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][C:15](=[O:17])[CH2:14]3)[O:10][N:9]=2)=[CH:4][C:3]=1[NH:18][C:19]([C:21]1[N:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]2=[N:23][CH:22]=1)=[O:20].[F:30][C:31]([Si](C)(C)C)([F:33])[F:32].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:17][C:15]1([C:31]([F:33])([F:32])[F:30])[CH2:16][CH:13]([C:11]2[O:10][N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([NH:18][C:19]([C:21]4[N:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]5=[N:23][CH:22]=4)=[O:20])[CH:4]=3)[N:12]=2)[CH2:14]1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: Cc1ccc(-c2noc(C3CC(=O)C3)n2)cc1NC(=O)c1cnc2ccccn12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ccc(-c2noc(C3CC(O)(C(F)(F)F)C3)n2)cc1NC(=O)c1cnc2ccccn12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirring solution of N-(2-methyl-5-(5-(3-oxocyclobutyl)-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-a]pyridine-3-carboxamide (10) (150 mg, 0.387 mmol) in ahydrous THF (2.5 mL) at 0° C. was added trifluoromethyltrimethylsilane (121 μL, 0.774 mmol) and TBAF (100 μL in THF and 5% water). The reaction was stirred to room temperature for 3 hours. Then TBAF (0.5 mL in THF and 5% water) was added and the reaction was stirred for 1 hour. The solvent was concentrated and the crude product was dissolved in ethyl acetate. The organic phase was washed with a water, brine and dried over anhydrous sodium sulfate. The crude product was purified by silica chromatography to yield N-(5-(5-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (F25). 1H NMR (400 MHz, d6-DMSO) δ 10.04 (s, 1H), 9.47-9.45 (m, 1H), 8.60 (s, 1H), 8.09 (d, J=1.6 Hz, 1H), 7.83 (dd, J=2.0, 8.0 Hz, 1H), 7.80-7.78 (m, 1H), 7.55-7.50 (m, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.20-7.16 (m, 1H), 6.92 (s, 1H), 3.32-3.28 (m, 1H), 2.99-2.93 (m, 2H), 2.68-2.60 (m, 2H), 2.37 (s, 3H). MS m/z 458.41 (M+1)+.
Reaction SMILES: [F:1][CH:2]([F:10])[C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[Br:11]N1C(=O)CCC1=O.O>C(#N)C>[Br:11][C:7]1[C:6]([NH2:9])=[CH:5][CH:4]=[C:3]([CH:2]([F:10])[F:1])[N:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc(C(F)F)nc1
Solvent: O
Solvent: CC#N
Product: Nc1ccc(C(F)F)nc1Br
Yield: 77.9 %

Procedure:
A solution of the compound obtained in Step D (2.1 g) and N-bromo-succinimide (2.56 g) in acetonitrile (50 ml) was stirred at 0° C. for 10 minutes. The reaction mixture was poured into water and extracted several times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and then concentrated in vacuo. Chromatography on silica gel (eluent: hexane/ethyl acetate 1:1) afforded 2-bromo-6-difluoromethyl-pyridin-3-yl-amine (2.5 g) as a solid. MS (ES+) 223/225 (MH+); 1H NMR (400 MHz, CDCl3) 4.38 (br s, 2H), 6.52 (t, 1H), 7.08 (d, 1H), 7.41 (d, 1H).
Reaction SMILES: [CH3:1][N:2]([C:7](=[S:10])[NH:8][CH3:9])[C:3](=O)[O:4]C.C([O-])(=O)C.[Na+].[F:16][C:17]1([F:39])[O:22][C:21]2[CH:23]=[C:24]([F:37])[C:25]([NH:27][C:28](=[O:36])OC3C=CC=CC=3)=[CH:26][C:20]=2[NH:19][C:18]1=[O:38]>CN(C=O)C>[CH3:1][N:2]1[C:7](=[S:10])[N:8]([CH3:9])[C:28](=[O:36])[N:27]([C:25]2[C:24]([F:37])=[CH:23][C:21]3[O:22][C:17]([F:16])([F:39])[C:18](=[O:38])[NH:19][C:20]=3[CH:26]=2)[C:3]1=[O:4]
Reactant: CNC(=S)N(C)C(=O)OC
Reactant: O=C(Nc1cc2c(cc1F)OC(F)(F)C(=O)N2)Oc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=S)n(C)c(=O)n(-c2cc3c(cc2F)OC(F)(F)C(=O)N3)c1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
0.97 g (5.0 mmol) methyl N-methyl-N-(methylcarbamothioyl)carbamate with a purity of 83.3% was dissolved in 4.2 g DMF. 0.14 g (1.7 mmol) sodium acetate was added. The mixture was stirred at 60° C. at a pressure of 25 mbar. Via syringe a solution of 1.32 g (3.7 mmol) phenyl N-(2,2,7-trifluoro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (purity 95.7%) in 4.2 g DMF was added within 2 h. From time to time fresh DMF was added to maintain the solvent volume. After a poststirring period of 1 h, a chemical yield 73% was determined by quantitative HPLC analytics (HPLC-method A; tR=4.9 min) of the product solution.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15]C)=[O:14])=[CH:11][C:10]([C:17]#[C:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]([C:17]#[C:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:27])[F:28])=[CH:21][CH:20]=3)=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(C#Cc2ccc(OC(F)(F)F)cc2)nn1-c1ncccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc(C#Cc2ccc(OC(F)(F)F)cc2)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.02 g (2.17 mmol) of methyl 1-(3-chloropyridin-2-yl)-3-{[4-(trifluoromethoxy)phenyl]ethynyl}-1H-pyrazole-5-carboxylate were dissolved in 20 ml of ethanol, 1.31 g (3.26 mmol) of 10% strength aqueous sodium hydroxide solution were added and the mixture was stirred at RT for 2 h. The solvent was distilled off under reduced pressure, the residue was taken up in water and the mixture was extracted once with methyl tert-butyl ether. The aqueous phase was then acidified with 2N hydrochloric acid and extracted three times with methyl tert-butyl ether. The combined organic phases were dried over sodium sulphate and concentrated.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:3])[CH3:2].[I:17]N1C(=O)CCC1=O>C(O)(C(F)(F)F)=O>[C:1]([O:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[C:11]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1I
Reactant: CC(=O)O[C@@H]1CCCC[C@H]1c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)O[C@@H]1CCCC[C@H]1c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of trans-racemic-2-phenylcyclohexyl acetate (5.60 g, 25.7 mmol) under nitrogen in TFA (50 ml) at 0° C. was added N-iodosuccinimide (5.77 g, 25.7 mmol) portionwise over 5 minutes. The mixture was allowed to warm and stir at room temperature for 3 hours. The mixture was concentrated under reduced pressure. The resultant oil was chromatographed using an 80 g silica gel cartridge eluted with 0-20% ethyl acetate in hexanes over 15 column volumes. The desired product fractions were combined and concentrated under reduced pressure to provide the desired product as a yellow oil. LC-MS: calculated for C14H17IO2 344.19 observed m/e: 345.33 (M+H)+ (Rt 2.60/4 min).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([S:15]([OH:17])=[O:16])[CH:11]=2)[CH:6]=1)(=[O:3])[CH3:2].Br[CH2:19][C:20]#[CH:21].C1COCC1>O>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([S:15]([CH2:21][C:20]#[CH:19])(=[O:17])=[O:16])[CH:11]=2)[CH:6]=1)(=[O:3])[CH3:2]
Reactant: C#CCBr
Reactant: CC(=O)Nc1ccc2cc(S(=O)O)ccc2c1
Solvent: O
Solvent: C1CCOC1
Product: C#CCS(=O)(=O)c1ccc2cc(NC(C)=O)ccc2c1
Yield: 90.5 %

Procedure:
160 g (0.64 mol) of 2-acetylaminonaphthalene-6-sulfinic acid were dissolved in 1000 ml of water at pH 6 and the solution was added dropwise to a solution of 84.1 g (0.7 mol) of 3-bromoprop-1-yne and 85 ml of THF. After the addition was complete, the reaction mixture was heated at from 40° to 60° C. until the reaction had ended (check by TLC). The precipitate formed was filtered off with suction at about 10° C., washed with water and dried, leaving 166.4 g of 2-acetylamino-6-(prop-1-yn-3-ylsulfonyl)naphthalene of the formula ##STR24## having a melting point of from 230° to 238° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:9]([CH:10]=1)[N:8]=[CH:7][N:6]=[C:5]2[OH:11].Br[C:13]1[CH:14]=[C:15]([C:18](OC)=O)[NH:16][CH:17]=1.N1C=CC=C(B(O)O)C=1>CN(C=O)C.C([O-])([O-])=O.[K+].[K+].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>[N:16]1[CH:17]=[CH:13][CH:14]=[C:18]([C:2]2[CH:3]=[C:4]3[N:9]([CH:10]=2)[N:8]=[CH:7][N:6]=[C:5]3[OH:11])[CH:15]=1
Reactant: Oc1ncnn2cc(Br)cc12
Reactant: COC(=O)c1cc(Br)c[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: OB(O)c1cccnc1
Solvent: CN(C)C=O
Product: Oc1ncnn2cc(-c3cccnc3)cc12
Temperature: 120 °C
Yield: 65 %

Procedure:
A solution of 6-bromopyrrolo[2,1-f][1,2,4]triazin-4-ol (100 mg, 0.47 mmol, prepared from methyl 4-bromo-1H-pyrrole-2-carboxylate: see, generally, Kitamura, C. and Yamashita, Y. J. Chem. Soc. Perkin Trans. 1, 1997, 1443, the disclosure of which is herein incorporated by reference, using a similar procedure outlined in the PCT Appl. WO 00/71129) and pyridin-3-ylboronic acid (172 mg, 1.40 mmol) in 2 mL of DMF and 2 mL of saturated aqueous K2CO3 was degassed and then Pd(PPh3)4 (57 mg, 0.05 mmol) was added. The mixture was then heated to 120° C. for 3 h. LC-MS analysis indicated the disappearance of starting material. The mixture was cooled down and the solution was filtered. The filtrate was purified on preparative HPLC to afford the title compound (100 mg, 65%) as a TFA salt. MS(ESI+) m/z 213.2 (M+H)+.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[N:4]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][N:20]=2)[N:3]=1.[NH4+].[Cl-]>CO.C1COCC1.O.[Fe]>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([N:4]2[C:5]3=[N:6][CH:7]=[N:8][C:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[C:10]3[C:2]([I:1])=[N:3]2)=[N:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)Nc1ncnc2c1c(I)nn2-c1ccc([N+](=O)[O-])cn1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ncnc2c1c(I)nn2-c1ccc(N)cn1
Temperature: 60 °C
Reaction time: 3 h
Yield: 58.6 %

Procedure:
To a solution of tert-butyl 3-iodo-1-(5-nitropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylcarbamate (62) (4 g, 8.28 mmol) in a mixture of MeOH/THF/H2O (50 mL/50 mL/10 mL) was added Fe (2.61 g, 46.6 mmol) and NH4Cl (4.98 g, 93.1 mmol). The mixture was stirred at 60° C. under N2 for 3 h and then filtered through a Celite pad. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0 to 10% MeOH in DCM) to give tert-butyl 1-(5-aminopyridin-2-yl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylcarbamate (63) (2.2 g, 52%) as a light yellow solid. LC-MS (ESI): m/z (M+1) 454.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:25]=[C:26]([CH3:28])[CH:27]=1)[CH2:5][C:6]([NH2:24])([C:20]([F:23])([F:22])[F:21])[CH2:7][C:8]([C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[O:18]C)([CH3:10])[CH3:9].B(Br)(Br)Br.CO>C(Cl)Cl>[NH2:24][C:6]([CH2:5][C:4]1[CH:25]=[C:26]([CH3:28])[CH:27]=[C:2]([CH3:1])[CH:3]=1)([C:20]([F:23])([F:21])[F:22])[CH2:7][C:8]([C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[OH:18])([CH3:10])[CH3:9]
Reactant: COc1ccc(F)cc1C(C)(C)CC(N)(Cc1cc(C)cc(C)c1)C(F)(F)F
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(C)cc(CC(N)(CC(C)(C)c2cc(F)ccc2O)C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 31.5 %

Procedure:
To a room temperature solution of 23 mg (0.058 mmol) of 1-(3,5-dimethylbenzyl)-3-(5-fluoro-2-methoxyphenyl)-3-methyl-1-trifluoromethylbutylamine (Example 2) in 0.5 mL of CH2Cl2 was added 0.5 mL (0.5 mmol) of a 1 M solution of BBr3 in CH2Cl2. After 1 h, the reaction was cooled to 0° C. and MeOH was added. The reaction was concentrated in vacuo and partitioned between aqueous sodium bicarbonate and EtOAc. The aqueous layer was separated and extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered and concentrated to afford an oil. The crude material was purified on a short silica gel column eluting with hexanes-EtOAc (95:5) to afford 7 mg (33%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]([NH2:14])=[O:13])=[C:10]2[C:5]([CH:6]=[C:7]([CH3:15])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>CN(C)C=O>[CH3:18][N:19]([CH3:21])[CH:20]=[N:14][C:12]([C:11]1[C:2]([Cl:1])=[CH:3][CH:4]=[C:5]2[C:10]=1[N:9]=[CH:8][C:7]([CH3:15])=[CH:6]2)=[O:13]
Reactant: Cc1cnc2c(C(N)=O)c(Cl)ccc2c1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: Cc1cnc2c(C(=O)N=CN(C)C)c(Cl)ccc2c1

Procedure:
55.1 g (0.25 mole) of 7-chloro-3-methylquinoline-8-carboxamide were dissolved in 50 ml of N,N-dimethylformamide, 39.3 g (0.32 mole) of N,N-dimethylformamide dimethyl acetal were added, and the mixture was refluxed for 4 hours. After precipitation on ether, 44.0 g (64%) of colorless crystals of melting point 183°-185° C. (decomposition) were isolated (compound No. 22).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([NH2:17])=[C:15]3[C:10]([CH:11]=[C:12]([F:19])[C:13]([F:18])=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[C:20]1(=O)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]([NH:17][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[C:15]3[C:10]([CH:11]=[C:12]([F:19])[C:13]([F:18])=[CH:14]3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: Nc1c2cc(F)c(F)cc2nn1-c1ccc(Cl)cc1
Reactant: O=C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Fc1cc2nn(-c3ccc(Cl)cc3)c(NC3CCCCC3)c2cc1F

Procedure:
In analogy to the procedure described in example 1.1, a mixture of 2-(4-chloro-phenyl)-5,6-difluoro-2H-indazol-3-ylamine and cyclohexanone ([108-94-1]) was reacted with sodium triacetoxyborohydride in the presence of acetic acid in CH2Cl2 under reflux conditions for 96 h to give the title compound as light brown solid. MS: m/e=362.5 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH2:9][C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[C:15]([O:19]C)=[C:14]([CH3:21])[CH:13]=2)=[O:11])=[CH:4][CH:3]=1.B(Br)(Br)Br>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH2:9][C:10]([C:12]2[CH:13]=[C:14]([CH3:21])[C:15]([OH:19])=[C:16]([CH3:18])[CH:17]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: COc1c(C)cc(C(=O)CC(c2ccc(Br)cc2)c2ccccc2C)cc1C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccccc1C(CC(=O)c1cc(C)c(O)c(C)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 151, step 2, 3-(4-bromo-phenyl)-1-(4-methoxy-3,5-dimethyl-phenyl)-3-o-tolyl-propan-1-one was treated with BBr3 in dichloromethane to give the title compound as a light yellow solid, MS (ESI+): m/z=420.9 [M−H]−.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([O:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[C:18]([N:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]([CH:30]3[CH2:32][CH2:31]3)[CH2:22][CH2:21]2)=[O:19])=[CH:6][C:5]=1[Cl:33].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(=O)(O)[O-].[Na+]>O1CCCC1>[CH:30]1([N:23]2[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:20]([C:18]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][C:12]=3[O:11][C:7]3[CH:6]=[C:5]([Cl:33])[C:4]([CH2:3][OH:2])=[CH:9][C:8]=3[Cl:10])=[O:19])[CH2:21][CH2:22]2)[CH2:31][CH2:32]1
Reactant: COC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: O=C(c1cnccc1Oc1cc(Cl)c(CO)cc1Cl)N1CCN(C2CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 26.6 %

Procedure:
To a solution of 0.10 g (0.20 mmol) 2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoic acid methyl ester (Example 27) in 1 mL tetrahydrofuran was added 0.008 g (0.21 mmol) lithium aluminium hydride. The resulting suspension was stirred at room temperature for 2.5 hours, poured on aqueous saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated to dryness. The resulting powder was purified by silica gel chromatography using a MPLC system (10 g silica gel column, CombiFlash Companion, Isco Inc.) with a gradient of n-heptane:ethyl acetate (100:0 to 50:50) to give 0.025 g (26%) of the desired compound as a light brown oil. MS (ESI): m/z=470.103 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH3:2]>[Rh].C(O)C>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH:6]1[CH2:7][CH2:8][CH:9]([OH:12])[CH2:10][CH2:11]1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(O)cc1
Agent: [Rh]
Solvent: CCO
Product: CCOC(=O)CC1CCC(O)CC1
Yield: 99.7 %

Procedure:
Stir a mixture of (4-hydroxy-phenyl)-acetic acid ethyl ester (78.86 g), Rhodium on aluminum oxide (40%, 31.87 g) and ethanol (1 L) on a hydrogenation parr shaker at 60 psi, 60° C. for 18 hours. Remove the reaction from parr shaker. Filter the mixture through celite and concentrate the to afford 81.25 g (99%) of the title compound.
Reaction SMILES: [CH:1]([C:4]1[N:24]=[C:7]2[CH:8]=[C:9]([NH:12][C:13]([C:15]3[N:19]([CH3:20])[N:18]=[CH:17][C:16]=3[C:21](O)=[O:22])=[O:14])[CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.CCCP(=O)=O.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH:1]([C:4]1[N:24]=[C:7]2[CH:8]=[C:9]([NH:12][C:13]([C:15]3[N:19]([CH3:20])[N:18]=[CH:17][C:16]=3[C:21]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:22])=[O:14])[CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:2])[CH3:3]
Reactant: C1CCNC1
Reactant: CC(C)c1nc2cc(NC(=O)c3c(C(=O)O)cnn3C)ccn2n1
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)c1nc2cc(NC(=O)c3c(C(=O)N4CCCC4)cnn3C)ccn2n1
Temperature: 25 °C
Reaction time: 84 h
Yield: 93.5 %

Procedure:
A mixture of 5-(2-isopropyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (70 mg, 213 μmol), pyrrolidine (70.5 μl, 853 μmol), propylphosphonic anhydride (50% in ethyl acetate, 314 μl, 533 μmol) and diisopropylethylamine (112 μl, 640 μmol) in tetrahydrofurane (4 ml) is stirred for 3.5 days at 25° C. The solvent is evaporated and the residue stirred for 1 hr with sat. aqueous sodium hydrogencarbonate solution. The precipitated solid is collected by filtration, washed with water and dried affording N-(2-isopropyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(pyrrolidine-1-carbonyl)-1H-pyrazole-5-carboxamide (76 mg, 93.5%) as a white solid. Mp.: 141-3° C. MS: m/z=380.3 (M−H+).
Reaction SMILES: [CH2:1]([S:5]([C:7]1[N:11]=[CH:10][NH:9][N:8]=1)=[O:6])[CH2:2][CH2:3][CH3:4].[CH2:12]([N:15]([CH2:19][CH:20]=[CH2:21])[C:16](Cl)=[O:17])[CH:13]=[CH2:14].O1CCCC1>C(N(CC)CC)C>[CH2:12]([N:15]([CH2:19][CH:20]=[CH2:21])[C:16]([N:9]1[CH:10]=[N:11][C:7]([S:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[O:6])=[N:8]1)=[O:17])[CH:13]=[CH2:14]
Reactant: CCCCS(=O)c1nc[nH]n1
Reactant: C=CCN(CC=C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCN(CC=C)C(=O)n1cnc(S(=O)CCCC)n1
Temperature: 100 °C

Procedure:
A mixture of 5.2 g. 3-butylsulphinyl-1,2,4-triazole, 6.0 g. diallylcarbamoyl chloride, 25 ml. dry tetrahydrofuran and 7.5 ml. dry triethylamine was refluxed under anhydrous conditions for 2 hours. The reaction mixture was filtered to remove triethylamine hydrochloride and the filtrate distilled under reduced pressure to remove solvent. Finally the residue was maintained at 100°C./0.5 mm. for 30 minutes in order to remove all traces of volatile material from the product. The product, 1-diallylcarbamoyl-3-n-butylsulphinyl-1,2,4-triazole, was obtained as an oil, nD26 1.5277. Elemental analysis satisfactory.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:35])[C@H:13]([O:14][Si](C)(C)C)[C@@H:12]([O:19][Si](C)(C)C)[C@H:11]([O:24][Si](C)(C)C)[C@@H:10]([CH2:29][O:30][Si](C)(C)C)[O:9]2)=[CH:4][C:3]=1[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH2:44][CH3:45])=[C:39]([F:46])[C:38]=1[F:47].[CH3:48]S(O)(=O)=O.C(=O)(O)[O-].[Na+]>O1CCCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([O:35][CH3:48])[C@H:13]([OH:14])[C@@H:12]([OH:19])[C@H:11]([OH:24])[C@@H:10]([CH2:29][OH:30])[O:9]2)=[CH:4][C:3]=1[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH2:44][CH3:45])=[C:39]([F:46])[C:38]=1[F:47]
Reactant: CS(=O)(=O)O
Reactant: CCOc1ccc(Cc2cc([C@]3(O)O[C@H](CO[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@H](O[Si](C)(C)C)[C@H]3O[Si](C)(C)C)ccc2Cl)c(F)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)c(F)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 106.9 %

Procedure:
To a solution of (2S,3R,4S,5R,6R)-2-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenyl)methyl]phenyl]-3,4,5-tris(trimethylsilyloxy)-6-(trimethylsilyloxymethyetetrahydropyran-2-ol 23f (0.97 g, 1.3 mmol) in tetrahydrofuran (10 mL) was added a solution of methylsulfonic acid (0.05 mL, 0.65 mmol) in methanol (2 mL) at −70° C. The mixture was warmed up to room temperature and stirred for 16 hours. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate till pH becomes 6-7 and extracted with ethyl acetate (10 mL×3). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by re-crystallization from a toluene/petroleum ether mixture ((v/v)=1/1, 30 mL) at −5° C. to give the title compound 23g as a pale yellow sticky solid (0.33 g, 54%).
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:21])[C:15]=2[C:14]2[C:9]1=[C:10]([CH3:22])[CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:24]([N:26]([CH2:30][CH3:31])[CH2:27][CH2:28]Cl)[CH3:25].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C=O)C>[CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:25][CH2:24][N:26]([CH2:30][CH3:31])[CH2:27][CH3:28])[C:15]=2[C:14]2[C:9]1=[C:10]([CH3:22])[CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)CCCl
Reactant: Cc1cccc2c3c(O)cccc3n(Cc3ccccc3)c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1cccc2c1c1cccc(C)c1n2Cc1ccccc1
Yield: 32.1 %

Procedure:
9-Benzyl-8-methyl-9H-carbazol-4-ol (0.0566 g, 0.20 mmol), 2-diethylaminoethylchloride hydrochloride (0.0505 g, 0.29 mmol), potassium carbonate (0.0922 g, 0.67 mmol), sodium iodide (0.0029 g, 0.019 mmol) and DMF (1 mL) are heated at 85° C. for 4 h. After the mixture had cooled, it is partitioned between water and ether. The combined organic layers are dried over magnesium sulfate and concentrated to an oil. The oil is chromatographed on silica gel (15 mL) using methanol/dichloromethane (1/99 to 2/98 to 4/96) to give 0.0248 g (32%) of the title compound; MS (ESI+) for C26H30N2O m/z 387.2 (M+H)+; IR (drift) 2966, 1585, 1497, 1449, 1353, 1336, 1268, 1251, 1140, 1106, 1069, 791, 743, 725, 715 cm−1; 1H NMR (CDCl3) δ1.18, 2.64, 2.81, 3.20, 4.41, 5.77, 6.69, 6.91, 6.99, 7.13, 7.22-7.33, 8.28. Anal. Calcd for C26H30N2O: C, 80.79; H, 7.82; N, 7.25. Found: C, 79.00; H, 7.76; N, 7.10.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[CH:11][CH:10]([OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[CH:11][C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=CC(O)C1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC=CC(=O)C1
Yield: 61.5 %

Procedure:
3-Hydroxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (3.1 g, 17.3 mmol) was dissolved in dichloromethane (30 mL) under an argon atmosphere. Pyridinium chlorochromate (5 g, 23 mmol) was added in portions over 1 hour. The dichloromethane solution was filtered through silica gel (100 g), eluting with dichloromethane. The crude brown solid (2.84 g) was purified by MPLC (Companion) on a silica cartridge (40 g), eluting with 100% heptane followed by a gradient of ethyl acetate/heptane (0 to 60%). The product containing fractions were combined, concentrated, and dried under high vacuum for 1 hour at room temperature to provide 3-oxo-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (2.1 g, 61% yield) as a clear oil that solidified on standing at low temperature. 1H NMR (300 MHz, CDCl3/TMS): δ=6.95 (m, 1H), 6.08 (d, 1H, J=10.5 Hz), 4.15 (m, 2H), 4.02 (br s, 2H), 1.39 (s, 9H). 13C NMR (75 MHz, CDCl3/TMS): δ=193.11, 154.02, 147.17, 127.40, 80.89, 51.97, 42.69, 28.41.