Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl.Cl.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2([CH2:26][NH:27][CH3:28])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1.C(N(CC)CC)C>C(O)CCC>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2([CH2:26][NH:27][CH3:28])[CH2:25][CH2:24][N:23]([C:2]3[C:3]4[CH:10]=[CH:9][NH:8][C:4]=4[N:5]=[CH:6][N:7]=3)[CH2:22][CH2:21]2)=[CH:16][CH:15]=1
Reactant: CNCC1(c2ccc(Cl)cc2)CCNCC1
Reactant: Clc1ncnc2[nH]ccc12
Agent: Cl
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: CNCC1(c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Yield: 34 %

Procedure:
A solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (15.5 mg, 0.1 mmol), [4-(4-chlorophenyl)-piperidin-4-ylmethyl]-methylamine bis-hydrochloride (34 mg, 0.11 mmol) and triethylamine (150 μL, 0.7 mmol) in n-butanol (1 ml) was heated at 100° C. in a microwave reactor for 60 minutes. After cooling the reaction the solvents were concentrated. Purification on SCX-II acid resin, eluting with methanol then 2M ammonia/methanol, followed by further purification by flash column chromatography on silica, eluting with 15% methanol in dichloromethane, gave [4-(4-chlorophenyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-ylmethyl]-methylamine (12.3 mg, 0.034 mmol, 34%). LC-MS (LCT2) m/z 356 [M+H+], Rt 2.64 min.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[CH2:37]([O:36][C:34](=[O:35])[NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)[CH3:38]
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c[nH]c23)c1
Reactant: CCOC(=O)Cl
Product: CCOC(=O)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4cc(OC)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from trans-4-(2-cyclopropylmethoxy-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A153) and ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:19][N:18]=1.[Si:28]([O:35][C:36]1([CH2:40][CH:41]=[O:42])[CH2:39][CH2:38][CH2:37]1)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]>C1COCC1.O>[Si:28]([O:35][C:36]1([CH2:40][CH:41]([C:22]2[C:17]([F:16])=[N:18][CH:19]=[C:20]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:21]=2)[OH:42])[CH2:37][CH2:38][CH2:39]1)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]
Reactant: CC(C)(C)Cc1ccc(F)nc1
Reactant: CC(C)(C)[Si](C)(C)OC1(CC=O)CCC1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)Cc1cnc(F)c(C(O)CC2(O[Si](C)(C)C(C)(C)C)CCC2)c1
Temperature: -78 °C
Reaction time: 0.05 h

Procedure:
2,2,6,6-tetramethylpiperidine (13.0 ml, 76.5 mmol) was dissolved in 500 ml THF and cooled to −78° C. Butyllithium (26.8 ml, 67.0 mmol) was added over the period of 10 min and the reaction was allowed to warm up to 0° C. and kept there for 3 min. The mixture was cooled back to −78° C. and a solution of 2-fluoro-5-neopentylpyridine (8.000 g, 47.8 mmol) in 10 ml THF was added over the period of 30 min. The mixture was stirred for 20 min at the same temperature and a solution of 2-(1-(tert-butyldimethylsilyloxy)cyclobutyl)acetaldehyde (19.7 g, 86.1 mmol) in 25 ml THF was added over the period of 20 min. The reaction was stirred for 15 min at the same temperature and hydrolyzed with 200 ml of H2O. The mixture was allowed to warm up to room temp and extracted 2 times with 1 L EtOAc (each). The combined organic extracts were dried over MgSO4 and evaporated. The crude material was used without further purification. MS found 396.2.
Reaction SMILES: O[CH2:2][CH:3]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[S:4]1.S(Cl)([Cl:16])=O>C(Cl)(Cl)Cl>[Cl:16][CH2:2][CH:3]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[S:4]1
Reactant: O=C1Nc2ccccc2SC1CO
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=C1Nc2ccccc2SC1CCl
Yield: 58.7 %

Procedure:
To a solution of 1.0 g of 2-hydroxymethyl-2H-1,4-benzothiazin-3(4H)-one in 20 ml of chloroform was added 0.9 ml of thionyl chloride, and the mixture was heated for 2 hours under reflux. The mixture was concentrated under reduced pressure and the residue was extracted with ether. The extract was washed with water, dried (MgSO4), and concentrated. The crude product was subjected to a column chromatography on silica-gel (40 g). From the eluate with hexane-ethyl acetate (4:1, v/v) was obtained 640 mg (58.7%) of 2-chloromethyl-2H-1,4-benzothiazin-3(4H)-one as crystals. Recrystallization from ethyl acetate and n-hexane gave needles, m.p. 152°-153° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH3:55][C:56]1[S:57][C:58]([S:62](Cl)(=[O:64])=[O:63])=[C:59]([CH3:61])[N:60]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([S:62]([C:58]2[S:57][C:56]([CH3:55])=[N:60][C:59]=2[CH3:61])(=[O:64])=[O:63])[CH2:49][CH2:48]1
Reactant: Cc1nc(C)c(S(=O)(=O)Cl)s1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(C)c(S(=O)(=O)N2CCC(CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)CC2)s1
Yield: 22 %

Procedure:
The desired compound was prepared according to the procedure of Example A42 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 2,4-dimethyl-1,3-thiazole-5-sulfonyl chloride as starting materials in 22% yield. LCMS for C29H32ClN8O3S2 (M+H)+: m/z=639.2.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C@H:30]12[CH2:37][C@H:33]([C@H:34]([OH:36])[CH2:35]1)[CH2:32][NH:31]2>>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20]([N:31]5[CH2:32][C@@H:33]6[CH2:37][C@H:30]5[CH2:35][C@H:34]6[OH:36])=[O:21])=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25]([N:26]([CH3:28])[CH3:27])=[O:29])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCC1
Reactant: O[C@@H]1C[C@@H]2C[C@H]1CN2
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4C[C@@H]5C[C@H]4C[C@H]5O)cn3)nc2n1C1CCCC1
Yield: 60 %

Procedure:
The 6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinic acid was combined with (1S,4S,5R)-2-azabicyclo[2.2.1]heptan-5-ol following amide formation method 3 which gave 7-cyclopentyl-2-(5-((1S,4S,5R)-5-hydroxy-2-azabicyclo[2.2.1]heptane-2-carbonyl)pyridin-2-ylamino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (40 mg) in 60% yield. 1H NMR (400 MHz, CDCl3) δ ppm 9.51-9.43 (m, 0.3H, Rotamer) 9.43-9.35 (m, 0.7H, Rotamer) 8.87 (s, 1H) 8.66-8.60 (m, 0.3H, Rotamer) 8.60-8.52 (m, 0.7H, Rotamer+1H) 7.94-7.84 (m, 1H) 6.48 (s, 1H) 4.86-4.75 (m, 1H) 4.75-4.71 (m, 0.3H, Rotamer) 4.32-4.25 (m, 0.7; H, Rotamer) 4.21-4.13 (m, 0.7H, Rotamer) 4.08-4.02 (m, 0.3H, Rotamer) 3.61-3.50 (m, 1H) 3.15 (s, 6H) 3.10-3.01 (m, 1H) 2.93-2.83 (m, 0.7H, Rotamer) 2.78-2.67 (m, 0.3H, Rotamer H) 2.65-2.50 (m, 3H) 2.36-2.20 (m, 1H) 2.15-1.99 (m, 4H) 1.99-1.88 (m, 1H) 1.80-1.65 (m, 2H) 1.59 (none, 2H). HR-MS (m/z MH+) 490.26 RT 4.34 min
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13](=[O:16])[CH2:14][CH3:15])[CH:9]=2)[CH:4]=1.Br>C(O)(=O)C>[C:13]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[CH:4]=[C:3]([OH:2])[CH:12]=[CH:11]2)(=[O:16])[CH2:14][CH3:15]
Reactant: CCC(=O)c1ccc2cc(OC)ccc2c1
Agent: Br
Solvent: CC(=O)O
Product: CCC(=O)c1ccc2cc(O)ccc2c1
Temperature: 0 °C
Yield: 56.7 %

Procedure:
To a solution of 10 g of 2-methoxy-6-propionyl-naphthalene, prepared according to J. Chem. Soc. (1934), p. 864, in acetic acid (45 ml) and kept under reflux, 47 ml of aqueous HBr (48% by weight) is added during a three-hour time period. The resulting suspension is poured onto 500 g of crushed ice; the formed tars are left in the reaction flask. A suspension is obtained which is filtered on a Buchner filter. The solid material is washed with 100 ml of water, 50 ml of saturated aqueous solution of NaHCO3, and then with 50 ml of water. After drying in air and in an oven at 60° C. for 10 hours, 5.3 g of pink-white product is obtained with the following characteristics:
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:4]([O:6][CH3:7])=[O:5].Cl[CH2:18][CH2:19][N:20]([CH2:23][CH2:24]Cl)[CH2:21][CH3:22]>C(N(CC)C(C)C)(C)C>[C:13]([O:12][C:10]([NH:9][CH2:8][C@H:3]([N:2]1[CH2:22][CH2:21][N:20]([CH2:23][CH3:24])[CH2:19][CH2:18]1)[C:4]([O:6][CH3:7])=[O:5])=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CCN(CCCl)CCCl
Reactant: COC(=O)[C@@H](N)CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCN([C@@H](CNC(=O)OC(C)(C)C)C(=O)OC)CC1
Yield: 40.4 %

Procedure:
A solution of 5.0 g (19.6 mmol) of commercial methyl (S)-2-amino-3-tert-butoxycarbonylaminopropanoate hydrochloride and 3.3 g (19.6 mmol) of bis(2-chloroethyl)ethylamine in 50 ml of N,N-diisopropylethylamine is heated at 127° C. for 5 h. After evaporation of a maximum amount of diisopropylethylamine, the reaction medium is diluted with ethyl acetate and washed with an aqueous solution of sodium hydroxide having a concentration of 1N. The organic phase obtained is then washed with water, dried over magnesium sulfate, filtered and concentrated under vacuum. The crude product obtained is purified by chromatography on silica gel, elution being carried out with a 30/70 heptane/ethyl acetate mixture. 2.5 g (40%) of methyl (S)-3-tert-butoxycarbonylamino-2-(4-ethylpiperazin-1-yl)propanoate are obtained in the form of an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH2:15][C:14]3=[O:19])[CH:8]=2)[N:3]=1.[Cl:20][C:21]1[S:25][C:24]([C:26]2[S:27][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:29][CH:30]=2)=[CH:23][CH:22]=1>>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([S:31]([C:28]4[S:27][C:26]([C:24]5[S:25][C:21]([Cl:20])=[CH:22][CH:23]=5)=[CH:30][CH:29]=4)(=[O:32])=[O:33])[CH2:15][C:14]3=[O:19])[CH:8]=2)[N:3]=1
Reactant: Nc1ccc2cc(CN3CCNCC3=O)ccc2n1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccc(Cl)s2)s1
Product: Nc1ccc2cc(CN3CCN(S(=O)(=O)c4ccc(-c5ccc(Cl)s5)s4)CC3=O)ccc2n1

Procedure:
The title compound is prepared as described in Example 101 using 1-(2-aminoquinolin-6-ylmethyl)piperazin-2-one, EXAMPLE 67, and 5′-chloro-[2,2′]bithiophenyl-5-sulfonyl chloride, EXAMPLE 2. The crude product is triturated in CH2Cl2 and filtered to provide the title compound as a white solid. 1H NMR (d6-DMSO, 300 MHz) δ7.82 (d, 1H), 7.68 (d, 1H), 7.42 (m, 3H), 7.36 (d, 1H), 7.25 (d, 1H), 7.20 (d, 1H), 6.70 (d, 1H), 6.43 (bs, 2H), 4.53 (s, 2H), 3.78 (s, 2H), 3.31 (m, 4H). MS (ion spray) m/z 519, 521, (M+H), Cl pattern.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].[C:16](OC(=O)C)(=[O:18])[CH3:17]>C(O)C>[C:16]([N:13]1[CH2:12][CH2:11][N:10]([C:4]2[CH:3]=[C:2]([Cl:1])[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=2)[CH2:15][CH2:14]1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: Clc1cc(N2CCNCC2)cc(Cl)c1Cl
Solvent: CCO
Product: CC(=O)N1CCN(c2cc(Cl)c(Cl)c(Cl)c2)CC1
Reaction time: 8 h
Yield: 76 %

Procedure:
A mixture of 1-(3,4,5-trichlorophenyl) piperazine (0.5 g) and acetic anhydride (0.4 ml) in ethanol (10 ml) was left to stand overnight at ambient temperature. The solvent was removed in vacuo and the residue was crystallised from ethyl acetate-light petroleum (b.p. 40°-60°) to give 1-acetyl-4-(3,4,5-trichlorophenyl) piperazine (0.43g, 76%), m.p. 133°-136°.
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[C:6](=[N:7][C:8]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][N:24]([CH2:27][C:28]([N:30]([CH3:32])[CH3:31])=[O:29])[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[N:9][CH:10]=2)[N:5]1[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39](O)([CH3:41])[CH3:40])[N:34]=1)[CH:2]=[CH2:3].COCCN(S(F)(F)[F:53])CCOC.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[C:6](=[N:7][C:8]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][N:24]([CH2:27][C:28]([N:30]([CH3:32])[CH3:31])=[O:29])[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[N:9][CH:10]=2)[N:5]1[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:53])([CH3:41])[CH3:40])[N:34]=1)[CH:2]=[CH2:3]
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: C=CCn1c(=O)c2cnc(Nc3ccc(N4CCN(CC(=O)N(C)C)CC4)cc3)nc2n1-c1cccc(C(C)(C)O)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: C=CCn1c(=O)c2cnc(Nc3ccc(N4CCN(CC(=O)N(C)C)CC4)cc3)nc2n1-c1cccc(C(C)(C)F)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
16 mg of the compound obtained in Example 92 was dissolved in 3 mL of chloroform, and 0.1 mL of bis(2-methoxyethyl)aminosulfur trifluoride was added thereto and stirred at room temperature for 1 hour. Aqueous saturated sodium hydrogencarbonate solution was added to it and extracted with chloroform. The chloroform layer was washed with saturated saline water, dried with anhydrous sodium sulfate, and the solvent was evaporated away under reduced pressure. This was purified through column chromatography (ethyl acetate/chloroform=3/1) and then solidified from ethyl acetate/hexane solution to obtain 8 mg of the entitled compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[OH:12].CC(C)=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]#[N:26]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:10])([F:11])[F:9])=[CH:4][C:3]=1[O:12][CH2:24][C:25]#[N:26]
Reactant: N#CCBr
Reactant: Oc1cc(C(F)(F)F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: N#CCOc1cc(C(F)(F)F)ccc1F
Reaction time: 20 h

Procedure:
A solution of 2-fluoro-5-trifluoromethylphenol (25 g) in reagent grade acetone (0.55 L) is treated with solid potassium carbonate (7.7 g) followed by the rapid addition of neat bromoacetonitrile (10 mL). The heterogenous mixture is stirred vigorously for approximately 20 hours whereupon it is poured into water and extracted into diethyl ether. The combined ether extracts are washed with saturated sodium chloride and dried over anhydrous potassium carbonate. Filtration and concentration under reduced pressure gives a pale orange solid which is then chromatographed on silica gel, eluting with dichloromethane, to give the desired product as white solid (28.3 g).
Reaction SMILES: [NH2:1][C@H:2]([CH3:17])[C:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[OH:18][C:19]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:20]=1[CH:21]=O>CO>[N+:27]([C:24]1[CH:23]=[C:20]([CH:21]=[N:1][C@H:2]([CH3:17])[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[OH:4])[C:19]([OH:18])=[CH:26][CH:25]=1)([O-:29])=[O:28]
Reactant: C[C@@H](N)C(O)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Solvent: CO
Product: C[C@@H](N=Cc1cc([N+](=O)[O-])ccc1O)C(O)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
2.0 g of (R)-2-amino-1,1-diphenyl-1-propanol, 1.47 g of 2-hydroxy-5-nitrobenzaldehyde and 30 ml of methanol were mixed, and the mixture was stirred at 80° C. for 1 hour. Thereafter, the mixture was cooled to 20° C. and the deposited crystals were collected by filtration. The collected crystals were washed with methanol and dried to give 3.22 g of (R)-N-(5-nitrosalicylidene)-2-amino-1,1-diphenyl-1-propanol. Yield 97.2%
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:34]=[N:33][N:32]([CH:35]([CH3:37])[CH3:36])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][CH2:22][N:23]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH2:24][CH:25]=2)[CH:19]=1)=[O:13]>CCO.[Pd]>[N:23]1([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH2:24][CH2:25][CH:20]([C:18]2[CH:19]=[C:14]([C:12]([NH:11][CH2:10][C:3]3[C:4](=[O:9])[NH:5][C:6]([CH3:8])=[CH:7][C:2]=3[CH3:1])=[O:13])[C:15]3[CH:34]=[N:33][N:32]([CH:35]([CH3:36])[CH3:37])[C:16]=3[N:17]=2)[CH2:21][CH2:22]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C4CCNCC4)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(C)c(CNC(=O)c2cc(C3CCN(C4CCNCC4)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 62 %

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-6-(1-(piperidin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.08 g, 0.159 mmol) in EtOH (2 mL), 10% Pd/C in catalytic amount was added and stirred it at room temperature under hydrogen pressure (balloon pressure) for 3-4 hr. On completion of reaction, reaction mass was filtered through celite bed, then filtrate was concentrated under reduce pressure, finally the residue was washed with diethyl ether to provide the desired compound (62% yield). LCMS: 506.40 (M+1)+; HPLC: 90.48% (@ 254 nm) (Rt; 4.196); 1H NMR (DMSO-d6, 400 MHz) δ 11.55 (bs, 1H), 9.79 (bs, 1H), 8.76 (t, 1H), 8.58 (bs, 1H), 8.27 (s, 1H), 7.47 (s, 1H), 5.90 (s, 1H), 5.17 (m, 1H), 4.37 (d, 2H, J=4.4 Hz), 3.60 (bs, 2H), 3.45 (bs, 2H), 3.16 (m, 4H), 2.95 (m, 4H), 2.21 (s, 3H), 2.12 (s, 3H), 2.25-2.05 (m, 4H), 1.85 (m, 2H), 1.50 (d, 6H, J=6.4 Hz).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[N:11]=[C:10]([CH2:12][OH:13])[CH:9]=[CH:8][C:6]=2[N:7]=1.[Si]([N:27]1[C:35]2[C:30](=[C:31](B3OC(C)(C)C(C)(C)O3)[C:32]([F:36])=[CH:33][CH:34]=2)[CH:29]=[CH:28]1)(C(C)(C)C)(C)C>>[F:36][C:32]1[C:31]([C:2]2[N:3]=[C:4]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:5]3[N:11]=[C:10]([CH2:12][OH:13])[CH:9]=[CH:8][C:6]=3[N:7]=2)=[C:30]2[C:35](=[CH:34][CH:33]=1)[NH:27][CH:28]=[CH:29]2
Reactant: OCc1ccc2nc(Cl)nc(N3CCOCC3)c2n1
Reactant: CC1(C)OB(c2c(F)ccc3c2ccn3[Si](C)(C)C(C)(C)C)OC1(C)C
Product: OCc1ccc2nc(-c3c(F)ccc4[nH]ccc34)nc(N3CCOCC3)c2n1

Procedure:
(2-Chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methanol 6 (0.1 g) was reacted with 1-(tert-butyldimethylsilyl)-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole via General Procedure A to produce 73.4 mg of 108 following reverse phase HPLC purification. MS (Q1) 380.1 (M)+
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH3:6][C:7](=[N:10][NH:11][C:12](N)=O)[CH2:8][CH3:9].[OH-].[Na+].CN([CH:20]=[O:21])C>>[CH2:8]([C:7]1[C:6]([CH:20]=[O:21])=[CH:12][NH:11][N:10]=1)[CH3:9]
Reactant: CN(C)C=O
Reactant: CCC(C)=NNC(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1n[nH]cc1C=O
Temperature: 0 °C
Yield: 16 %

Procedure:
To cool DMF (50 mL) at 0° C., POCl3 (30 mL) was added dropwise over 30 minutes, and maintained at 0° C. for 1 hour. To the mixture was added butan-2-one semicarbazone (10 g, 78 mmol) in portions at 70° C. and maintained at 70° C. for 4 hours. The mixture was poured into crushed ice (700 g), neutralized using 10% NaOH solution and extracted using ethyl acetate (3×100 mL). The combined organic layers were washed with water (2×80 mL), saturated aqueous NaCl (100 mL), dried over anhydrous Na2SO4 and concentrated to obtain a crude product, which was purified by column chromatography (60-120 mesh silica gel) using 3-5% methanol in chloroform as eluents to afford 3-ethyl-1H-pyrazole-4-carbaldehyde (1.5 g, 16%) as solid. 1H NMR (CDCl3) δ 9.95 (s, 1H), 8.0 (s, 1H), 3.0 (q, 2H), 1.35 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7](B2OC(C)(C)C(C)(C)O2)=[CH:6][C:5]([S:17]([N:20]([CH3:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)(=[O:19])=[O:18])=[C:4]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][OH:33])[CH:3]=1.Br[C:35]1[C:40]([C:41]#[N:42])=[CH:39][C:38]([C:43]([F:46])([F:45])[F:44])=[N:37][CH:36]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[Cl:1][C:2]1[C:7]([C:35]2[CH:36]=[N:37][C:38]([C:43]([F:45])([F:46])[F:44])=[CH:39][C:40]=2[C:41]#[N:42])=[CH:6][C:5]([S:17]([N:20]([CH3:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)(=[O:19])=[O:18])=[C:4]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][OH:33])[CH:3]=1
Reactant: N#Cc1cc(C(F)(F)F)ncc1Br
Reactant: CN(c1ccccn1)S(=O)(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(Cl)cc1OCCCCO
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CN(c1ccccn1)S(=O)(=O)c1cc(-c2cnc(C(F)(F)F)cc2C#N)c(Cl)cc1OCCCCO
Temperature: 90 °C
Yield: 37.5 %

Procedure:
A mixture of 4-chloro-2-(4-hydroxy-butoxy)-N-methyl-N-pyridin-2-yl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzenesulfonamide (150 mg, 0.34 mmol), 5-bromo-2-trifluoromethyl-isonicotinonitrile (111 mg, 0.44 mmol), Pd(Ph3P)4 (40 mg, 0.034 mmol) and Na2CO3 (217 mg, 2.1 mmol) in dioxane (2 mL) and water (0.2 mL) was degassed with N2 for 5 min. The reaction vessel was sealed and then heated at 90° C. for 16 hrs. The mixture was absorbed onto silica gel and purified by chromatography on silica gel eluting with 20-25% acetone in hexanes to give 4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(4-hydroxy-butoxy)-N-methyl-N-pyridin-2-yl-benzenesulfonamide as an oil (69 mg). A small sample was also purified by prep. LCMS. MS: 541.1 (M+H)+; tR=7.59 min (method 2).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[CH3:20][CH:21]([NH:23][CH2:24][CH:25]1[CH2:29][CH2:28][NH:27][CH2:26]1)[CH3:22].N12CCCN=C1CCCCC2>C(#N)C>[CH3:20][CH:21]([NH:23][CH2:24][CH:25]1[CH2:29][CH2:28][N:27]([C:2]2[N:11]=[C:10]3[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]3[CH:12]3[CH2:14][CH2:13]3)=[CH:4][C:3]=2[F:19])[CH2:26]1)[CH3:22]
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: CC(C)NCC1CCNC1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)NCC1CCN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 111.6 %

Procedure:
A suspension of 1.13 g (3.0 mmole) of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 0.63 g (4.4 mmole) of 3-[(2-propyl)aminomethyl]pyrrolidine, 1.22 g (8.0 mmole) of 1,8-diazabicyclo[5.4.0]undec-7-ene and 30 ml of acetonitrile was stirred at room temperature for two hours. The precipitate was removed by filtration, washed with acetonitrile, and dried in vacuo to give 1.3 g (84%) of the title compound, mp 240°-243° C.