, until the solution appeared light blue. To the reaction was added sodium borohydride (0.138 g, 3.64 mmol) and the reaction was removed from the dry-ice bath and stirred at room temperature for 1 h. Excess solvent was removed under reduced pressure and the reaction was extracted with EtOAc/H2O, dried over MgSO4, and purified by column chromatography to give the title compound as white solid (0.54 g). LCMS m/z=279.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.25 (s, 3H), 2.71 (t, J=7.33 Hz, 2H), 3.57 (t, J=7.33 Hz, 2H), 4.65 (bs, 1H), 7.03-7.09 (m, 2H), 7.16-7.23 (m, 3H), 7.24-7.31 (m, 2H), 7.32-7.40 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.FC1C=CC(C(C2C=CC(C(F)(F)F)=CC=2)O)=CC=1>>[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]([C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=2)[OH:15])=[CH:12][CH:11]=1
Reactant: Fc1ccc(Br)cc1
Reactant: O=Cc1ccc(Cl)cc1
Agent: OC(c1ccc(F)cc1)c1ccc(C(F)(F)F)cc1
Product: OC(c1ccc(F)cc1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared starting from 6.00 g (34.29 mmol) of 4-bromofluorobenzene and 5.78 g (41.14 mmol) of 4-chlorobenzaldehyde in analogy to the synthesis of the compound from Example 80A. 7.14 g (88% of theory) of the title compound were obtained.
Reaction SMILES: N#N.[O:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[N:9]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]#[C:19][Si](C)(C)C)=[CH:17][C:12]=2[N:11]=[N:10]1.C([O-])([O-])=O.[K+].[K+]>CO>[C:18]([C:16]1[CH:15]=[CH:14][C:13]2[N:9]([CH:4]3[CH2:5][CH2:6][CH2:7][CH2:8][O:3]3)[N:10]=[N:11][C:12]=2[CH:17]=1)#[CH:19]
Reactant: C[Si](C)(C)C#Cc1ccc2c(c1)nnn2C1CCCCO1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc2c(c1)nnn2C1CCCCO1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A 100-mL round-bottom flask equipped with a magnetic stir bar, a rubber septum and N2 inlet was charged with a solution of 1-(tetrahydro-2H-pyran-2-yl)-5-((trimethylsilyl)ethynyl)-1H-benzo[d][1,2,3]triazole (3.5 g, 11.7 mmol) in MeOH (59 mL). To this solution, solid K2CO3 (0.16 g, 1.17 mmol) was added in one portion. The resulting mixture was stirred at room temperature for 5 h. Reaction was monitored by TLC. Upon completion, the reaction mixture was filtered and concentrated to give the crude material. This crude product was purified on a silica gel column eluted with 5% ethyl acetate in hexanes affording the title compound as a pale yellow solid (2.6 g). LCMS: 144 [(M-THP+H)+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[NH:7][C:6](=[O:8])[NH:5][C:4]=1[C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2([OH:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CC(O)C.O.C(O)C>[ClH:18].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2([OH:31])[CH2:26][CH2:27][N:28]([CH2:2][C:3]3[NH:7][C:6](=[O:8])[NH:5][C:4]=3[C:9](=[O:17])[C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[CH2:29][CH2:30]2)=[CH:21][CH:20]=1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Reactant: O=C(c1ccc(F)cc1)c1[nH]c(=O)[nH]c1CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Solvent: CCO
Product: O=C(c1ccc(F)cc1)c1[nH]c(=O)[nH]c1CN1CCC(O)(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4.3 g (14.2 mmole) of 5-(bromomethyl)-1,3-dihydro-4-(4-fluorobenzoyl)-2H-imidazol-2-one, 3.0 g (14.2 mmole) of 4-(4-chlorophenyl)-4-hydroxypiperidine, 2.0 g (14.2 mmole) of potassium carbonate and 75 ml of ethanol is stirred under argon for 16 hours at 25° C. Water (100 ml) is added and the precipitate which forms is collected and washed with water. It is then suspended in 2-propanol and 1 equivalent of hydrogen chloride in 2-propanol is added. The resulting solid is separated and recrystallized twice from a mixture of 2-propanol and water to give 4-[[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]methyl]-5-(4-fluorobenzoyl)-1,3-dihydro-2H-imidazol-2-one hydrochloride melting at about 235°-236° C. with decomposition.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:13][N:14]1[C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][CH:16]=[N:15]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>CO.O>[CH3:13][N:14]1[C:18]([C:2]2[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:3]=2[NH2:4])=[CH:17][CH:16]=[N:15]1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: Nc1ccc(C(F)(F)F)cc1Br
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: Cn1nccc1-c1cc(C(F)(F)F)ccc1N
Yield: 13.4 %

Procedure:
A round-bottom flask was charged with 2-bromo-4-(trifluoromethyl)aniline (4.115 g, 17.14 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4.64 g, 22.29 mmol), potassium phosphate (10.92 g, 51.4 mmol), and Pd(AmPhos)2Cl2 (0.607 g, 0.857 mmol). Dioxane (30 mL) and water (10 mL) were added to give a thick suspension. The flask was fitted with a reflux condenser and placed in a 90° C. oil bath for 4 h. The mixture was removed from the heat, then diluted with water and extracted with EtOAc (3×). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The residue was partially purified twice by chromatography on silica gel, first with 25 to 75% EtOAc/Heptane, then with 20 to 70% EtOAc/Heptane. The partially purified material thus obtained was dissolved in methanol and loaded onto a 10 g SCX-2 ion exchange column. The column was eluted with methanol, then with 2N ammonia in methanol. The basic fractions were combined and concentrated to give 2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)aniline (0.5526 g, 2.291 mmol, 13.36% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ=7.52 (d, J=1.9 Hz, 1 H), 7.43 (ddd, J=0.5, 2.3, 8.6 Hz, 1 H), 7.26 (d, J=1.9 Hz, 1 H), 6.88 (d, J=8.5 Hz, 1 H), 6.32 (d, J=1.9 Hz, 1 H), 5.62 (s, 2 H), 3.64 (s, 3 H). m/z (ESI) 242.2 (M+H)+.
Reaction SMILES: C1(C[N:5]([C:15]2[C:16]([S:34][CH3:35])=[N:17][N:18]3[C:23]([C:24]4[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=4[O:32][CH3:33])=[CH:22][CH:21]=[CH:20][C:19]=23)[CH2:6][C:7]2[C:8]([O:13]C)=[N:9][CH:10]=[CH:11][CH:12]=2)CC1.Cl.C(O[CH2:41][CH3:42])(=O)C.C(=O)([O-])O.[Na+].[C:48](OCC)(=O)[CH3:49]>C(O)C>[CH:41]1([CH2:42][CH:6]([NH:5][C:15]2[C:16]([S:34][CH3:35])=[N:17][N:18]3[C:23]([C:24]4[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=4[O:32][CH3:33])=[CH:22][CH:21]=[CH:20][C:19]=23)[C:7]2[C:8]([OH:13])=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:49][CH2:48]1
Reactant: CCOC(C)=O
Reactant: COc1cc(C)cc(C)c1-c1cccc2c(N(Cc3cccnc3OC)CC3CC3)c(SC)nn12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1cc(C)cc(C)c1-c1cccc2c(NC(CC3CC3)c3cccnc3O)c(SC)nn12

Procedure:
After dissolving N-cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-[(2-methoxy-3-pyridyl)methyl]amine (63 mg) in ethanol (1 mL), a 4 N hydrochloric acid/ethyl acetate solution (1 mL) was added at room temperature and the mixture was heated to reflux for 3 hours. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture for neutralization while cooling on ice, and extraction was performed with ethyl acetate. The obtained organic layer was washed with water and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (49 mg) as white crystals.
Reaction SMILES: Cl.C1C2C(COC([N:19]3[CH2:24][C@@H:23]([C:25](=[O:44])[N:26]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([O:38][CH2:39][CH2:40][CH2:41][O:42][CH3:43])[CH:32]=4)[CH:27]4[CH2:29][CH2:28]4)[CH2:22][C@@H:21]([NH2:45])[CH2:20]3)=O)C3C(=CC=CC=3)C=2C=CC=1.[CH:46]1([C:50](Cl)=[O:51])[CH2:49][CH2:48][CH2:47]1>CC#N>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][N:26]([CH:27]2[CH2:29][CH2:28]2)[C:25]([CH:23]2[CH2:22][CH:21]([NH:45][C:50]([CH:46]3[CH2:49][CH2:48][CH2:47]3)=[O:51])[CH2:20][NH:19][CH2:24]2)=[O:44])=[CH:32][C:33]=1[O:38][CH2:39][CH2:40][CH2:41][O:42][CH3:43]
Reactant: COCCCOc1cc(CN(C(=O)[C@H]2C[C@@H](N)CN(C(=O)OCC3c4ccccc4-c4ccccc43)C2)C2CC2)ccc1Cl
Reactant: O=C(Cl)C1CCC1
Agent: Cl
Solvent: CC#N
Product: COCCCOc1cc(CN(C(=O)C2CNCC(NC(=O)C3CCC3)C2)C2CC2)ccc1Cl

Procedure:
The title compound is prepared analogously as described in Example 61 using (3R*,5S*)-3-amino-5-{[4-chloro-3-(3-methoxy-propoxy)-benzyl]-cyclopropyl-carbamoyl}piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester, hydrochloride (Example 92A.) and cyclobutanecarbonyl chloride. MS: 478.4 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 4.97 min.