Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[NH:13][C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([NH:21][C:22]([C@@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][N:25]2C(OC(C)(C)C)=O)=[O:23])=[CH:16][CH:15]=3)=[O:11])=[C:4]([F:37])[C:3]=1[O:38][C:39]1[CH:44]=[C:43]([C:45]#[N:46])[CH:42]=[C:41]([Cl:47])[CH:40]=1.[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51]>ClCCl>[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[NH:13][C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([NH:21][C:22]([C@@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][NH:25]2)=[O:23])=[CH:16][CH:15]=3)=[O:11])=[C:4]([F:37])[C:3]=1[O:38][C:39]1[CH:44]=[C:43]([C:45]#[N:46])[CH:42]=[C:41]([Cl:47])[CH:40]=1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)Nc1ccc2[nH]c(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)cc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4cc(NC(=O)[C@@H]5CCCCN5)ccc4[nH]3)c2F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
To a solution of 1,1-dimethylethyl (2S)-2-{[(2-{[({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)amino]carbonyl}-1H-indol-5-yl)amino]carbonyl}-1-piperidinecarboxylate (0.025 g, 0.036 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.5 mL, 6.49 mmol). The mixture was stirred at room temperature for 1 hr. The solvent was evaporated and the residue was purified by reverse phase HPLC (acetonitrile:water with 0.1% TFA) to give the title compound (0.012 g, 47%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.63 (br. s., 1H), 10.29 (s, 1H), 8.94-9.03 (m, 1H), 8.82-8.94 (m, 1H), 8.62-8.79 (m, 1H), 7.90 (s, 1H), 7.78 (s, 1H), 7.41-7.52 (m, 2H), 7.30-7.41 (m, 1H), 7.24 (d, 1H), 7.11 (s, 1H), 4.53 (d, 2H), 3.74-3.88 (m, 1H), 3.16-3.31 (m, 1H), 2.85-3.02 (m, 1H), 2.10-2.24 (m, 1H), 1.74-1.88 (m, 1H), 1.41-1.75 (m, 4H). ES MS: m/z 580 (M+1).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:18])[CH:8]=2)[N:3]=1.C(#N)C.Cl.[CH3:23][O:24][NH2:25].C(N(CC)CC)C>O>[Cl:18][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:25][O:24][CH3:23])[N:11]=[C:10]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CON
Reactant: Clc1ccc2nc(Cl)nc(-c3ccccc3)c2c1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CONc1nc(-c2ccccc2)c2cc(Cl)ccc2n1
Reaction time: 3.5 h
Yield: 19.3 %

Procedure:
To a mixture of 275 mg of 2,6-dichloro-4-phenylquinazoline (compound No. Ia1-3), 10 ml of acetonitrile and 334 mg of methoxyamine hydrochloride was added dropwise 506 mg of triethylamine at room temperature to obtain a mixture. The mixture was charged in a pressure-resistant reaction vessel made of stainless steel and the reaction was carried out at 105° C. for 3.5 hours. After cooling, the reaction solution was poured into 100 ml of water. The mixture was extracted with ethyl acetate and the resultant extract was washed with water and then concentrated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain 156 mg of crude crystals. The crude crystals were recrystallized from ethyl acetate to obtain 55 mg of the titled compound. Mp.173.9° C. 1H NMR (CDCl3): 3.98 (3H, s), 7.47-7.72 (6H, m), 7.87 (1H, d, J=9.0 Hz), 7.89 (1H, d, J=2.2 Hz), 8.03 (1H, br. s).
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:28])[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[CH3:31][S:32]([C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1)(=[O:34])=[O:33]>N1C=CC=CC=1.C(OCC)(=O)C>[OH:22][C:21]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:13](=[O:28])[C:12]=1[C:7]1[NH:6][C:5]2[CH:29]=[CH:30][C:2]([NH:1][S:41]([C:38]3[CH:37]=[CH:36][C:35]([S:32]([CH3:31])(=[O:34])=[O:33])=[CH:40][CH:39]=3)(=[O:43])=[O:42])=[CH:3][C:4]=2[S:9](=[O:11])(=[O:10])[N:8]=1
Reactant: CS(=O)(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(N)ccc3N2)c(O)c2cccnc21
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(=O)(=O)c4ccc(S(C)(=O)=O)cc4)ccc3N2)c(O)c2cccnc21
Temperature: 100 °C
Yield: 49.4 %

Procedure:
To the product of Example 205 (0.020 g, 0.047 mmol) in pyridine (0.2 mL) was added 4-methylsulfonylbenzenesulfonyl chloride (0.014 g, 0.056 mmol). The reaction mixture was heated in a microwave reactor at 100° C. for 30 minutes. The reaction was cooled to 25° C. and diluted with ethyl acetate (40 mL), washed with water and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was chromatographed on silica gel eluting with 99: 1dichloromethane:methanol to give the title compound (15 mg, 50%). 1H NMR (300 MHz, DMSO-d6) δ 0.97 (d, J=6.25 Hz, 6 H) 1.56 (m, 2 H) 1.68 (m, 1 H) 3.28 (s, 3 H) 4.46 (m, 2 H) 7.48 (m, 3 H) 7.65 (d, J=8.82 Hz, 1 H) 8.04 (d, J=8.82 Hz, 2 H) 8.15 (d, J=8.46 Hz, 2 H) 8.54 (dd, J=8.09, 1.84 Hz, 1 H) 8.86 (dd, J=4.60, 1.65 Hz, 1 H) 11.11 (s, 1 H) 14.14 (s, 1 H). MS (ESI−) m/z 644 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:11][CH2:12][CH:13]=O>>[ClH:11].[N:1]1[CH:12]=[CH:13][N:10]2[CH:9]=[CH:8][CH:7]=[C:3]([C:4]([OH:6])=[O:5])[C:2]=12
Reactant: O=CCCl
Reactant: Nc1ncccc1C(=O)O
Product: Cl
Product: O=C(O)c1cccn2ccnc12
Yield: 86.4 %

Procedure:
Using 2-aminonicotinic acid (14.1 g, 0.102 mol) and chloroacetaldehyde [45% aqueous solution (8.6 g, 0.11 mol)], the same procedure as described above in example C was used. After workup 17.5 g (88%) of the title compound, m.p. 299°-300° C. (decomp), was isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:23])[C:10]([C:16]1[CH:21]=[CH:20][NH:19][C:18](=[O:22])[CH:17]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].Br[CH2:25][C:26]([NH2:28])=[O:27]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:23])[C:10]([C:16]1[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH2:25][C:26]([NH2:28])=[O:27])[CH:17]=1)([OH:15])[C:11]([F:14])([F:13])[F:12]
Reactant: NC(=O)CBr
Reactant: CC(c1ccc(Cl)cc1Cl)C(O)(c1cc[nH]c(=O)c1)C(F)(F)F
Product: CC(c1ccc(Cl)cc1Cl)C(O)(c1ccnc(OCC(N)=O)c1)C(F)(F)F

Procedure:
The title compound was prepared in analogy to Example 120 from 4-[2-(2,4-dichloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1H-pyridin-2-one (Example 119, 100 mg) and 2-bromo-acetamide (45 mg). MS (m/e)=423.1 (MH+).
Reaction SMILES: O=[Cr](=O)=O.C1C=CC=CN=1.C1C=CC=CN=1.N1C=CC=CC=1.[OH:23][CH:24]([C:45]([F:50])([F:49])[CH2:46][CH2:47][CH3:48])[CH2:25][CH2:26][CH2:27][C@H:28]1[C@H:32]([CH3:33])[CH2:31][C:30](=[O:34])[C@@H:29]1[CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][C:41]([O:43][CH3:44])=[O:42]>C(Cl)Cl>[F:49][C:45]([F:50])([CH2:46][CH2:47][CH3:48])[C:24](=[O:23])[CH2:25][CH2:26][CH2:27][C@H:28]1[C@H:32]([CH3:33])[CH2:31][C:30](=[O:34])[C@@H:29]1[CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][C:41]([O:43][CH3:44])=[O:42]
Reactant: CCCC(F)(F)C(O)CCC[C@H]1[C@H](C)CC(=O)[C@@H]1C/C=C\CCCC(=O)OC
Agent: O=[Cr](=O)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC(F)(F)C(=O)CCC[C@H]1[C@H](C)CC(=O)[C@@H]1C/C=C\CCCC(=O)OC
Yield: 81 %

Procedure:
Celite (5 g) was added to Collins reagent prepared from chromic anhydride (1.2 g) and pyridine in methylene chloride (20 ml), followed by addition of a solution of the alcohol (31) (0.138 g) in methylene chloride (10 ml). The resultant mixture was stirred at room temperature for 30 minutes, followed by the usual work-up. The obtained crude product was subjected to silicagel column chromatography to give the titled compound (32).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.F[C:13]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:14]=1[CH:15]=[O:16].C(=O)([O-])[O-].[K+].[K+].CC#N>C1COCC1>[CH:15]([C:14]1[CH:17]=[C:18]([C:21]([F:22])([F:23])[F:24])[CH:19]=[CH:20][C:13]=1[O:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1)=[O:16]
Reactant: O=C(O)Cc1cccc(O)c1
Reactant: O=Cc1cc(C(F)(F)F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: C1CCOC1
Product: O=Cc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)O)c1
Yield: 14.8 %

Procedure:
3-Hydroxyphenylacetic acid (1.0 g, 5.2 mmol), 2-fluoro-5-(trifluoromethyl)benzaldehyde (1.0 g, 6.6 mmol), and potassium carbonate (2.2 g, 15.6 mmol) were combined in THF (20 mL) and MeCN (20 mL) and heated to 70° C. for 3 days. After acidic work-up, the crude material was purified by silica gel chromatography (20-100% EtOAc in hexanes) to give the desired product (0.25 g).
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH2:12][O:13][CH2:14][CH2:15][CH2:16][OH:17])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:21][C:22]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:23]=1[C:24]([O:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[O:25].O>CN1C(=O)N(C)CCC1.C1COCC1>[CH3:21][C:22]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][O:17][CH2:16][CH2:15][CH2:14][O:13][CH2:12][C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][CH:9]=2)[C:23]=1[C:24]([O:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[O:25]
Reactant: OCCCOCc1coc(-c2ccccc2)n1
Reactant: Cc1cccc(CBr)c1C(=O)OCC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN1CCCN(C)C1=O
Product: Cc1cccc(COCCCOCc2coc(-c3ccccc3)n2)c1C(=O)OCC(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 44.9 %

Procedure:
3-(2-Phenyl-oxazol-4-ylmethoxy)-propan-1-ol (1.26 g, 5.4 mmol) is dissolved in 10% DMPU in THF (20 mL) and cooled to 0° C. Sodium hydride (60%, 237 mg, 5.9 mmol) is added portionwise. The contents are stirred for 10 min. at 0° C., warmed to r.t. and stirred for another 10 min. isobutyl 2-bromomethyl-6-methyl-benzoate (2.69 g, 5.4 mmol, EXAMPLE 2b) is added, allowed to come to r.t. and stirred overnight. The reaction is poured into water (200 mL) and extracted with ethyl acetate (2×200 mL). The organic fractions were pooled and washed with brine (2×200 mL), dried over MgSO4, filtered and reduced under vacuum to an oil. The crude material was purified by flash chromatography (silica, 15-20% ethyl acetate in hexane) to give the title compound (1.06 g). MS (ESI) 438 (M+H)+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9](F)[C:10]([F:16])=[C:11]([F:15])[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:24]([NH:31][C:9]1[C:10]([F:16])=[C:11]([F:15])[C:12]([F:14])=[C:13]2[C:8]=1[C:7](=[O:18])[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5][N:4]2[CH:1]1[CH2:2][CH2:3]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)c(F)c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)c(NCc3ccccc3)c2c1=O

Procedure:
A mixture of ethyl 1-cyclopropyl-5,6,7,8-tetrafluor-1,4-dihydro-4-oxoquinoline-3-carboxylate (28.2 g) prepared in Referential Example 1 (2), benzylamine (9.8 ml), anhydrous potassium carbonate (23.6 g), and acetonitrile (140 ml) was heated at 100°-110° C. for 1 hour to give ethyl 5-benzylamino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline3-carboxylate (21.4 g), which was recrystallized from ethanol, m.p. 134°-135° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:35]=[CH:34][C:30]([C:31]([NH2:33])=[O:32])=[CH:29][CH:28]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:27]3[CH:35]=[CH:34][C:30]([C:31]([NH2:33])=[O:32])=[CH:29][CH:28]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: NC(=O)c1ccc(Br)cc1
Product: NC(=O)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 g, 1.0 mmol) and commercially available 4-bromobenzamide (180 mg, 0.9 mmol) according to general procedure II. Obtained as a yellow solid (290 mg, 61%). MS (ISP) 475.1 [(M+H)+]; mp 260° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[NH:8][C:7]2=[CH:9][S:10][CH:11]=[C:6]2[N:5]=1.Br[CH2:13][C:14]1[CH:33]=[CH:32][C:17]2/[C:18](=[C:28](/[CH3:31])\[C:29]#[N:30])/[C:19]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:20]=3[O:21][CH2:22][C:16]=2[CH:15]=1>>[F:27][C:24]1[CH:25]=[CH:26][C:19]2=[C:20]([CH:23]=1)[O:21][CH2:22][C:16]1[CH:15]=[C:14]([CH2:13][N:5]3[C:6]4=[CH:11][S:10][CH:9]=[C:7]4[N:8]=[C:4]3[CH2:3][O:2][CH3:1])[CH:33]=[CH:32][C:17]=1/[C:18]/2=[C:28](/[CH3:31])\[C:29]#[N:30]
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Reactant: COCc1nc2cscc2[nH]1
Product: COCc1nc2cscc2n1Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Yield: 96.1 %

Procedure:
[step 2] Using 2-(methoxymethyl)-1H-thieno[3,4-d]imidazole (65 mg, 0.39 mmol) obtained in step 1 and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (141 mg, 0.39 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, the title compound (167 mg, 97%) was obtained.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.O.[OH-].[Li+]>C1COCC1.O.CO.Cl>[F:24][C:20]1[CH:19]=[C:18]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:25])=[O:2])=[CH:5][N:6]=3)=[C:16]([CH3:17])[O:15][N:14]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3cccc(F)c3)noc2C)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1onc(-c2cccc(F)c2)c1COc1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a suspension of sodium hydride (55% dispersion in mineral oil, 852 mg, 20 mmol) in THF (27 mL) was added a solution of [3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol (3.68 g, 18 mmol) in THF (54 mL) at 0° C. and the reaction mixture warmed to room temperature over 30 min. Then a solution of methyl 6-chloronicotinate (3.35 g, 20 mmol) in THF (1.5 mL) was added dropwise at 0° C. and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then poured into aqueous sodium chloride (saturated) and the mixture was extracted with ethyl acetate. The combined organic layers were then washed with water and brine and then dried over sodium sulfate, filtered and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=7:3) afforded 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (4.1 g, 68%) which was obtained as a white solid. To a solution of 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (1.1 mmol) in THF (5 mL) was added a solution of lithium hydroxide monohydrate (94 mg, 2.2 mmol) in water (5 mL) and methanol (1 mL) added and the resulting mixture stirred at room temperature overnight. The mixture was acidified to pH 4 with HCl (25%, 3 drops) and methanol (2 drops) added. A gum began to form and the mixture was cooled at 0° C. for 1.5 h and then the aqueous layer decanted off. Trituration with diethylether and hexane afforded the title compound (95%) which was obtained as an off white solid. MS: m/e=327.4 [M−H]−.
Reaction SMILES: C([O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3(O)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:14][CH:15]=2)[NH:10][N:9]=1)=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[O:20]1[CH2:19][CH:18]=[C:17]([C:13]2[CH:12]=[C:11]3[C:16]([C:8]([C:6]([OH:7])=[O:5])=[N:9][NH:10]3)=[CH:15][CH:14]=2)[CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)c1n[nH]c2cc(C3(O)CCOCC3)ccc12
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1n[nH]c2cc(C3=CCOCC3)ccc12
Temperature: 25 °C
Yield: 76 %

Procedure:
6-(4-Hydroxytetrahydropyran-4-yl)-1H-indazole-3-carboxylic acid tert-butyl ester (0.86 mmol) was dissolved in trifluoroacetic acid (3 mL) and the mixture was maintained at room temperature for 16 h. The solvent was removed in vacuo and the residue was triturated with ethyl acetate to provide 6-(3,6-dihydro-2H-pyran-4-yl)-1H-indazole-3-carboxylic acid (76%). The acids were coupled with quinuclidine amine according to procedure A.
Reaction SMILES: Br[CH2:2][C:3]1[N:13]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]2[N:7]=[C:8]([C:11]#[N:12])[N:9]=[CH:10][C:5]=2[CH:4]=1.CN(C=O)C.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][N:26]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.O>[Cl:24][C:25]1[N:26]=[CH:27][C:28]([O:31][CH2:2][C:3]2[N:13]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]3[N:7]=[C:8]([C:11]#[N:12])[N:9]=[CH:10][C:5]=3[CH:4]=2)=[CH:29][CH:30]=1
Reactant: Oc1ccc(Cl)nc1
Reactant: CC(C)(C)Cn1c(CBr)cc2cnc(C#N)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)Cn1c(COc2ccc(Cl)nc2)cc2cnc(C#N)nc21
Temperature: 25 °C
Reaction time: 11 h
Yield: 99 %

Procedure:
6-Bromomethyl-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (1.3 mmol) is dissolved in DMSO (or DMF) (4 ml). To the solution, 2-chloro-5-hydroxypyridine (1.56 mmol) and K2CO3 (1.69 mmol) are added. The mixture is stirred at room temperature under nitrogen atomosphere for 11 h. The reaction mixture is diluted with water and extracted with AcOEt (twice) and Et2O (twice). The combined organic layer is washed with water and brine, dried over MgSO4, and concentrated in vacuo. The residue is purified by silica gel column chromatography (n-hexane:AcOEt=1:1) to give the product in 99% yield.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][OH:18])=[CH:11][CH:10]=2)[CH2:4][O:3]1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>CCOCC>[CH3:1][C:2]1([CH3:19])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][O:18][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:11][CH:10]=2)[CH2:4][O:3]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)OC[C@@H](COc2ccc(CCCO)cc2)O1
Solvent: CCOCC
Product: CC1(C)OC[C@@H](COc2ccc(CCCOS(C)(=O)=O)cc2)O1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To (3-[4-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-propan-1-ol (12.2 g, 46 mmol) in dry ether (150 ml) is added TEA (12.8 ml, 92 mmol). The mixture is cooled to 0° C. and treated dropwise with methanesulfonyl chloride (5.3 ml, 69 mmol). The reaction mixture is allowed to warm to room temperature and then stirring continued for 3 hours. The resulting mixture is washed with water (2×100 ml), saturated aqueous sodium hydrogencarbonate, brine, dried (MgSO4) and concentrated in vacuo to give Methanesulfonic acid 3-[4-((R)-2,2-dimethyl [1,3]dioxolan-4-ylmethoxy)-phenyl]-propylester as a white solid; 1H NMR (CDCl3): 1.39 (3H, s), 1.43 (3H,$), 2.02 (2H, pent, J=6.9 Hz), 2.63 (2H, tr, J=6.9 Hz), 3.00 (3H, s), 3.90 (2H, m), 4.05 (1H, m), 4.14 (3 h, m), 4.46 (1H, pent, J=6.8 Hz), 6.82 (2H, d, J=7.4 Hz), 7.10 (2H, d, J=7.4 Hz).
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)[CH:2]([CH3:4])[CH3:3].[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([O:33][CH3:34])=[C:27]([S:29](Cl)(=[O:31])=[O:30])[CH:28]=1.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([O:33][CH3:34])=[C:27]([S:29]([N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:6][C:7]2[S:8][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=3)=[CH:10][CH:11]=2)(=[O:30])=[O:31])[CH:28]=1
Reactant: CC(C)CNCc1ccc(-c2cccc(S(C)(=O)=O)c2)s1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cl)cc1S(=O)(=O)N(Cc1ccc(-c2cccc(S(C)(=O)=O)c2)s1)CC(C)C

Procedure:
In analogy to example 13, step 2, isobutyl-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-amine (example 15, step 2) was reacted with 5-chloro-2-methoxyphenylsulfonyl chloride and N,N-diisopropyl ethyl amine in dichloromethane to give 5-chloro-N-isobutyl-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-2-methoxy-benzenesulfonamide as a colorless oil. MS: 544.8 ([M+NH4]+)
Reaction SMILES: [N:1]([N:3]1[CH2:8][CH:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[S:6][C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]1=2)=O.[Cl-].[NH4+].O.[CH3:22][C:23]([CH3:25])=O>[Zn]>[CH3:22][C:23](=[N:1][N:3]1[CH2:8][CH:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[S:6][C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]1=2)[CH3:25]
Reactant: O=NN1CC(c2ccncc2)Sc2ccccc21
Reactant: CC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Product: CC(C)=NN1CC(c2ccncc2)Sc2ccccc21
Temperature: -5 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-nitroso-2-(pyridin-4-yl)-3,4-dihydro-2H-benzo[b][1,4]thiazine (0.3 g, 0.00116 mol) in acetone (12 mL) was added saturated ammonium chloride solution (3 mL) and water (3 mL) at RT, and the resulting brown colored reaction mixture was cooled to −5° C. Zinc dust (0.15 g, 0.00233 mol) was added portionwise at the same temperature and stirred for 10 min. After completion of reaction (monitored by TLC), solvent was removed under reduced pressure and extracted with EtOAc (3×50 mL). The organic layer was dried over anhydrous sodium sulfate, solvent was removed under reduced pressure to obtain product as a brown colored oil (0.25 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1(N)[CH:10]=[CH:9][NH:8][NH:7]1)=[O:5])[CH3:2].Br[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C[N:28](C)C=O>>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([NH2:28])[N:8]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: BrCCc1ccccc1
Reactant: CN(C)C=O
Reactant: CCOC(=O)C1(N)C=CNN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOC(=O)c1cc(N)n(CCc2ccccc2)n1
Yield: 35 %

Procedure:
200 mg (1.3 mM) of 3-amino-1H-pyrazole-3-carboxylic acid ethyl ester was dissolved in 3 ml of N,N-dimethylformamide, to which 0.21 ml (1.6 mM, 1.2 eq) of 2-bromoethylbenzene and 840 mg (2.6 mM, 2.0 eq) of cesium carbonate were added dropwise, and the resulting mixture was stirred under a nitrogen atmosphere for a day. The solvent was distilled off under reduced pressure, and the resultant was extracted with ethyl acetate and brine. The organic solvent layer was dried over anhydrous sodium sulfate, filtered, and then distilled under reduced pressure. The resulting impure compound was purified by column chromatography (hexane:ethyl acetate=4:1), to obtain 117 mg (35.0%) of the title compound.