Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])[O:5][CH:6]=1.C([Sn](CCCC)(CCCC)[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1)CCC>>[N:28]1[CH:29]=[CH:30][C:25]([C:2]2[CH:3]=[C:4]([N:7]3[CH2:11][C@:10]4([CH:16]5[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]5)[CH2:12]4)[O:9][C:8]3=[O:19])[O:5][CH:6]=2)=[CH:26][CH:27]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Reactant: O=C1O[C@]2(CN3CCC2CC3)CN1c1cc(Br)co1
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1cc(-c2ccncc2)co1

Procedure:
The title compound was prepared by a method analogous to that described in Example 14 from (R)-3′-(4-bromofuran-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and 4-(tri-n-butylstannyl)pyridine. The title compound (21 mg) was obtained as a pale solid, m/z (MH+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:45])([CH3:44])[CH2:9][O:10][CH2:11][C:12](=[O:43])[N:13]([CH3:42])[C@@H:14]([C:26](=[O:41])[N:27]([CH3:40])[C@@H:28]([C:36](=[O:39])[NH:37][CH3:38])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[NH2:7][C:8]([CH3:45])([CH3:44])[CH2:9][O:10][CH2:11][C:12]([N:13]([C@H:14]([CH2:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)[C:26]([N:27]([CH3:40])[C@@H:28]([C:36](=[O:39])[NH:37][CH3:38])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:41])[CH3:42])=[O:43]
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1cccc2ccccc12)N(C)C(=O)COCC(C)(C)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1cccc2ccccc12)N(C)C(=O)COCC(C)(C)N
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 114.5 %

Procedure:
(1,1-Dimethyl-2-((N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(1-naphthyl)-ethyl)carbamoyl)methoxy)ethyl)carbamic acid tert-butylester (0.26 g; 0.41 mmol) was dissolved in methylene chloride (3 mL) and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred for 5 min at room temperature. Methylene chloride (5 mL), an aqueous solution of sodium hydrogen carbonate (saturated) and sodium hydrogen carbonate (solid) were added until pH 8. The aqueous phase was extrated with methylene chloride (3×15 mL) and the combined organic layers were dried (magnesium sulfate). The solvent was removed in vacuo to afford 0.25 g of the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:12]2[O:11][C:10]([CH3:14])([CH3:13])[CH2:9][C:8]=2[C:7]([C:15]2[C:16]([CH3:28])([CH3:27])[C:17](=[O:26])[N:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:19]=2)=[CH:6][CH:5]=1.[F:29][CH:30]([F:42])[O:31][C:32]1[CH:33]=[CH:34][C:35]([CH3:41])=[C:36]([CH:40]=1)[C:37](O)=[O:38]>>[F:29][CH:30]([F:42])[O:31][C:32]1[CH:33]=[CH:34][C:35]([CH3:41])=[C:36]([C:37]([N:23]2[CH2:24][CH2:25][CH:20]([N:18]3[C:17](=[O:26])[C:16]([CH3:28])([CH3:27])[C:15]([C:7]4[C:8]5[CH2:9][C:10]([CH3:14])([CH3:13])[O:11][C:12]=5[C:4]([O:3][CH3:2])=[CH:5][CH:6]=4)=[N:19]3)[CH2:21][CH2:22]2)=[O:38])[CH:40]=1
Reactant: Cc1ccc(OC(F)F)cc1C(=O)O
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)c2c1OC(C)(C)C2
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cc(OC(F)F)ccc4C)CC3)C(=O)C2(C)C)c2c1OC(C)(C)C2

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(7-methoxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-4-yl)-4,4-dimethyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one (compound B5) and 5-(difluoromethoxy)-2-methylbenzoic acid (compound F4) as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) and by crystallization from DCM and diethyl ether to yield the title compound.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[C:12]([CH:17]=[CH:18][C:19](=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:11]([CH3:26])[CH2:10]1)(C(C)(C)C)(C)C.[OH:27]C1(C)CC(O)CC(C)(C)C1C=CC(O)C>>[OH:27][C:11]1([CH3:26])[CH2:10][CH:9]([OH:8])[CH2:14][C:13]([CH3:16])([CH3:15])[CH:12]1[CH:17]=[CH:18][CH:19]([OH:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCC(=O)C=CC1=C(C)CC(O[Si](C)(C)C(C)(C)C)CC1(C)C
Reactant: CC(O)C=CC1C(C)(C)CC(O)CC1(C)O
Product: CCCCCC(O)C=CC1C(C)(C)CC(O)CC1(C)O

Procedure:
The entitled compound was prepared from 1-[4-(t-butyldimethylsilyl)oxy-2,6,6-trimethylcyclohex-1enyl]oct-1-en-3-one in the same manner as described in Example 1-(4), (5), and (6).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:11])[C:9]#[N:10].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.CCN(CC)CC.O>C(#N)C>[CH3:22][C:12]1[CH:17]=[CH:16][C:15]([S:18]([O:11][CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:9]#[N:10])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: N#CC(O)c1ccccc1Cl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)OC(C#N)c2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 93.2 %

Procedure:
2-(2-chlorophenyl)-2-hydroxyacetonitrile (16.8 g, 0.1 mol) and 4-toluene sulfonyl chloride (21 g, 0.11 mol) was dissolved in acetonitrile (80 mL) in a suitable reaction flask, and Et3N (20 g, 0.2 mol) was added to the reaction dropwise at 0-25° C. Then the solution was stirred at room temperature for 5 h and afterwards refluxed until the reaction was completed by TLC monitoring. The acetonitrile was recovered and reaction mixture was diluted by water and extracted with butyl acetate. The organic layer was washed repeatedly with water and the butyl acetate was removed under reduced pressure giving the target product (30 g, yield 93.75%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([N+:9]([O-])=O)[CH:5]=[CH:4][CH:3]=1.ClC1C=C(O)C(N)=CC=1Cl>>[Cl:1][C:2]1[C:7]([OH:8])=[C:6]([NH2:9])[CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cccc(Cl)c1O
Agent: Nc1cc(Cl)c(Cl)cc1O
Product: Nc1cccc(Cl)c1O

Procedure:
6-chloro-2-aminophenol (12B) was prepared from 12A according to the procedure described for preparing 9B in Example 9.
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:27])[CH:11]=[C:12]([CH2:15][NH:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=2)(=[O:19])=[O:18])[O:13][CH:14]=1)C1C=CC=CC=1.OC1C(=O)C=C(CNS(C2C=CC=CC=2)(=O)=O)OC=1>>[OH:8][C:9]1[C:10](=[O:27])[CH:11]=[C:12]([CH2:15][NH:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=2)(=[O:19])=[O:18])[O:13][CH:14]=1
Reactant: Cc1cccc(S(=O)(=O)NCc2cc(=O)c(OCc3ccccc3)co2)c1
Agent: O=c1cc(CNS(=O)(=O)c2ccccc2)occ1O
Product: Cc1cccc(S(=O)(=O)NCc2cc(=O)c(O)co2)c1
Yield: 81.5 %

Procedure:
N-(5-Hydroxy-4-oxo-4H-pyran-2-ylmethyl)-3-methyl-benzenesulfonamide (8-04) (15 g, crude) was synthesized as a light brown solid from N-(5-benzyloxy-4-oxo-4H-pyran-2-ylmethyl)-3-methyl-benzenesulfonamide (7-04) (24.0 g, 62.33 mmol) following the procedure described for N-(5-hydroxy-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (8-01).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH3:34][O:35][C:36]1[CH:42]=[C:41]([N:43]2[CH2:48][CH2:47][N:46]([CH2:49][CH2:50][S:51]([CH3:54])(=[O:53])=[O:52])[CH2:45][CH2:44]2)[CH:40]=[CH:39][C:37]=1[NH2:38].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:38][C:37]3[CH:39]=[CH:40][C:41]([N:43]4[CH2:48][CH2:47][N:46]([CH2:49][CH2:50][S:51]([CH3:54])(=[O:53])=[O:52])[CH2:45][CH2:44]4)=[CH:42][C:36]=3[O:35][CH3:34])[N:7]=2)[CH:18]=1
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Reactant: COc1cc(N2CCN(CCS(C)(=O)=O)CC2)ccc1N
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: COc1cc(N2CCN(CCS(C)(=O)=O)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 130 °C
Yield: 47.9 %

Procedure:
3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (100 mg, 0.21 mmol), 2-(methyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}aniline (60 mg, 0.19 mmol), and p-toluenesulfonic acid (98 mg, 0.51 mmol) were weighed into a 20 mL vial. 7 mL of iPrOH was added and the mixture was heated to 130° C. for 72 h. The mixture was transferred to a 50 mL round bottom and neutralized with 2 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (67 mg, 0.091 mmol, 46%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.23 (s, 1H), 9.39 (d, J=2.01 Hz, 1H), 8.46 (s, 1H), 8.32 (s, 1H), 8.19 (s, 1H), 8.01-8.07 (m, 1H), 7.78-7.83 (m, 1H), 7.68-7.75 (m, 1H), 7.56-7.63 (m, 1H), 7.36-7.47 (m, 3H), 7.16-7.23 (m, 2H), 6.93-7.01 (m, 1H), 6.67 (s, 1H), 6.45 (d, J=4.40 Hz, 2H), 3.79 (s, 3H), 3.31-3.36 (m, 2H), 3.10-3.18 (m, 4H), 3.03 (s, 3H), 2.71-2.78 (m, 2H), 2.53-2.61 (m, 4H). MS (ESI): 739 [M+H]+.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][N:8]1[C:12](=[O:13])[C@H:11]([OH:14])[CH2:10][C@H:9]1[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=1>CN(C=O)C.C1(=O)OC(=O)CC1>[CH3:7][N:8]1[C:12](=[O:13])[CH:11]([OH:14])[CH2:10][CH:9]1[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=1
Reactant: CN1C(=O)[C@H](O)C[C@H]1c1cccnc1
Agent: O=C1CCC(=O)O1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CN1C(=O)C(O)CC1c1cccnc1

Procedure:
Hydroxycotinine hemisuccinate was prepared as follows. In a glass tube, 19 mg of trans-3'-hydroxycotinine were dissolved in 1 ml of DMF. In this solution 21 mg of succinic anhydride were dissolved. After adding 20 μl of pyridine, the tube was covered (PARAFILM®) and incubated overnight at 37° C.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[N:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:6]=1)[CH:2]=[CH2:3].[C:23]([O:27][C:28](=[O:36])[CH2:29][O:30][CH2:31][CH2:32][CH2:33][CH2:34]Br)([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28](=[O:36])[CH2:29][O:30][CH2:31][CH2:32][CH2:33][CH2:34][N:4]([CH2:1][CH:2]=[CH2:3])[C:5]1[CH:10]=[N:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:7]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:6]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: C=CCNc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Reactant: CC(C)(C)OC(=O)COCCCCBr
Product: C=CCN(CCCCOCC(=O)OC(C)(C)C)c1cnc(-c2ccccc2)c(-c2ccccc2)n1

Procedure:
In the same manner as in Example 22, except that 2-allylamino-5,6-diphenylpyrazine was used in place of 5,6-diphenyl-2-(methylamino)pyrazine and 2-(4-bromobutyloxy)acetic acid tert-butyl ester was used in place of 2-(4-bromobutyloxy)acetic acid methyl ester, the desired compound was prepared as a pale yellow oily substance.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)([O-])=O>CCOC(C)=O.[Pd]>[O:14]1[CH2:13][CH2:12][CH:11]([NH:10][C:5]2[C:4]([NH2:1])=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:16][CH2:15]1
Reactant: O=[N+]([O-])c1ccccc1NC1CCOCC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccccc1NC1CCOCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of (2-nitrophenyl)(tetrahydropyran-4-yl)amine (1.58 g, 7.09 mmol) and 10% Pd/C (400 mg) in EtOAc (30 mL) was degassed with a stream of nitrogen and stirred at RT under a hydrogen atmosphere for 3 days. The suspension was then filtered through a pad of celite and the filtrate was concentrated in vacuo affording N-(Tetrahydropyran-4-yl)benzene-1,2-diamine as a colourless oil (quantitative). 1H NMR (CDCl3, 400 MHz): δ 6.83-6.64 (4H, m), 4.01 (2H, d, J=11.69 Hz), 3.57-3.41 (3H, m), 3.40-3.19 (3H, bs), 2.08-1.99 (2H, m), 1.59-1.46 (2H, m).
Reaction SMILES: Br[CH:2]([CH3:24])[CH2:3][CH2:4][C:5](=[O:23])[C:6]([N:9]1[C:14](=[O:15])[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([CH3:22])[O:11][CH2:10]1)([CH3:8])[CH3:7].C([O-])(=[O:27])C.[Na+].O>CN(C)C=O>[CH3:22][C:12]1[O:11][CH2:10][N:9]([C:6]([CH3:8])([C:5](=[O:23])[CH2:4][CH2:3][CH:2]([OH:27])[CH3:24])[CH3:7])[C:14](=[O:15])[C:13]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)CCC(C)Br)CO1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)CCC(C)O)CO1
Temperature: 70 °C
Yield: 25.2 %

Procedure:
A mixture of 6-bromo-2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylheptan-3-one (1.04 g), sodium acetate (0.43 g) and water (0.10 g) in N,N-dimethylformamide was heated at 70° C. for 2 hours. Water was added and the mixture extracted (dichloromethane) and the organic phase dried (magnesium sulphate) and evaporated. The residue was purified by chromatography on silica gel eluting with hexane/ethyl acetate (3:1), to give 2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methyl-3-oxo-heptan-6-ol (Compound 212, 0.22 g) as a brown gum, NMR 1.2(d,3H), 1.4(2s,6H), 1.6(m,1H), 1.9(m,2H), 1.9(s,3H), 2.5(m,1H), 2.8(m,1H), 3.8(m,1H), 5.3(m,2H), 7.3(m,5H).
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:12])(=[O:11])[N:3]=1.[Cl:13][C:14]1[C:18]([Cl:19])=[C:17]([CH2:20][OH:21])[S:16][N:15]=1.C(N(CC)CC)C.O>C(#N)C>[Cl:13][C:14]1[C:18]([Cl:19])=[C:17]([CH2:20][O:21][C:2]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[S:4](=[O:12])(=[O:11])[N:3]=2)[S:16][N:15]=1
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Reactant: OCc1snc(Cl)c1Cl
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: O=S1(=O)N=C(OCc2snc(Cl)c2Cl)c2ccccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.2 %

Procedure:
In 6 ml of acetonitrile were dissolved 0.62 g (3.10 mmol) of 3-chloro-1,2-benzoisothiazole 1,1-dioxide and 0.57 g (3.10 mmol) of the (3,4-dichloroisothiazol-5-yl)methanol. To the resulting solution was dropwise added 0.34 g (3.4 mmol) of triethylamine, followed by stirring at room temperature for 5 hours to give rise to a reaction. After the completion of the reaction, 12 ml of water was added. The resulting crystals were obtained by filtration. The crystals were washed with water and isopropyl alcohol to obtain 0.89 g (yield: 82%) of 3-(3,4-dichloroisothiazol-5-ylmethoxy)-1,2-benzoisothiazole 1,1-dioxide as a colorless powder (melting point: 165 to 167° C.).
Reaction SMILES: [CH3:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.ClS(O)(=O)=O.[CH3:16][N:17]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]1[CH2:23][C:24]([O:26][CH3:27])=[O:25].[Cl:28]([OH:32])(=[O:31])(=[O:30])=[O:29]>>[Cl:28]([OH:32])(=[O:31])(=[O:30])=[O:29].[CH3:16][N:17]1[C:21]([C:3](=[N:2][CH3:1])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[C:20]([CH3:22])[CH:19]=[C:18]1[CH2:23][C:24]([O:26][CH3:27])=[O:25]
Reactant: CN=C(Cl)c1ccccc1
Reactant: COC(=O)Cc1cc(C)cn1C
Agent: O=S(=O)(O)Cl
Agent: [O-][Cl+3]([O-])([O-])O
Product: CN=C(c1ccccc1)c1c(C)cc(CC(=O)OC)n1C

Procedure:
The title compound was prepared as in Example X from N-methyl benzimidoyl chloride (6.87 g, 44.8 mmole), chlorosulfonic acid (0.52 g, 4.5 mmole), methyl 1,4-dimethyl-1H-pyrrole-2-acetate (7.43 g, 44.5 mmole), and 70% perchloric acid (7.0 g, 49 mmole) to yield 10.4 g (61%) as a yellow solid, m.p. 145°-147° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[C:3](/[C:12](=[N:25]/[O:26][CH2:27][CH:28]2[CH2:30][CH2:29]2)/[CH2:13][N:14]2C(=O)C3=CC=CC=C3C2=O)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.O.NN.O>C(O)C>[CH:28]1([CH2:27][O:26]/[N:25]=[C:12](/[C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][N:4]=2)\[CH2:13][NH2:14])[CH2:29][CH2:30]1
Reactant: O=C1c2ccccc2C(=O)N1C/C(=N\OCC1CC1)c1ncc(C(F)(F)F)cc1Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: NC/C(=N\OCC1CC1)c1ncc(C(F)(F)F)cc1Cl
Temperature: 80 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
To 98 mg of (E)-N-[2-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-2-(cyclopropylmethoxyimino)ethyl]phthalimide in 3 ml of ethanol, 76 mg of hydrazine monohydrate was added, and the mixture was stirred at 80° C. for 1 hour. After completion of the reaction, the reaction mixture was allowed to cool to room temperature, mixed with 5 ml of water and extracted with ethyl acetate (5 ml×3). The resulting organic layers were combined, dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using methanol-chloroform (1:10) as the eluent to obtain 65 mg of the desired product as a pale yellow oil. The oil was used in the next step without further purification.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]#[C:7][C:8]#[C:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20].[OH-].[Li+].Cl>C1COCC1.O.CO.CCCCCCC>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]#[C:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20]
Reactant: O=C(O)CCCCCCC/C=C\C#CC#Cc1ccco1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCCC
Product: O=C(O)CCCCCCCCCC#CC#Cc1ccco1
Reaction time: 5 h
Yield: 68.3 %

Procedure:
To a solution of crude ester 9 (10 g) in 200 mL of THF:water:methanol (150:25:25) was added with stirring 4.2 g Lithium hydroxide (3 eq). The atmosphere was replaced with nitrogen and the mixture was stirred for 5 h and then cooled via ice-water bath. The golden-brown mixture was slowly acidified with 2N aqueous hydrochloric acid to pH2. The partially precipitated acid was extracted in two portions with 4×250 mL of ethyl acetate. The combined organic layers were washed with 2×75 mL of water and 75 mL of brine, dried over sodium sulfate, and concentrated in vacuo. The dark brown solid was partially purified by suction filtration column chromatography on silica gel (0 to 30% ethyl acetate in heptane) to give a yellow solid. This solid was resuspended in heptane and cooled in an ice bath. The mixture was filtered to yield a fine tan-yellow powder (6.88 g, 72%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][N:20]3[CH:24]=[CH:23][N:22]=[N:21]3)[O:16][C:15]2=[O:25])[CH:5]=[CH:6][C:7]=1[C:8]#[C:9][Si](C)(C)C.[OH-].[K+].Cl>CO.C(Cl)Cl.O>[C:8]([C:7]1[CH:6]=[CH:5][C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][N:20]3[CH:24]=[CH:23][N:22]=[N:21]3)[O:16][C:15]2=[O:25])=[CH:3][C:2]=1[F:1])#[CH:9]
Reactant: C[Si](C)(C)C#Cc1ccc(N2C[C@H](Cn3ccnn3)OC2=O)cc1F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: C#Cc1ccc(N2C[C@H](Cn3ccnn3)OC2=O)cc1F
Reaction time: 0.33 h
Yield: 47.3 %

Procedure:
(5R)-3-{3-Fluoro-4-[(trimethylsilyl)ethynyl]phenyl}-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Intermediate 17, 6.1 g, 17 mmol) was stirred in methanol (155 ml). 1 N Potassium hydroxide (30 ml) was added and the reaction was stirred for 20 minutes. The solution was diluted with methylene chloride (200 ml) then acidified to pH 1.5 using 1 N hydrochloric acid. The solution was diluted with water and the compound was extracted using methylene chloride. The organic layer was washed with water, dried (magnesium sulfate), filtered, and concentrated. The orange solid was adsorbed onto silica gel and chromatographed using ethyl acetate to give the title compound as a yellow solid (2.3 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][O:18][CH2:17]2)=[C:4]([O:22][CH3:23])[CH:3]=1.[CH3:24][S:25]([C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[C:31](O)=[O:32])(=[O:27])=[O:26]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][O:18][CH2:17]2)[C:31](=[O:32])[C:30]2[CH:34]=[C:35]([C:37]([F:40])([F:38])[F:39])[CH:36]=[C:28]([S:25]([CH3:24])(=[O:27])=[O:26])[CH:29]=2)=[C:4]([O:22][CH3:23])[CH:3]=1
Reactant: COc1cc(F)ccc1-c1ccncc1NCC1CCCOC1
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Product: COc1cc(F)ccc1-c1ccncc1N(CC1CCCOC1)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1

Procedure:
The title compound was prepared in analogy to example 90, from 4-(4-fluoro-2-methoxyphenyl)-N-((tetrahydro-2H-pyran-3-yl)methyl)pyridin-3-amine and 3-(methylsulfonyl)-5-(trifluoromethyl)benzoic acid (example 114, intermediate a) after a reaction time of 90 hours at room temperature. The compound was purified by silica gel chromatography on a 20 g column using an MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Chiral chromatography on a Ciralpak AD column with a gradient of ethanol (containing 0.05% formic acid): n-heptane (40:60) furnished both enantiomers, with the desired enantiomer eluting second. Colorless solid (19%). MS (ESI): m/z=567.158 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[N-:30]=[N+]=[N-].[Na+].CCOCC>CN(C)C=O>[CH:18]1([NH:17][C:13]2[N:12]=[C:11]([C:10]3[C:9]([C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)=[N:8][N:7]4[C:2]([NH2:30])=[CH:3][CH:4]=[CH:5][C:6]=34)[CH:16]=[CH:15][N:14]=2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: [N-]=[N+]=[N-]
Reactant: Fc1ccc(-c2nn3c(Cl)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Nc1cccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn12
Temperature: 25 °C
Yield: 59.4 %

Procedure:
To a solution of 4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (53 mg, 0.13 mmol) in N,N-dimethylformamide (4 mL) was added sodium azide (85 mg, 1.3 mmol). The resultant mixture was heated to 100° C. for 18 hours. The reaction mixture was cooled to room temperature and ether was added. The organic layer was washed with brine. The aqueous layer was extracted with ether and the combined organics dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (2:1 to 1:1 hexanes:ethyl acetate) provided 3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-7-amine (30 mg, 60%) as an oil. 1H NMR (CDCl3) δ 7.97 (d, 1H), 7.77 (d, 1H), 7.60 (m, 2H), 7.22 (m, 1H), 7.10 (t, 2H), 6.26 (d, 1H), 6.14 (d, 1H), 5.26 (s, 2H), 5.09 (d, 1H), 4.29 (m, 1H), 2.06–1.99 (m, 2H), 1.75–1.45 (m, 6H); MS m/z 389 (M+1). This material was taken up in ether and treated with hydrochloric acid in ether to yield a yellow precipitate which was isolated by filtration as a hydrochloride salt.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:27]([F:30])([F:29])[F:28])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20](=O)[CH2:21][CH:22]([CH3:24])[CH3:23])=[C:16]([CH3:26])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[NH2:32][OH:33].Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:27]([F:30])([F:29])[F:28])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20](=[N:32][OH:33])[CH2:21][CH:22]([CH3:24])[CH3:23])=[C:16]([CH3:26])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: NO
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)CC(C)C
Agent: Cl
Solvent: CO
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(CC(C)C)=NO
Temperature: 70 °C
Reaction time: 4 h
Yield: 40 %

Procedure:
To a solution of 1-{4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-phenyl}-3-methyl-butan-1-one (i.e. the product of Step 2, 228 mg) in methanol (14.3 mL) was added hydroxylamine hydrochloride (38 mg) and a catalytic amount of concentrated hydrochloric acid. The mixture was stirred at 70° C. for 4 h and concentrated in vacuum. Water was added and the mixture was extracted with ethyl acetate. Combined organic layers were dried (Na2SO4) and evaporated. Flash chromatography of the residue on silica gel obtained the title compound (94 mg, 40%).