Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([C:27]4[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=4)=[CH:21][C:22]=3[C:23]([F:26])([F:25])[F:24])[CH:13]=2)[CH:8]=[CH:7]1)C.[Li+].[OH-]>>[F:37][C:34]([F:35])([F:36])[O:33][C:30]1[CH:29]=[CH:28][C:27]([C:20]2[N:19]=[CH:18][C:17]([CH2:16][O:15][C:12]3[CH:13]=[C:14]4[C:9]([CH:8]=[CH:7][N:6]4[CH2:5][C:4]([OH:38])=[O:3])=[CH:10][CH:11]=3)=[C:22]([C:23]([F:24])([F:25])[F:26])[CH:21]=2)=[CH:32][CH:31]=1
Reactant: CCOC(=O)Cn1ccc2ccc(OCc3cnc(-c4ccc(OC(F)(F)F)cc4)cc3C(F)(F)F)cc21
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)Cn1ccc2ccc(OCc3cnc(-c4ccc(OC(F)(F)F)cc4)cc3C(F)(F)F)cc21

Procedure:
In analogy to the procedure described in example 5 g], {6-[6-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-pyridin-3-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester was treated with LiOH to obtain the title compound as yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](O)=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[C:21]1([NH:27][OH:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)(=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:19])[N:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[OH:28])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: ONc1ccccc1
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23)N(O)c1ccccc1
Yield: 26.4 %

Procedure:
A procedure similar to that described in Example 5 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (150 mg, 0.44 mmol) and N-phenylhydroxylamine (80 mg, 0.73 mmol) to give 50 mg of the title compound (26%) after silica gel column chromatography with 2% acetic acid/ethyl acetate: mp>270° C.; 1H NMR (270 MHz, DMSO-d6) δ12.04 (s, 1H), 10.01 (s, 1H), 7.56 (d, 2H, J=7.9 Hz), 7.30 (t, 2H, J=7.9 Hz), 7.24 (d, 1H, J=2 Hz), 7.17 (d, 1H, J=2 Hz), 7.05 (t, 1H, J=7.4 Hz), 5.17~5.26 (m, 1H), 3.06 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.83 (dm, 1H, J=17.1 Hz), 2.58~2.62 (m, 2H), 2.09 (dm, 1H, J=13.5 Hz), 1.81~1.95 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([CH3:19])[C:8]1[S:12][C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Br:21]N1C(=O)CCC1=O>C(#N)C>[C:1]([O:5][C:6](=[O:20])[N:7]([C:8]1[S:12][C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:10][C:9]=1[Br:21])[CH3:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CN(C(=O)OC(C)(C)C)c1cnc(-c2cccnc2)s1
Solvent: CC#N
Product: CN(C(=O)OC(C)(C)C)c1sc(-c2cccnc2)nc1Br
Reaction time: 1 h
Yield: 64.3 %

Procedure:
To a solution of methyl-(2-pyridin-3-yl-thiazol-5-yl)-carbamic acid tert-butyl ester (100 mg, 0.34 mmol) in acetonitrile (2 mL) was added N-bromosuccinimide (122 mg, 0.68 mmol) in one portion and the reaction mixture was stirred for 1 h. The reaction mixture was concentrated and the crude product was purified by silica gel chromatography (0 to 100% ethyl acetate/hexanes) to give the desired product as a white solid (81 mg, 64%): mp 88-91° C.; IR (KBr) 1715 cm−1; 1H NMR (300 MHz, CDCl3) δ 9.11 (s, 1H), 8.70 (d, J=4.2 Hz, 1H), 8.28-8.17 (m, 1H), 7.42 (dd, J=8.1, 4.8 Hz, 1H), 3.27 (s, 3H), 1.48 (s, 9H); ESIMS m/z 372 (M+2).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.CC(O[C:24]([N:26]([CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)C)=O)(C)C.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:31]3[CH2:32][CH2:33][CH:28]([NH:26][CH3:24])[CH2:29][CH2:30]3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CNC1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.3 %

Procedure:
To a stirred suspension of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (1.0 g; 3.5 mmol), 4-N-Boc-4-N-methylaminopiperidine (1.0 g; 4.7 mmol) and AcOH (0.2 mL) in 1,2-dichloroethane (25 mL) was added NaB(OAc)3H (1.0 g; 4.7 mmol). The reaction mixture was stirred at RT for 5 h upon which time it was quenched with saturated NaHCO3 solution (30 mL), diluted with H2O (50 mL) and extracted with EtOAc (200 mL). The organic layer was dried (Na2SO4) and concentrated to a yellow foam (1.84 g). This foam was dissolved in CH2Cl2 (20 mL) and treated with TFA (10 mL) at RT overnight (17 h). Volatiles were removed in vacuo, the residue was taken up in 2M HCl (30 mL) and washed with CH2Cl2 (40 mL). The aqueous layer was basified with saturated Na2CO3 solution, extracted into CH2Cl2, the organic layer separated (hydrophobic frit) and solvent evaporated to give the title compound as a pale yellow solid (1.18 g; 88%).
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]2[C:18]([NH2:19])=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1([S:25](N2C=C[N+](C)=C2)(=[O:27])=[O:26])C=CN=C1.FC(F)(F)S([O-])(=O)=O>CC#N>[C:1]1([N:7]2[S:25](=[O:27])(=[O:26])[NH:19][C:18]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][N:16]=4)[CH:11]=[CH:10][C:9]=3[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[n+]1ccn(S(=O)(=O)n2ccnc2)c1
Reactant: Nc1c(CNc2ccccc2)ccc2cccnc12
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CC#N
Product: O=S1(=O)Nc2c(ccc3cccnc23)CN1c1ccccc1
Temperature: 25 °C
Yield: 4 %

Procedure:
A solution of 7-phenylaminomethyl-quinolin-8-ylamine (Intermediate 206) (350 mg, 1.4 mmol) and 1-(1H-imidazole-1-sulfonyl)-3-methyl-1H-imidazol-3-ium; trifluoromethanesulfonate (762 mg, 2.1 mmol) in MeCN (10 ml) was stirred at 0° C. then allowed to warm to room temperature overnight. The reaction mixture was concentrated in vacuo and the crude residue was purified by preparative HPLC (basic conditions) to give the title compound (18 mg, 4%).
Reaction SMILES: [S:1]1[N:5]=[CH:4][C:3]([NH2:6])=[N:2]1.[CH3:7][O:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[C:19]1[C:28]2[C:23](=[CH:24][C:25]([S:29](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:31])=[O:30])=[CH:26][CH:27]=2)[CH:22]=[CH:21][N:20]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH3:7][O:8][C:9]1[CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:12]=[CH:11][C:10]=1[C:19]1[C:28]2[C:23](=[CH:24][C:25]([S:29]([NH:6][C:3]3[CH:4]=[N:5][S:1][N:2]=3)(=[O:31])=[O:30])=[CH:26][CH:27]=2)[CH:22]=[CH:21][N:20]=1
Reactant: Nc1cnsn1
Reactant: COc1cc(C(F)(F)F)ccc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(C(F)(F)F)ccc1-c1nccc2cc(S(=O)(=O)Nc3cnsn3)ccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1,2,5-thiadiazol-3-amine (28 mg, 0.273 mmol) (Aquila Pharmtech) and perfluorophenyl 1-(2-methoxy-4-(trifluoromethyl)phenyl)isoquinoline-6-sulfonate (Intermediate LLL; 100 mg, 0.182 mmol) were dissolved in THF (1 mL) in a round bottom flask and cooled to 0° C., then lithium bis(trimethylsilyl)amide (1 M in THF, 364 μl, 0.364 mmol) was added and the reaction was stirred for 30 min. The reaction was quenched with saturated ammonium chloride and extracted with EtOAc (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated via rotary evaporation. The residue was purified using reverse-phase HPLC with a Waters-Xbridge C18, 19×100 mm, 10 μm column with a gradient 5-95% acetonitrile and water with 0.1% ammonium hydroxide modifier to yield 1-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(1,2,5-thiadiazol-3-yl)isoquinoline-6-sulfonamide. m/z (ESI) 467.0 (M+H)+.
Reaction SMILES: S([O-])(O)(=O)=O.[K+].O[C:8]1([C:23]2[CH:24]=[C:25]([F:29])[CH:26]=[CH:27][CH:28]=2)[CH2:13][CH2:12][CH:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([CH2:20][CH2:21][CH3:22])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1>>[CH2:20]([C@H:17]1[CH2:16][CH2:15][C@H:14]([CH:11]2[CH2:12][CH2:13][C:8]([C:23]3[CH:24]=[C:25]([F:29])[CH:26]=[CH:27][CH:28]=3)=[CH:9][CH2:10]2)[CH2:19][CH2:18]1)[CH2:21][CH3:22]
Reactant: CCC[C@H]1CC[C@H](C2CCC(O)(c3cccc(F)c3)CC2)CC1
Agent: O=S(=O)([O-])O
Agent: [K+]
Product: CCC[C@H]1CC[C@H](C2CC=C(c3cccc(F)c3)CC2)CC1

Procedure:
Slaked magnesium (4.8 g, 0.2 mol) was placed in a three-necked flask, followed by slowly dropwise adding a solution of 3-fluorobromobenzene (I) (35.0 g, 0.2 mol) dissolved in anhydrous tetrahydrofuran (50 ml) in nitrogen gas current with stirring while keeping the reaction temperature at 30°-35° C. to obtain a black-gray colored, uniform tetrahydrofuran solution of 3-fluorophenylmagnesium bromide (II), dropwise adding to this solution, a solution of 4-(trans-4-propylcyclohexyl)cyclohexanone (a compound of the formula (III) wherein R1 =C3H7) (46.7 g, 0.21 mol) dissolved in tetrahydrofuran (50 ml) over 30 minutes while keeping the reaction temperature at 5°-10° C., raising the temperature up to 35° C. after completion of the dropwise addition, aging the resulting solution for one hour, adding 3N hydrochloric acid (100 ml), extracting the resulting separated oily substance with toluene (100 ml) with stirring, washing the extract solution with water until the washing water became neutral to obtain a toluene solution of a 3-[1-hydroxy-4-(trans-4-propylcyclohexyl)cyclohexyl]fluorobenzene (a compound of the formula (IV) wherein R1 =C3H7), adding potassium hydrogen sulfate (3.2 g) to the toluene extract solution, removing the resulting water in the form of an azeotrope with toluene under reflux on heating, washing the toluene solution after completion of the reaction with water until the washing water became neutral, distilling off toluene to obtain a concentrated substance of 3-[4-(trans-4-propylcyclohexyl)cyclohexen -1-yl]fluorobenzene (a compound of the formula (V) wherein R1 =C3H7), dissolving this substance without purification in ethyl alcohol (200 ml), subjecting the solution to catalytic reduction reaction using a developed Raney Ni (2.0 g) as a catalyst under the atmospheric pressure and at 25° C., filtering off Raney Ni after hydrogen absorption has ceased, distilling off ethyl alcohol from the ethyl alcohol filtrate and recrystallizing the residue from ethyl acetate, to obtain 3-[trans-4-(trans-4-propylcyclohexyl)cyclohexyl]fluorobenzene (a compound of the formula (VI) wherein R1 =C3H7) . (38.7 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11](Cl)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[NH:16][NH2:17]>C(O)CCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([NH:17][NH:16][C:15]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)NN
Reactant: Clc1ccc(-c2ccc(Br)cc2)nn1
Solvent: CCCCO
Product: CCOC(=O)NNc1ccc(-c2ccc(Br)cc2)nn1
Temperature: 25 °C

Procedure:
A mixture of 2.69 g. of 6-(p-bromophenyl)-3-chloropyridazine and 3.12 g. of ethyl carbazate in 50 ml. of n-butyl alcohol is prepared. This solution is stirred and heated at reflux temperature for 4 hours. The reaction mixture is cooled to room temperature and the solvent removed on a rotation evaporator. The residue is triturated with water and the resulting solid collected by filtration. The product is recrystallized from ethanol to give crystalline material, m.p. 190°-192° C.
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][N:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:33]([S:35](Cl)(=[O:37])=[O:36])[CH3:34]>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH2:33]([S:35]([N:23]1[CH2:24][CH2:25][CH:20]([C:11]2[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=[C:8]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:9]=3)[NH:13][N:12]=2)[CH2:21][CH2:22]1)(=[O:37])=[O:36])[CH3:34]
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)n[nH]c12
Reactant: CCS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4ccccc4)cc23)CC1
Reaction time: 12 h

Procedure:
The crude 5-phenyl-3-(4-piperidinyl)-1H-indazole-7-carboxamide hydrochloride (Example 2) was suspended in DMF (8 mL) and treated with triethylamine (0.3 mL, 2.2 mmols), DMAP (0.0056 g, 0.065 mmol), and ethane sulfonyl chloride (0.044 mL, 0.47 mmols) at ambient temperature. After 12 hrs, the mixture was concentrated to dryness in vacuo at ambient temperature, treated with water (10 mL), and extracted with ethyl acetate (3×25 mL). The organic phase was washed with water, dried over MgSO4, filtered, and concentrated to give a light brown solid. This was purified via preparative HPL, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) to give 0.080 g of a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([Br:25])[CH:16]=3)=[C:7]([C:13]#[N:14])[C:8](=[NH:12])[O:9]2)=[CH:4][CH:3]=1.C(ON=O)(C)(C)C.NC1C=C2C(C(C3C=C(OC)C(OC)=C(Br)C=3)=C(C#N)C(=N)O2)=CC=1>C(#N)C.CCOC(C)=O>[NH2:12][C:8]1[O:9][C:10]2[C:5]([CH:6]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([Br:25])[CH:16]=3)[C:7]=1[C:13]#[N:14])=[CH:4][CH:3]=[C:2]([Br:1])[CH:11]=2
Reactant: COc1cc(-c2c(C#N)c(=N)oc3cc(Br)ccc23)cc(Br)c1OC
Agent: CC(C)(C)ON=O
Agent: COc1cc(-c2c(C#N)c(=N)oc3cc(N)ccc23)cc(Br)c1OC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cc(C2C(C#N)=C(N)Oc3cc(Br)ccc32)cc(Br)c1OC
Temperature: 0 °C
Reaction time: 4 h
Yield: 43 %

Procedure:
7-Bromo-4-(3-bromo-4,5-dimethoxy-phenyl)-3-cyano-2-imino-2H-chromene: To a suspension of t-butyl-nitrite (34 mg, 0.33 mmol), CuBr2 (68 mg, 0.30 mmol) in anhydrous acetonitrile (1.5 mL) at 0° C. was added 7-amino-3-cyano-2-imino-4-(3-bromo-4,5-dimethoxy-phenyl)-2H-chromene (100 mg, 0.25 mmol). The mixture was stirred at 0° C. for 4 h, then was diluted with EtOAc (50 mL), washed with saturated NaHCO3 (25 mL), brine (10 mL), dried over MgSO4, and evaporated to yield a yellow solid. The crude was purified by column chromatography (silica gel, EtOAc:hexanes, 1:2 to 1:1) to yield 50 mg (43%) of the title compound as a yellow solid. 1H NMR (CDCl3): 7.82 (brs, 1H), 7.38 (m, 1H), 7.30 (dd, J=2.1, 8.7 Hz, 1H), 7.18 (d, J=2.1 Hz, 1H), 7.09 (d, J=9.0 Hz, 1H), 6.93 (m, 1H), 3.96 (s, 3H), 3.92 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2Br)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CNCCN1
Reactant: CC(C)(C)OC(=O)N1CCCC(Oc2ccccc2Br)C1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)(C)OC(=O)N1CCCC(Oc2ccccc2N2CCNCC2)C1
Temperature: 100 °C
Yield: 51 %

Procedure:
The compound of Step 1 (600 mg, 1.68 mmol), piperazine (174 mg, 2.02 mmol), Pd2(dba)3 (77 mg, 0.084 mmol), BINAP (157 mg, 0.252 mmol), and sodium tert-butoxide (226 mg, 2.35 mmol) were mixed together and degassed followed by the addition of toluene (20 mL). The mixture was heated to 100° C. for about 16 hours. The mixture was cooled to r.t, and then diluted with ether (50 mL), filtered through celite and concentrated. The residue was subjected to SCX purification, and the resultant oil was chromatographed on silica gel (MeOH (NH3 2M)/DCM) to give the final compound (311. mg, 51%) as a yellow foam. MS found 362.3, M+1
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:12]2[Br:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:31][C:30]1[CH:33]=[CH:34][C:27]([F:26])=[CH:28][CH:29]=1)[C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:12]2[Br:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1[nH]c2ccc(OCc3ccccc3)cc2c1Br
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Br)c2cc(OCc3ccccc3)ccc2n1Cc1ccc(F)cc1
Temperature: 0 °C
Yield: 75 %

Procedure:
A solution of ethyl 5-(benzyloxy)-3-bromo-1H-indole-2-carboxylate, Ref. WO96/18393 (6.77 g, 20.3 mmol, Ref. 96/18393) in N,N-dimethylformamide (10+5 mL rinse) was added slowly (10 min) to a cooled (0° C.) and stirred suspension of sodium hydride (0.72 g, 30 mmol) in N,N-dimethylformamide (30 mL). The reaction was stirred for 1 h and then 4-fluorobenzylbromide (3.7 mL, 5.7 g, 30 mmol) was added. The cold bath was removed and the mixture was stirred for 18 h. The reaction was quenched by pouring over ice water (400 mL) and then the product was extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. Flash chromatography of the residue over silica gel using 50% dichloromethane/hexane gave 6.80 g (75%) of the desired product containing trace impurities. The product had: 1H NMR (300 MHz, CDCl3) δ 6.84-7.53 (m, 12 H), 5.72 (s, 2 H), 5.13 (s, 2 H), 4.38 (q, 2 H), 1.40 (t, 3 H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[N:7]=[CH:8][C:9]2[CH:15]=[CH:14][C:13]([CH3:16])=[N:12][C:10]=2[N:11]=1.C1C(=O)N([Br:24])C(=O)C1>C1COCC1>[Br:24][C:14]1[C:13]([CH3:16])=[N:12][C:10]2[N:11]=[C:6]([NH:5][CH2:4][CH2:3][O:2][CH3:1])[N:7]=[CH:8][C:9]=2[CH:15]=1
Reactant: COCCNc1ncc2ccc(C)nc2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: COCCNc1ncc2cc(Br)c(C)nc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.3 %

Procedure:
Heat a solution of 7-methyl-2-(methylthio)pyrido[2,3-d]pyrimidine (2.6 g, 13.6 mmol) and 2-methoxyethanamine (6 mL) with microwave irradiation at 180° C. for 2 h. Cool the mixture to RT, dissolve in EtOAc, wash with water, then brine, dry over Na2SO4 and concentrate under reduced pressure to give N-(2-methoxyethyl)-7-methylpyrido[2,3-d]pyrimidin-2-amine (2.7 g, 91%). Treat a solution of N-(2-methoxyethyl)-7-methylpyrido[2,3-d]pyrimidin-2-amine (2.35 g, 10.7 mmol) in THF (100 mL) portion wise with NBS (1.8 g, 10.7 mmol) and stir at RT for 2 h. Concentrate the reaction mixture to dryness, dissolve in EtOAc, wash with water, then brine, dry the organics over Na2SO4, concentrate and purify by HPLC to afford the title compound (0.55 g, 26%). MS (m/z): 297.0 (M+1+).
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][C@H:8]([O:19][S:20]([CH3:23])(=[O:22])=[O:21])[C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=1)[CH3:10])(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.Cl>[Cl:18][C:13]1[CH:12]=[C:11]([C@@H:9]([CH3:10])[C@@H:8]([O:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH2:7][OH:6])[CH:16]=[CH:15][C:14]=1[Cl:17]
Reactant: C[C@H](c1ccc(Cl)c(Cl)c1)[C@H](CO[Si](C)(C)C(C)(C)C)OS(C)(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@H](c1ccc(Cl)c(Cl)c1)[C@H](CO)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 94.1 %

Procedure:
To a solution of (2R,3R)-1-(tert-butyl-dimethyl-silyloxy)-3-(3,4-dichloro-phenyl)-2-methanesulfonyloxy-butane (4.99 g, 11.7 mmol) in THF (117 mL) at 0° C. was added tetrabutylammonium fluoride (TBAF; 1.0 M in THF, 23.4 mL). The solution was stirred at 0° C. for 15 min, then was diluted with 1 N HCl (100 ml) and extracted with DCM (3×). The combined organic layers were dried (Na2SO4) and concentrated to yield a yellow oil. The product was purified by flash chromatography (EtOAc/hexanes) to give 3.45 g (94%) of the desired product. 1H NMR (400 MHz, CDCl3): 7.41 (d, J=8.0, 1H), 7.35 (d, J=2.0, 1H), 7.12 (dd, J=8.2, 2.4, 1H), 4.82-4.78 (m, 1H), 3.88-3.84 (m, 1H), 3.74-3.69 (m, 1H), 3.17 (q, J=7.1, 1H), 2.78 (s, 3H), 1.98 (br s, 1H), 1.36 (d, J=7.2, 3H).
Reaction SMILES: [CH2:1]1[C:3]2([CH2:7][CH:6](CS([O-])(=O)=O)[CH2:5][O:4]2)[CH2:2]1.[OH:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18]([O:24][C:25]3[CH:30]=[CH:29][C:28]([N:31]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:32]([C:34]4([C:37]([NH2:39])=[O:38])[CH2:36][CH2:35]4)=[O:33])=[CH:27][C:26]=3[F:46])=[CH:19][CH:20]=[N:21]2)=[CH:16][C:15]=1[O:47][CH3:48].C([O-])([O-])=O.[Cs+].[Cs+]>CC(N(C)C)=O>[CH2:2]1[C:3]2([CH2:7][CH:6]([O:13][C:14]3[CH:23]=[C:22]4[C:17]([C:18]([O:24][C:25]5[CH:30]=[CH:29][C:28]([N:31]([C:40]6[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=6)[C:32]([C:34]6([C:37]([NH2:39])=[O:38])[CH2:36][CH2:35]6)=[O:33])=[CH:27][C:26]=5[F:46])=[CH:19][CH:20]=[N:21]4)=[CH:16][C:15]=3[O:47][CH3:48])[CH2:5][O:4]2)[CH2:1]1
Reactant: O=S(=O)([O-])CC1COC2(CC2)C1
Reactant: COc1cc2c(Oc3ccc(N(C(=O)C4(C(N)=O)CC4)c4ccccc4)cc3F)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc(N(C(=O)C4(C(N)=O)CC4)c4ccccc4)cc3F)ccnc2cc1OC1COC2(CC2)C1

Procedure:
The title compound was prepared according to the procedure described in Example 24 by using (4-oxaspiro[2.4]heptane-6-yl)methanesulfonate (138 mg, 0.72 mmol), N-(4-(7-hydroxy-6-methoxyquinolin-4-yloxy)-3-fluorophenyl)-N-phenylcyclopropane-1,1-dicarboxamide (300 mg, 0.616 mmol), and Cs2CO3 (602.5 mg, 1.848 mmol) in 3 mL of DMA. The residue was purified by a silical gel column chromatography (2:1 (v/v) EtOAc/n-hexane). The title compound was obtained as a white solid (186.7 mg, 52%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[O:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1.[O-]S([O-])(=O)=O.[Na+].[Na+]>C(O)(=O)C>[Br:11][C:8]1[CH:9]=[CH:10][C:2]([NH:1][CH:15]2[CH2:16][CH2:17][O:12][CH2:13][CH2:14]2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: Nc1ccc(Br)cc1C(=O)O
Reactant: O=C1CCOCC1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)c1cc(Br)ccc1NC1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
A mixture of 5 g of 2-amino-5-bromobenzoic acid, 9.27 g of tetrahydro-4H-pyran-4-one and 32 g of Na2SO4 in 50 ml of acetic acid is stirred overnight at room temperature. The reaction mixture is filtered. A further 9.27 g of tetrahydro-4H-pyran-4-one and 32 g of Na2SO4 are added and the resulting mixture is stirred overnight at room temperature. This mixture is filtered and 9.81 g of NaBH(OAc)3 are added. The resulting mixture is allowed to cool to room temperature over 2 hours. The reaction medium is evaporated under reduced pressure and the residue is taken up in EtOAc. It is washed with aqueous 1N HCl solution. The organic phase is dried over Na2SO4, filtered and evaporated under reduced pressure to give 3.35 g of the expected product.
Reaction SMILES: C([SiH2][O:6][C:7](C1C=CC=CC=1)(C1C=CC=CC=1)[C:8]1[CH:13]=[CH:12][C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][N:9]=1)(C)(C)C.Cl[C:36]1[N:37]=[C:38]([N:56]2[CH2:61][CH2:60][O:59][CH2:58][CH2:57]2)[C:39]2[CH:44]=[C:43]([CH2:45][N:46]3[CH2:51][CH2:50][N:49]([S:52]([CH3:55])(=[O:54])=[O:53])[CH2:48][CH2:47]3)[S:42][C:40]=2[N:41]=1>>[CH3:55][S:52]([N:49]1[CH2:50][CH2:51][N:46]([CH2:45][C:43]2[S:42][C:40]3[N:41]=[C:36]([C:11]4[CH:12]=[CH:13][C:8]([CH2:7][OH:6])=[N:9][CH:10]=4)[N:37]=[C:38]([N:56]4[CH2:57][CH2:58][O:59][CH2:60][CH2:61]4)[C:39]=3[CH:44]=2)[CH2:47][CH2:48]1)(=[O:54])=[O:53]
Reactant: CC(C)(C)[SiH2]OC(c1ccccc1)(c1ccccc1)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Product: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(-c4ccc(CO)nc4)nc3s2)CC1

Procedure:
2-(tert-Butyl-diphenyl-silanyloxymethyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine was reacted with 2-chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[2,3-d]pyrimidine in General Procedure A. Purification on silica yielded 362. NMR: (CDCl3): 2.58-2.60 (4 H, m), 2.73 (3 H, s, Me), 3.20-3.22 (4 H, m), 3.75 (2 H, s), 3.81-3.84 (4 H, m), 3.90-3.92 (4 H, m), 4.76 (2 H, s, NH2), 6.92 (1 H, s, Ar), 7.25 (1 H, d, J 8.3, Ar), 8.61 (1 H, d, J 8.3, Ar) and 9.51 (1 H, s, Ar). MS: (ESI+): MH+=505.14