Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=5[Cl:26])[N:18]=[C:17]([NH2:27])[N:16]=4)[N:14]=[C:7]3[C:6]=2[CH:28]=1.[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[N:19]1[C:15]([C:13]2[N:14]=[C:7]3[C:6]4[CH:28]=[C:2]([C:33]5[CH:34]=[N:29][CH:30]=[N:31][CH:32]=5)[CH:3]=[CH:4][C:5]=4[O:11][CH2:10][CH2:9][N:8]3[CH:12]=2)=[N:16][C:17]([NH2:27])=[N:18]1
Reactant: OB(O)c1cncnc1
Reactant: Nc1nc(-c2cn3c(n2)-c2cc(Br)ccc2OCC3)n(-c2ccccc2Cl)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Nc1nc(-c2cn3c(n2)-c2cc(-c4cncnc4)ccc2OCC3)n(-c2ccccc2Cl)n1
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 16.7 %

Procedure:
A mixture of 5-(10-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-amine (0.5 mmol), pyrimidin-5-ylboronic acid (200 mg, 0.75 mmol), Cs2CO3 (490 mg, 1.5 mmol) was stirred in dioxane and water (5:1, 3.0 mL) followed by the addition of Pd(dppf)Cl2 (30 mg). The reaction mixture was bubbled with N2 gas for 10 min, the reaction tube was sealed, and the contents were stirred at 130° C. under microwave irradiation for 30 min. The mixture was filtered through celite and the filtrate was concentrated and purified with prep-HPLC to give 559 (38.2 mg, 8.3%). 1H-NMR (CDCl3, 400 MHz): δ 9.22 (s, 1H), 8.79 (s, 2H), 8.01 (s, 1H), 7.55-7.42 (m, 6H) 7.00-7.07 (d, J=8 Hz, 1H), 4.45 (s, 2H), 4.41 (s, 2H), 4.258 (s, 2H). MS (ESI) m/z 457.12 [M+H+]
Reaction SMILES: [CH3:1][SH:2].[OH-].[Na+].Cl.[NH2:6][CH:7]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([CH2:18]Cl)[CH:12]=1)[C:8]([OH:10])=[O:9]>O>[NH2:6][CH:7]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([CH2:18][S:2][CH3:1])[CH:12]=1)[C:8]([OH:10])=[O:9]
Reactant: CS
Reactant: NC(C(=O)O)c1ccc(O)c(CCl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSCc1cc(C(N)C(=O)O)ccc1O
Reaction time: 8 h

Procedure:
To a solution of methanethiol (3 g, 0.04 mmole) in 250 ml of water is added sodium hydroxide (0.04 mole) followed by (-)-α-amino-3-(chloromethyl)-4-hydroxybenzeneacetic acid hydrochloride (5 g, 0.02 mole). The solution obtained is stirred overnight. Removal of the solvent by flash evaporation gives a quantitative yield of the title compound combined with 2 equivalents of sodium chloride.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:24])=[C:19]([CH:21]=[CH:22][CH:23]=2)[NH2:20])[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[F:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1[S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:24])=[C:19]([NH:20][S:39]([C:33]3[CH:34]=[C:35]([F:38])[CH:36]=[CH:37][C:32]=3[F:31])(=[O:41])=[O:40])[CH:21]=[CH:22][CH:23]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(Cl)n2)s1
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Temperature: 0 °C
Reaction time: 8 h
Yield: 45.7 %

Procedure:
To a solution of 3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluoroaniline (30 g, 82.8 mmol) in DCM (250 mL) was added pyridine (19.6 g, 248 mmol). The mixture was cooled to 0° C. 2,5-Difluorobenzene-1-sulfonyl chloride (17.6 g, 82.8 mmol) in DCM (20 mL) was added dropwise to the mixture. The reaction was stirred at rt overnight. Then the reaction was washed with water (300 mL), and extracted with DCM (2×400 mL). The organic layer was washed with brine, dried over anhydrous NaSO4, filtrated and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (petroleum ether:EtOAc:DCM 20:1:5) to afford the title compound (20.4 g, 45.8% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.26 (d, J=5.3 Hz, 1H), 7.60-7.66 (m, 1H), 7.51-7.60 (m, 1H), 7.30-7.36 (m, 1H), 7.17-7.30 (m, 3H), 7.07-7.17 (m, 1H), 6.68 (d, J=5.3 Hz, 1H), 1.45 (s, 9H). MS (ES+): 539 [M+H]+.
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:12][CH2:11][CH:10]([CH2:13][O:14][CH:15]=[CH2:16])[CH2:9][CH2:8]1)(=O)=O.CS(C)=O.[C-:21]#[N:22].[Na+]>>[CH:15]([O:14][CH2:13][CH:10]1[CH2:11][CH2:12][CH:7]([CH2:6][C:21]#[N:22])[CH2:8][CH2:9]1)=[CH2:16]
Reactant: [C-]#N
Reactant: C=COCC1CCC(COS(C)(=O)=O)CC1
Agent: [Na+]
Solvent: CS(C)=O
Product: C=COCC1CCC(CC#N)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.2 %

Procedure:
4-[(Vinyloxy)methyl]cyclohexylmethyl methanesulfonate (1.43 g, 0.00576 mol) was dissolved in dimethyl sulfoxide (5 mL, 0.07 mol), and then sodium cyanide (1 g, 0.02 mol) was added. The reaction was stirred at 60° C. for 2 hours at 25° C. for 16 hours. The reaction was extracted with ethyl acetate and the extracts were washed with water, brine 3×, and then dried over MgSO4 and concentrated in vacuo. The product was purified via column chromatography on silica gel (20% ethyl acetate, 80% hexanes) to give 0.90 g of the desired product as a mixture of the two diastereomers. 1H NMR (400 MHz, CDCl3): δ 6.33-6.48 (m, 1 H), 4.96-4.13 (m, 1H), 4.00-3.96 (m, 1H), 3.49-3.50 (m, 2H), 2.26 (d, 2H, J=6.8 Hz), 1.86-1.93 (m, 4H), 1.56-1.70 (m, 3H), 1.41-1.52 (m, 1H), 0.95-1.20 (m, 4H). (major isomer).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[CH:4][C:3]=1[Cl:9].[H-].[Na+].[CH:12]1([O:17][C:18]2[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=2[O:27][CH3:28])[C:21](Cl)=[O:22])[CH2:16][CH:15]=[CH:14][CH2:13]1.C1(OC2C=C(C=CC=2OC)C(O)=O)CC=CC1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[Cl:9][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([Cl:8])[C:2]=1[NH:1][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[C:18]([O:17][CH:12]2[CH2:13][CH:14]=[CH:15][CH2:16]2)[CH:19]=1
Reactant: COc1ccc(C(=O)Cl)cc1OC1CC=CC1
Reactant: Nc1c(Cl)cncc1Cl
Agent: COc1ccc(C(=O)O)cc1OC1CC=CC1
Agent: O=C([O-])[O-]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)cc1OC1CC=CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 4-amino-3,5-dichloropyridine (0.93 g) in dry tetrahydrofuran (56 mL) under nitrogen at 5°-10° C. is treated portionwise with sodium hydride (60% dispersion in oil, 0.57 g). After 1 hour it is treated dropwise with a solution of 3-cyclopent-3-enyloxy-4-methoxybenzoyl chloride in dry tetrahydrofuran (30 mL) prepared as described in Reference Example 33 from 1.33 g 3-cyclopent-3-enyloxy-4-methoxybenzoic acid). The resulting mixture is allowed to warm to room temperature, stirred for a further 3 hours and then poured into 5% aqueous potassium carbonate (430 mL). The resulting emulsion is extracted with ethyl acetate (3×150 mL), the combined organic extracts washed with water (2×20 mL), followed by ice-cold 1M aqueous hydrochloric acid (2×20 mL) and dried over sodium sulfate. The sovent is removed under reduced pressure and the resulting residue subject to flash chromatography on silica gel, eluting with mixtures of t-butyl methyl ether and cyclohexane (2:3 to 7:3 v/v), to give a cream solid, which is recrystallized fromacetonitrile to give N-(3,5-dichloropyrid-4-yl)-3-cyclopent-3-enyloxy-4-methoxybenzamide (0.54 g), as a white solid, m.p. 193°-195° C. [Elemental analysis: C,56.7; H,4.2; N,7.3%; calculated: C,57.0; H,4.3; N,7.4%].
Reaction SMILES: [CH3:1]N(C)C=O.P(Cl)(Cl)(Cl)=O.[C:11]1([NH:17][C:18]([C:24]([O:26][CH3:27])=[O:25])=[CH:19][C:20]([O:22][CH3:23])=[O:21])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)CCl>[N:17]1[C:11]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:1]=[C:19]([C:20]([O:22][CH3:23])=[O:21])[C:18]=1[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)C=C(Nc1ccccc1)C(=O)OC
Reactant: CN(C)C=O
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cc2ccccc2nc1C(=O)OC
Temperature: 25 °C

Procedure:
To a solution of dimethylformamide (DMF, 0.1 mol) in ethylenedichloride (EDC, 100 ml), cooled in an ice bath, is added dropwise with stirring phosphorous oxychloride (POCl3, 0.10 mol). The resulting solution is stirred for one and one-half hours at room temperature and then cooled in an ice bath. To the cooled solution is then added, in small increments, a solution of dimethyl 3-phenylaminobut-2-ene-dioate in ethylene dichloride. The resulting mixture is thereafter heated to reflux for three hours, cooled, and washed with half saturated brine. The organic phase is separated from the aqueous phase and dried. The solvent is removed under vacuum, and the residue recrystallized from methanol to afford 18.2 g (0.074 mol) of dimethyl 2,3-quinolinedicarboxylate, mp 105°-106.5° C.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[C:11]([NH2:13])[C:10]([N+:14]([O-])=O)=[CH:9][N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CO>[Pd].C1COCC1>[O:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:8]=[CH:9][C:10]([NH2:14])=[C:11]([NH2:13])[CH:12]=2)[CH2:2][CH2:3]1
Reactant: Nc1cc(N2CCOCC2)ncc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cnc(N2CCOCC2)cc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.4 %

Procedure:
Into a 50-mL round-bottom flask were placed 2-(morpholin-4-yl)-5-nitropyridin-4-amine (compound 151.1, 350 mg, 1.56 mmol), methanol (20 mL), THF (10 mL), and Pd/C (35 mg). The above solution was purged with N2 and then H2. The reaction mixture was stirred for 4 h at room temperature. The solids were filtered out. The resulting mixture was concentrated under reduced pressure. This resulted in 280 mg (92%) of the title compound as a pink solid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].[CH3:11][C:12]([OH:16])([C:14]#[CH:15])[CH3:13].CS(C)=O.[OH-].[K+]>>[C:4]([C:3]1[C:6]([F:10])=[CH:7][CH:8]=[CH:9][C:2]=1[O:16][C:12]([CH3:13])([CH3:11])[C:14]#[CH:15])#[N:5]
Reactant: C#CC(C)(C)O
Reactant: N#Cc1c(F)cccc1F
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: C#CC(C)(C)Oc1cccc(F)c1C#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.5 %

Procedure:
To a stirred solution of 108.3 grams (0.78 mole) of 2,6-difluorobenzonitrile and 78.2 grams (0.93 mole) of 2-methyl-3-butyn-2-ol in 800 mL of dimethyl sulfoxide 65.5 grams (1.17 moles) of potassium hydroxide was added portionwise during a 20 minute period. Upon completion of the addition, the reaction mixture was stirred at ambient temperature for about 18 hours, after which the reaction mixture was poured into ice-water and extracted with diethyl ether. The extract was washed with water and dried with magnesium sulfate. The mixture was filtered and the filtrate concentrated under reduced pressure, yielding 75.3 grams of 3-(2-cyano-3-fluoro-phenoxy)-3-methyl-1-butyne. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]1([NH:17][C:18]([NH:20][C@@H:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]2[NH:27][CH:28]2[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]2)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:30]2[CH2:31][CH2:32][CH2:33][C@H:28]([NH:27][C@@H:22]3[CH2:23][CH2:24][CH2:25][CH2:26][C@H:21]3[NH:20][C:18]([NH:17][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:19])[CH2:29]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: O=C(Nc1ccccc1)N[C@@H]1CCCC[C@H]1NC1CCCNC1
Product: O=C(Nc1ccccc1)N[C@@H]1CCCC[C@H]1N[C@H]1CCCN(c2ccc([N+](=O)[O-])cc2)C1
Yield: 13.6 %

Procedure:
1-((1R,2R)-2-((S)-1-(4-Nitrophenyl)piperidin-3-ylamino)cyclohexyl)-3-phenylurea (15 mg) was synthesized in 13% yield using the procedures as described in General Procedure A using 1-fluoro-4-nitrobenzene (39.2 mg, 0.278 mmol) and 1-phenyl-3-((1R,2R)-2-(piperidin-3-ylamino)cyclohexyl)urea (80 mg, 0.253 mmol). Anal. Calcd. for C24H31N5O3 m/z 437.5, found: 438.4 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 9.12 (s, 1H), 7.66 (d, J=8.8 Hz, 2H), 7.37 (br. s., 1H), 7.31 (d, J=8.2 Hz, 2H), 7.15 (t, J=7.7 Hz, 2H), 6.98 (t, J=6.9 Hz, 1H), 6.59 (d, J=8.8 Hz, 2H), 3.68 (br. s., 3H), 3.43-3.34 (m, 1H), 3.26-3.17 (m, 2H), 2.95 (br. s., 1H), 2.32 (br. s., 1H), 2.20-2.11 (m, 1H), 2.05 (br. s., 2H), 1.96 (br. s., 2H), 1.82-1.75 (m, 1H), 1.65 (d, J=15.9 Hz, 2H), 1.46 (br. s., 1H), 1.19 (d, J=9.9 Hz, 2H); 13C NMR (126 MHz, CDCl3) δ ppm 158.96, 153.92, 138.94, 138.78, 128.79, 125.85, 122.92, 118.37, 113.48, 64.58, 53.54, 53.22, 49.48, 47.42, 45.94, 31.34, 29.50, 23.76, 21.69, 14.11, 8.63.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:25]1[C:34]2[C:29](=[CH:30][C:31]([CH2:35][N:36]3[C:44]4[C:39](=[N:40][CH:41]=[C:42]([C:45]5[CH:53]=[CH:52][C:48]([C:49]([OH:51])=O)=[CH:47][CH:46]=5)[N:43]=4)[N:38]=[N:37]3)=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1.[CH3:54][N:55]([CH3:60])[CH2:56][CH2:57][NH:58][CH3:59].C(N(CC)CC)C>CN(C=O)C>[CH3:54][N:55]([CH3:60])[CH2:56][CH2:57][N:58]([CH3:59])[C:49](=[O:51])[C:48]1[CH:47]=[CH:46][C:45]([C:42]2[N:43]=[C:44]3[N:36]([CH2:35][C:31]4[CH:30]=[C:29]5[C:34](=[CH:33][CH:32]=4)[N:25]=[CH:26][CH:27]=[CH:28]5)[N:37]=[N:38][C:39]3=[N:40][CH:41]=2)=[CH:53][CH:52]=1
Reactant: O=C(O)c1ccc(-c2cnc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1
Reactant: CNCCN(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)CCN(C)C(=O)c1ccc(-c2cnc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1
Reaction time: 18 h
Yield: 57.9 %

Procedure:
HATU (82 mg, 0.22 mmol) was added to a mixture of 4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)benzoic acid (75 mg, 0.20 mmol), N1,N1,N2-trimethylethane-1,2-diamine (22 mg, 0.22 mmol) and triethylamine (0.060 mL, 0.43 mmol) in DMF (2.0 mL). After stirring for 18 hours, the reaction was partitioned between dichloromethane:ethanol (9:1) and water. The organic layer was separated, dried over Na2SO4, filtered and concentrated by rotary evaporation to afford 108 mg of crude material. The material was purified by pre-HPLC to give N-(2-(dimethylamino)ethyl)-N-methyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)benzamide (54 mg, yield 48%).
Reaction SMILES: [OH:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:11]([CH:15]1[CH2:20][CH2:19][CH:18]([O:21][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[CH:28]=[C:27]([CH2:32]N2CCC(CC)(C(O)=O)CC2)[CH:26]=[CH:25]3)[CH2:17][CH2:16]1)([CH3:14])([CH3:13])[CH3:12].C(C1CCC(OC2C=C3C(=CC=2)C=C(C=O)C=C3)CC1)(C)(C)C.C(O)(=O)C.C([BH3-])#N.[Na+]>>[C:11]([CH:15]1[CH2:20][CH2:19][CH:18]([O:21][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[CH:28]=[C:27]([CH2:32][N:5]2[CH2:6][CH2:7][C:2]([OH:1])([C:8]([OH:10])=[O:9])[CH2:3][CH2:4]2)[CH:26]=[CH:25]3)[CH2:17][CH2:16]1)([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(O)C1(O)CCNCC1
Reactant: CCC1(C(=O)O)CCN(Cc2ccc3cc(OC4CCC(C(C)(C)C)CC4)ccc3c2)CC1
Agent: CC(C)(C)C1CCC(Oc2ccc3cc(C=O)ccc3c2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)C1CCC(Oc2ccc3cc(CN4CCC(O)(C(=O)O)CC4)ccc3c2)CC1
Yield: 30 %

Procedure:
The compound was prepared in a manner similar as to that described for 1-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-4-ethyl-piperidine-4-carboxylic acid 4-Hydroxy-piperidine-4-carboxylic acid (0.0561 g, 0.387 mmol), 6-(4-tert-Butyl-cyclohexyloxy)-naphthalene-2-carbaldehyde (0.100 g, 0.322 mmol), Acetic acid (0.064 mL, 1.1 mmol) and Sodium cyanoborohydride (30.126 mg, 0.47939 mmol) to give 51 mg 1-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-4-hydroxy-piperidine-4-carboxylic acid (36%). ESI-LCMS 440 (M+H). 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 9.37-9.69 (m, 1H), 7.75-8.07 (m, 4H), 7.50-7.64 (m, 1H), 7.43 (d, J=2.0 Hz, 1H), 7.13-7.27 (m, 1H), 4.47 (d, J=3.8 Hz, 3H), 3.05-3.47 (m, 4H), 1.97-2.29 (m, 4H), 1.83 (d, J=13.3 Hz, 4H), 1.02-1.45 (m, 5H), 0.89 (s, 9H)
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[N:15][CH:16]=3)[CH:9]=2)[N:4]([S:30]([C:33]2[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH:3]=1.[CH3:40][C:41]1[CH:42]=[C:43]([CH:59]=[CH:60][CH:61]=1)[CH2:44][N:45]1[CH:49]=[C:48](B2OC(C)(C)C(C)(C)O2)[CH:47]=[N:46]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:40][C:41]1[CH:42]=[C:43]([CH:59]=[CH:60][CH:61]=1)[CH2:44][N:45]1[CH:49]=[C:48]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[CH:13][C:14]([N:17]5[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]5)=[N:15][CH:16]=4)[CH:9]=3)[N:4]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[CH:3]=2)[CH:47]=[N:46]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)nc4)cnc32)cc1
Reactant: Cc1cccc(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(C)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)nc4)cnc32)cc1
Yield: 93.8 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, tert-butyl 4-(5-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperazine-1-carboxylate (Intermediate 66K) (200 mg, 0.303 mmol) was coupled with 1-(3-methylbenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 64D) (99 mg, 0.333 mmol) using sodium carbonate (96 mg, 0.909 mmol) and Pd(PPh3)2Cl2 (11 mg, 0.015 mmol) in toluene/ethanol/water (2/2/0.5 ml) to afford 200 mg (94% yield) of titled compound after purification by column (Silica gel 60/120) using 0.5% methanol in DCM as eluent. MS: m/z=704.3 (M+1).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:20]=[C:19]([C:21]3[CH:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=4)[CH:24]=[C:23]([CH3:37])[N:22]=3)[CH:18]=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:37][C:23]1[N:22]=[C:21]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([C:11]3[CH:10]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:14]=[CH:13][CH:12]=3)[N:20]=2)[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:29][CH:28]=2)[CH:24]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(N)(=O)=O)c3)n2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 55 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonamide (example 261) (0.570 g, 1.085 mmol) in dichloromethane (10 mL) was added TFA (10 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane/diethyl ether and dried to yield the title compound as a white solid (0.28 g, 55%). MS (ISP) 468.2 [(M+H)+]; mp 250° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[O:3]1.[N:17]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=1)=[C:18]=[O:19]>C1COCC1>[CH3:26][C:22]1[CH:21]=[C:20]([NH:17][C:18]([NH:13][C:12]2[CH:14]=[CH:15][C:9]([B:4]3[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]3)=[CH:10][CH:11]=2)=[O:19])[CH:25]=[CH:24][CH:23]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: Cc1cccc(N=C=O)c1
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
A 0° C. mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (5.03 g, 23 mmol) and 1-isocyanato-3-methylbenzene (2.95 mL, 23 mmol) in THF (90 mL) was stirred at room temperature for 1 hour, concentrated, suspended in acetonitrile, and filtered. The filter cake was dried to provide 8.09 g of the desired product.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([O:13][C:14]3[C:15]4[CH:22]=[C:21]([CH2:23][CH2:24][NH:25][C:26](=O)OC(C)(C)C)[S:20][C:16]=4[N:17]=[CH:18][N:19]=3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>C(Cl)Cl.O>[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[N:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([O:13][C:14]3[C:15]4[C:22]5[CH2:26][NH:25][CH2:24][CH2:23][C:21]=5[S:20][C:16]=4[N:17]=[CH:18][N:19]=3)[CH2:9][CH2:8]2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)NCCc1cc2c(OC3CCC(N4CCOCC4)CC3)ncnc2s1
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: c1nc(OC2CCC(N3CCOCC3)CC2)c2c3c(sc2n1)CCNC3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl N-[2-(4-[[4-(morpholin-4-yl)cyclohexyl]oxy]thieno[2,3-d]pyrimidin-6-yl)ethyl]carbamate (150 mg, 0.32 mmol, 1.00 equiv) in DCM/H2O (10/0.5 mL) was added trifluoroacetic acid (0.8 mL) at 0° C. and stirred overnight at room temperature. After concentration under vacuum, the residue was dissolved in DCE (30 mL) and paraformaldehyde (180 mg) and trifluoroacetic acid (1 mL) were added. The resulting solution was stirred overnight at 45° C. under nitrogen. After concentration under vacuum, the residue was purified by preparative HPLC under the following conditions: Column: XBridge Shield RP18 OBD, 5 μm, 19*150 mm; mobile phase: water (with 0.5% TFA) and CH3CN (0% CH3CN up to 21% in 12 min, up to 95% in 2 min, down to 0% in 2 min); flow rate: 20 mL/min; UV detection at 254/220 nm. After concentration under vacuum, the desired 3-[[4-(morpholin-4-yl)cyclohexyl]oxy]-8-thia-4,6,12-triazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraene trifluoroacetate (100 mg, crude) was obtained as a light yellow solid. MS (ES): m/z 375 (M+H)+.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[CH:5]=[N+:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[Cl:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([OH:27])=[CH:19][CH:18]=1>>[Cl:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([OH:27])=[C:19]([CH:5]([C:4]2[CH:12]=[CH:13][CH:14]=[CH:15][C:3]=2[Cl:2])[N:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH:18]=1
Reactant: Clc1ccccc1C=[N+]1CCCCC1
Reactant: Oc1ccc(Cl)c2ccccc12
Agent: [Cl-]
Product: Oc1c(C(c2ccccc2Cl)N2CCCCC2)cc(Cl)c2ccccc12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-(2-chloro-benzylidene)-piperidinium chloride and 4-chloro-1-naphthol.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH:14][C:15]2[NH:16][N:17]=[C:18]([CH:20]3[CH2:22][CH2:21]3)[CH:19]=2)[N:3]=1.C(OC([N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([NH2:39])[CH:37]=2)[C:32](=[O:40])[NH:31]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(O)CCC.ClCCl>[CH:20]1([C:18]2[CH:19]=[C:15]([NH:14][C:4]3[N:5]=[C:6]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[N:7]=[C:2]([NH:39][C:36]4[CH:37]=[C:38]5[C:33]([C:32](=[O:40])[NH:31][NH:30]5)=[CH:34][CH:35]=4)[N:3]=3)[NH:16][N:17]=2)[CH2:22][CH2:21]1
Reactant: Clc1nc(Nc2cc(C3CC3)n[nH]2)nc(-c2ccccc2)n1
Reactant: CC(C)(C)OC(=O)n1[nH]c(=O)c2ccc(N)cc21
Solvent: CCCCO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH][nH]c2cc(Nc3nc(Nc4cc(C5CC5)n[nH]4)nc(-c4ccccc4)n3)ccc12
Temperature: 85 °C
Yield: 49.9 %

Procedure:
To a sealed tube was added (4-Chloro-6-phenyl-[1,3,5]triazin-2-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine (50 mg, 0.16 mmol) and 6-amino-3-oxo-2,3-dihydro-indazole-1-carboxylic acid tert-butyl ester (80 mg, 0.32 mmol) in 1 ml of n-butanol. The contents were heated to 85° C. for 3 hours. The reaction was concentrated in vacuo to give a white solid that was dissolved in 3 ml of dichloromethane and 1 ml of trifluoro acetic acid and stirred for 5 hours at room temperature. The reaction concentrated and the crude residue purified by prep HPLC to afford 34 mg of the desired product as a light yellow solid (39.4% yield). H-NMR (DMSO-d6, 500 mHz) δ 10.95 (m, 1H), 10.30 (m, 1H), 9.91 (s, 1H), 8.32 (m, 2H), 8.04 (m, 1H), 7.49 (m, 4H), 7.25 (m, 1H), 6.14 (s br, 1H), 1.85 (s, 1H), 0.87 (s, 2H), 0.67 (s, 2H).