Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]3)[O:10][N:9]=2)=[CH:4][C:3]=1[N+:24]([O-:26])=[O:25].[ClH:27]>C(#N)C.O1CCOCC1>[ClH:27].[NH:15]1[CH2:14][CH:13]([C:11]2[O:10][N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([N+:24]([O-:26])=[O:25])[CH:4]=3)[N:12]=2)[CH2:16]1
Reactant: Cc1ccc(-c2noc(C3CN(C(=O)OC(C)(C)C)C3)n2)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: Cc1ccc(-c2noc(C3CNC3)n2)cc1[N+](=O)[O-]

Procedure:
To stirring suspension of tert-butyl 3-(3-(4-methyl-3-nitrophenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (28) (1 g, 2.78 mmol) in acetonitrile (2 mL) was added 4 N HCl in dioxane (5 mL). The reaction was stirred at room temperature for 1 hour. The solvent was concentrated and the crude product was dried under high vacuum to yield 5-(azetidin-3-yl)-3-(4-methyl-3-nitrophenyl)-1,2,4-oxadiazole hydrochloride (29). MS m/z 261.4 (M+1)+.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:38](Br)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: BrCc1ccccc1
Agent: Cl
Product: CC(C)c1ccc(N(Cc2cnn(Cc3ccccc3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.36 g) and benzyl bromide (0.18 mL) as starting materials, 5-benzyloxy-N-[(1-benzylpyrazol-4-yl)methyl]-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.34 g) was obtained.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:34]2[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:33])[N:11]([C@H:21]2[CH2:26][CH2:25][C@H:24]([O:27][CH:28]([CH:30]3[CH2:32][O:31]3)[CH3:29])[CH2:23][CH2:22]2)[C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17].CCCC[N+](CCCC)(CCCC)CCCC.[FH:59].[FH:60].[F-]>ClC1C=CC=CC=1>[F:59][C:2]1[CH:3]=[C:4]([C:34]2[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:33])[N:11]([C@H:21]2[CH2:26][CH2:25][C@H:24]([O:27][CH:28]([CH3:29])[CH:30]([OH:31])[CH2:32][F:60])[CH2:23][CH2:22]2)[C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OC(C)C3CO3)CC2)c2ncnn12
Reactant: F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: Clc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OC(C)C(O)CF)CC2)c2ncnn12
Temperature: 120 °C
Reaction time: 24 h

Procedure:
A mixture of 3′-fluoro-4′-({4-[trans-4-(1-oxiran-2-ylethoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.15 g), tetra-n-butylammonium dihydrogentrifluoride (0.49 g) and chlorobenzene (0.5 mL) was stirred at 120° C. for 24 hr and then at room temperature for 40 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.081 g, 51%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].[CH3:10][O:11][C:12](OC)([O:17]C)[C:13](OC)=O>CO>[F:8][C:4]1[C:3]2[O:9][C:13]([C:12]([O:11][CH3:10])=[O:17])=[N:1][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)C(OC)(OC)OC
Reactant: Nc1cccc(F)c1O
Solvent: CO
Product: COC(=O)c1nc2cccc(F)c2o1
Temperature: 25 °C
Yield: 53.3 %

Procedure:
A solution of 2-amino-6-fluorophenol (14) (254 mg, 2 mmol) and methyl 2,2,2-trimethoxyacetate (15) (328 mg, 2 mmol) in 3 ml MeOH was heated in micro wave reactor at 140° C. for 1 h. After cooling down to r.t. crystals formed. Filtration followed by washing with MeOH furnished 208 mg of methyl 7-fluorobenzoxazole-2-carboxylate (16) as brown needles. Yield: 53.3%. LC-MS: calculated M=195.15; observed M=195.96.
Reaction SMILES: Br[CH2:2][C:3]([NH2:5])=[O:4].Cl.Cl.Cl.[NH2:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]2[N:16]([CH:20]([C:22]3[CH:23]=[C:24]([Cl:40])[C:25]([C:38]#[N:39])=[C:26]4[C:32]=3[O:31][CH:30]([CH3:33])[CH2:29][N:28]([CH:34]3[CH2:37][NH:36][CH2:35]3)[CH2:27]4)[CH3:21])[N:17]=[C:18]([CH3:19])[C:11]=12.C(N(CC)CC)C>CN(C)C=O>[NH2:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]2[N:16]([CH:20]([C:22]3[C:32]4[O:31][CH:30]([CH3:33])[CH2:29][N:28]([CH:34]5[CH2:37][N:36]([CH2:2][C:3]([NH2:5])=[O:4])[CH2:35]5)[CH2:27][C:26]=4[C:25]([C:38]#[N:39])=[C:24]([Cl:40])[CH:23]=3)[CH3:21])[N:17]=[C:18]([CH3:19])[C:11]=12
Reactant: Cc1nn(C(C)c2cc(Cl)c(C#N)c3c2OC(C)CN(C2CNC2)C3)c2ncnc(N)c12
Reactant: NC(=O)CBr
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nn(C(C)c2cc(Cl)c(C#N)c3c2OC(C)CN(C2CN(CC(N)=O)C2)C3)c2ncnc(N)c12
Temperature: 80 °C

Procedure:
2-Bromoacetamide (0.01 g, 0.09 mmol) was added to a mixture of 9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-4-azetidin-3-yl-7-chloro-2-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile trishydrochloride (20 mg, 0.04 mmol) and triethylamine (20 μL, 0.18 mmol) in N,N-dimethylformamide (2 mL) and then heated to 80° C. for 2 h. The reaction was allowed to cool and was purified without work up by prep HPLC on a C-18 column eluting water:acetonitrile gradient buffered pH 10 to give the title compounds as two separated diastereomers: Peak #1 (Example 50): LCMS calculated for C24H29ClN9O2 (M+H)+: m/z=510.2; found: 510.2; Peak #2 (Example 51): LCMS calculated for C24H29ClN9O2 (M+H)+: m/z=510.2; found: 510.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-])=O.[H][H]>CO.[Pd]>[NH2:9][C:3]1[CH:4]=[C:5]([OH:8])[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: [H][H]
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(O)cc1N
Yield: 95.3 %

Procedure:
7.82 g of 4-amino-3-nitrophenol in 460 ml of methanol were hydrogenated with catalytic amount of palladium on carbon (800 mg, 10% Pd/C). After hydrogen uptake was complete, the catalyst was filtered off, washed with methanol and the filtrate was concentred under reduced pressure to give 6 g of crude 3,4-diaminophenol.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:36])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=3)(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:35])[CH:14]=2)[CH:9]=1>C1COCC1.O>[Cl:35][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:7][C:6]([OH:36])=[O:5])[C:17]([CH3:18])=[C:16]2[C:19]1[CH:20]=[CH:21][C:22]([S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)(=[O:27])=[O:26])=[CH:23][CH:24]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(S(=O)(=O)c3cccc(Cl)c3)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CC(=O)O)cc2ccc(Cl)cc2c1-c1ccc(S(=O)(=O)c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Lithium hydroxide monohydrate (0.007 g, 0.16 mmol) was added to a stirred solution of {6-chloro-4-[4-(3-chloro-benzenesulfonyl)-phenyl]-3-methyl-naphthalen-2-yl acetic acid methyl ester (0.020 g, 0.04 mmol) in a 3:1 THF—H2O mixture (4 mL). The reaction mixture was stirred for 16 hours at room temperature. The THF was distilled off under reduced pressure, and the crude residue was diluted with water, acidified [pH˜2] via the drop-wise addition of an aqueous solution of hydrochloric acid (6.0 N). The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Trituration with hexanes afforded {6-chloro-4-[4-(3-chloro-benzenesulfonyl)-phenyl]-3-methyl-naphthalen-2-yl acetic acid (0.018 g, 93%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.48 (br. s, 1 H) 8.20 (d, J=7.82 Hz, 2 H) 8.14 (s, 1 H) 8.06 (d, J=6.85 Hz, 1 H) 7.97 (d, J=8.80 Hz, 1 H) 7.91 (s, 1 H) 7.85 (d, J=8.20 Hz, 1 H) 7.73 (t, J=7.80 Hz, 1 H) 7.55 (d, J=7.83 Hz, 2 H) 7.48 (d, J=8.80 Hz, 1 H) 6.95 (s, 1 H) 3.84 (s, 2 H) 2.02 (s, 3 H) MS calcd. for C25H17Cl2O4S [(M−H)−] 483, obsd. 482.3.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[NH:9][CH2:8][CH2:7]2)=[N+:2]=[N-:3].O=[C:16]([CH2:23][CH2:24][CH3:25])[CH2:17][C:18]([O:20]CC)=[O:19].[O-]CC.[Na+]>C(O)C>[O:14]=[C:10]1[C:11]2[C:6](=[CH:5][C:4]([N:1]3[C:16]([CH2:23][CH2:24][CH3:25])=[C:17]([C:18]([OH:20])=[O:19])[N:3]=[N:2]3)=[CH:13][CH:12]=2)[CH2:7][CH2:8][NH:9]1
Reactant: CCCC(=O)CC(=O)OCC
Reactant: [N-]=[N+]=Nc1ccc2c(c1)CCNC2=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCc1c(C(=O)O)nnn1-c1ccc2c(c1)CCNC2=O
Reaction time: 3 h
Yield: 57 %

Procedure:
To a solution of 6-azido-3,4-dihydroisoquinolin-1(2H)-one (0.24 g) obtained in Example 132b) and ethyl 3-keto-n-hexanoate (0.25 ml) in ethanol (7 ml) was added 28% sodium ethoxide in ethanol solution (0.60 ml) at room temperature, and the mixture was stirred for 3 hr. The solvent was evaporated under reduced pressure, and water was added to the obtained residue. The mixture was washed with ethyl acetate, 1N hydrochloric acid was added to acidify the aqueous solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a yellow solid (0.22 g, 57%).
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].[Cl:5][C:6]1[C:15]([N+:16]([O-:18])=[O:17])=[C:14](Cl)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1.C(N(CC)CC)C>ClCCl>[Cl:5][C:6]1[C:15]([N+:16]([O-:18])=[O:17])=[C:14]([NH:4][CH2:1][C:2]#[CH:3])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: C#CCN
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
Propargylamine (25 mL, 0.36 mol) was added dropwise over a period of five minutes to a 4.5° C. solution of 2,4-dichloro-3-nitroquinoline (84.4 g, 0.347 mol) and triethylamine (73 mL, 0.52 mol) in dichloromethane (1.2 L). After one hour, the solution was allowed to warm to room temperature. After several days, the solvent was evaporated under reduced pressure and the resulting solid was triturated with water and isolated by filtration. The solid was rinsed with water and toluene (500 mL), then was dissolved in dichloromethane and toluene and concentrated under reduced pressure to remove residual water. The solid was dissolved in methanol and ether and concentrated under reduced pressure to afford 2-chloro-3-nitro-N-prop-2-ynylquinolin-4-amine as yellow-brown solid (79.5 g) that contained some impurities and was used without further manipulation.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH3:12].[OH2:13]>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:7][C:6]1[C:5]([C:2]2[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=2[O:11][CH3:12])=[C:4]([CH3:3])[O:13][N:8]=1
Reactant: COc1ccc([N+](=O)[O-])cc1I
Reactant: O
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: COc1ccc([N+](=O)[O-])cc1-c1c(C)noc1C
Temperature: 80 °C

Procedure:
To a solution of 2-iodo-1-(methoxy)-4-nitrobenzene (2 g, 7.17 mmol, 1 eq.) and (3,5-dimethylisoxazole)boronic acid (3.03 g, 21.5 mmol, 3 eq.) in DME (44 ml) and water (7 ml) were added tetrakis(triphenylphosphine) palladium(0) (0.415 g, 0.05 eq.) and Ba(OH)2.8H2O (4.52 g, 14.33 mmol, 2 eq.). The mixture was heated at 80° C. for 16 h. To complete the reaction (3,5-dimethylisoxazole)boronic acid (1 eq.) was added and the mixture was heated for 4 h. The cooled mixture was filtered and extracted with DCM. The organic phase was washed with saturated aqueous Sodium hydrogen carbonate and water, dried over Na2SO4 and filtered. Evaporation of the solvent in vacuo gave a crude oil which was precipitated with iPr2O to afford the title compound as a rust solid (1.735 g, 97%). GC/MS m/z: 248
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[C:5](=[O:10])[CH:6]=[C:7]([CH3:9])[N:8]=1)[CH3:2].[H][H]>O1CCOCC1.[Pd]>[CH2:1]([C:3]1[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=2)[C:5](=[O:10])[CH:6]=[C:7]([CH3:9])[N:8]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCc1nc(C)cc(=O)n1CCOc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: C1COCCO1
Product: CCc1nc(C)cc(=O)n1CCOc1ccc(N)cc1
Yield: 69.3 %

Procedure:
A solution of 4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]nitrobenzene (1.0 g. 3.3 mmol) (obtained from preparation 20) in 1.4-dioxane (20 ml) was reduced with hydrogen in the presence of 10% palladium on charcoal (100 mg) at 30 psi for 16 h. The mixture was filtered through a bed of celite and washed with dioxane and evaporated to dryness under reduced pressure to yield the title compound (625 mg, 70%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Cl[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1.[OH-].[K+]>CS(C)=O>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: CC(C)c1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)c1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 90 °C
Reaction time: 48 h
Yield: 114.7 %

Procedure:
A mixture of 4-isopropylphenol (16.3 g), 4-chloronitrobenzene (15.8 g), dimethylsulfoxide (150 ml) and potassium hydroxide (5.6 g) was stirred at 90° C. for 48 hours. The reaction solution was poured into ice-water (500 ml), and extracted with ethyl acetate (250 ml), washed (3 times) with water, and d ried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to give 4-(4-isopropylphenoxy)nitrobenzene (29.6 g). Further, it was dissolved in ethanol (300 ml), and thereto was added 5 % palladium/carbon (2.9 g) and the mixture was subjected to catalytic reduction at room temperature for 18 hours. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give 4-(4-isopropylphenoxy)aniline (24.6 g).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].C(S)C.[CH3:8][N:9]([CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:25]([C:26]3[CH:31]=[CH:30][C:29]([O:32]C)=[CH:28][CH:27]=3)=[CH:24][CH:23]=[C:22]([CH3:34])[N:21]=2)=[CH:16][CH:15]=1)[CH3:10]>ClCCCl>[CH3:10][N:9]([CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:25]([C:26]3[CH:27]=[CH:28][C:29]([OH:32])=[CH:30][CH:31]=3)=[CH:24][CH:23]=[C:22]([CH3:34])[N:21]=2)=[CH:18][CH:19]=1)[CH3:8]
Reactant: COc1ccc(-c2ccc(C)nc2-c2ccc(OCCN(C)C)cc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: ClCCCl
Product: Cc1ccc(-c2ccc(O)cc2)c(-c2ccc(OCCN(C)C)cc2)n1
Reaction time: 0.25 h
Yield: 34.4 %

Procedure:
The AlCl3 (7 g, 52 mmol) was stirred in 150 mL of DCE at 0° C., ethanethiol (5.5 mL, 75 mmol) was added, and the mixture stirred for 15 min. The 2-[4-[2-(N,N-dimethylamino)ethoxy]phenyl]-3-(4-methoxyphenyl)-6-methylpyridine (2.7 g, 7.5 mmol) in 50 mL DCE was added dropwise to the reaction mixture and stirred for 2 h as it was allowed to come to rt, then quenched with 25 mL THF at 0° C., followed by 25 mL 1N HCl and worked up. The crude product was recrystallised from hot EtOAc/ pet. ether to give 0.9 g (34 % yield) of white solid: mp 155°-157° C.; 1H NMR (CDCl3) d 2.37 (s, 6H, NCH3), 2.62 (s, 3H, pyr-CH3), 2.78-2.81 (t, 2H, J=5 Hz, CH2N), 4.05-4.07 (t, 2H, J=5 Hz, OCH2), 6.64-6.69 (m, 4H, ArH), 6.94-6.96 (d, 2H, J=8 Hz, ArH), 7.09-7.12 (d, 1H, J=8 Hz, ArH), 7.24-7.27 (comp, 2H, ArH), 7.52-7.55 (d, 1H, J=8 Hz, ArH); MS(FD) 348 (M+). Anal. Calcd for C22H24 N2O2 : C, 75.84; H, 6.94; N, 8.04. Found: C, 75.70; H, 6.98; N, 8.00.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:26](O)=[O:27])[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36](=[N:38]O)[NH2:37]>>[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]1[N:38]=[C:26]([CH:12]2[CH2:13][CH:14]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:20][CH:21]=3)[CH2:15][N:10]([C:8]([N:5]3[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]3)=[O:9])[CH2:11]2)[O:27][N:37]=1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Reactant: NC(=NO)c1ccccc1F
Product: O=C(N1CCC(O)CC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3ccccc3F)no2)C1

Procedure:
100 mg (0.250 mmol) of 1-[(4-hydroxypiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 99A) and 42.3 mg (0.275 mmol) of 2-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 55.6 mg (42% of theory).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:26][N:27](C)[C:28](=O)OC(C)(C)C)=[CH:4][N:5]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[C:6]=1[C:7]1[C:8]([C:13]([F:16])([F:15])[F:14])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.[ClH:42]>C(O)C>[ClH:42].[F:1][C:2]1[C:3]([CH2:26][NH:27][CH3:28])=[CH:4][N:5]([S:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)(=[O:18])=[O:19])[C:6]=1[C:7]1[C:8]([C:13]([F:15])([F:14])[F:16])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2ccccc2)c(-c2cccnc2C(F)(F)F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNCc1cn(S(=O)(=O)c2ccccc2)c(-c2cccnc2C(F)(F)F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
To a solution of tert-butyl ({4-fluoro-1-(phenylsulfonyl)-5-[2-(trifluoromethyl)pyridin-3-yl]-1H-pyrrol-3-yl}methyl)methylcarbamate (389 mg) in ethanol (4 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (4 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as a white solid (yield 188 mg, 55%).
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]#[C:10][CH2:11][OH:12])[CH2:5][CH2:4]1.[Br:13][C:14]1[CH:15]=[CH:16][C:17](F)=[N:18][CH:19]=1.C(N(C(C)C)C(C)C)C.[Na+].[I-]>CN(C=O)C>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([N:2]([CH3:1])[C@H:3]2[CH2:4][CH2:5][C@H:6]([C:9]#[C:10][CH2:11][OH:12])[CH2:7][CH2:8]2)=[N:18][CH:19]=1
Reactant: CN[C@H]1CC[C@H](C#CCO)CC1
Reactant: Fc1ccc(Br)cn1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ccc(Br)cn1)[C@H]1CC[C@H](C#CCO)CC1
Temperature: 120 °C

Procedure:
A mixture of 0.67 g (4 mmol) trans-3-(4-Methylamino-cyclohexyl)-prop-2-yn-1-ol, 1.24 ml (12 mmol) of 5-bromo-2-fluoropyridine and 1.76 ml (13.6 mmol) N-ethyldiisopropylamine was heated for 3 h at 80° C. and 24 h at 120° C. The mixture was diluted with 1 ml DMF, treated with a catalytic amount of NaI and heated for 2 days at 120° C. The reaction was cooled, evaporated and partitioned between aqueous saturated NaHCO3/Et2O (3×). The organic phases were washed with aqueous 10% NaCl, dried (NaSO4) and evaporated. Flash chromatography on silica gel (MeCl2/Et2O 97.5:2.5 to 92.5:7.5) gave 0.57 g (44%) of trans-3-{4-[(5-Bromo-pyridin-2-yl)-methyl-amino]-cyclohexyl}-prop-2-yn-1-ol, MS: 323 (MH+, 1Br).
Reaction SMILES: [C:1]1(=O)O[CH2:4][CH2:3][CH2:2]1.[Cl-].[NH4+].[NH2:9][CH2:10][C:11]([CH2:15][NH2:16])([CH2:13][NH2:14])[CH3:12]>O>[NH2:9][CH2:10][C:11]1([CH3:12])[CH2:15][N:16]2[CH2:4][CH2:3][CH2:2][C:1]2=[N:14][CH2:13]1
Reactant: O=C1CCCO1
Reactant: CC(CN)(CN)CN
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: CC1(CN)CN=C2CCCN2C1
Temperature: 250 °C
Reaction time: 1.5 h

Procedure:
A mixture of 21.03 g (0.24 mol) of γ-butyrolactone and 1.31 g (24 mmol) of ammonium chloride in 114.5 g (0.98 mol) of 1,1,1-tris(aminomethyl)ethane was heated at 250° C. in an autoclave. After 1.5 h, the mixture was cooled and the excess amine and the water formed were removed by distillation. The residue was distilled at 200°-240° C./18 mbar. The yield was 22.0 g (54%) of yellowish oil. The boiling point was 117°-120° C./1 mbar. Other data concerning the product was:
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2Br)=[N:8][N:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C.Cl>C1COCC1.BrCCBr>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[B:17]([OH:22])[OH:18])=[N:8][N:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1nnnc1-c1ccccc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: BrCCBr
Product: CC(C)(C)n1nnnc1-c1ccccc1B(O)O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 47.6 %

Procedure:
To dry Mg turnings (76 mg, 3.13 mmol) in THF (1 mL) was added a solution of 1-tert-butyl-5-(2-bromophenyl)-1H-tetrazole (733 mg, 2.61 mmol) in THF (1.5 mL), 1,2-Dibromoethane (20 mL) was added and the mixture was warmed slightly with a heat gun. After 5 min, triisopropyl borate (564 mg, 3.00 mmol) was added and the mixture was stirred at room temperature for 23 h. Ice and 0.5 N HCl (7 mL) were added and the mixture was stirred for 5 min. The mixture was extracted with ether, and the combined extracts were extracted with 1N KOH (10 mL). The aqueous extracts were filtered and acidified to pH 3 with 2N HCl. The precipitate was collected by filtration to give 306 mg (48%) of product as an off-white solid, mp 112°-115° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:17][C:18]#[N:19])=[N:4][CH:5]=[C:6]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[N:9]2)[CH:7]=1.[H][H]>CO.[Ni]>[Cl:1][C:2]1[C:3]([CH2:17][CH2:18][NH2:19])=[N:4][CH:5]=[C:6]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([F:14])([F:16])[F:15])=[N:9]2)[CH:7]=1
Reactant: N#CCc1ncc(-n2ccc(C(F)(F)F)n2)cc1Cl
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: NCCc1ncc(-n2ccc(C(F)(F)F)n2)cc1Cl

Procedure:
A solution of 3-chloro-5-[3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridineacetonitrile (i.e. the product of Step B; 5.0 g, 0.017 mol) in methanol (50 mL) was shaken in a Parr hydrogenation apparatus in the presence of Raney nickel (5.0 g) and a hydrogen pressure of 50 psi (345 kPa) at room temperature for 2 h. The mixture was filtered through a pad of Celite® diatomaceous filter aid, and the filter pad was washed with dichloromethane. The filtrate was concentrated under reduced pressure to afford the title compound (2.0 g), which was used without further purification.