Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl.[CH3:50][O:51][C:52]1[N:57]=[C:56]2[S:58][C:59]([NH2:61])=[N:60][C:55]2=[CH:54][CH:53]=1>C(Cl)Cl.CN(C=O)C.O>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([NH:61][C:59]2[S:58][C:56]3[C:55]([N:60]=2)=[CH:54][CH:53]=[C:52]([O:51][CH3:50])[N:57]=3)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCN(S(=O)(=O)c2ccc(C(CC3CCCC3)C(=O)O)cc2)CC1
Reactant: COc1ccc2nc(N)sc2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc2nc(NC(=O)C(CC3CCCC3)c3ccc(S(=O)(=O)N4CCN(C)CC4)cc3)sc2n1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A solution of the title E compound, 3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid (5 g, 0.013 mol) in DCM (250 mL) is cooled to 0° C. and then charged HOBt hydrate (2.66 g, 0.019 mol), followed by EDCI hydrochloride (6 g, 0.031 mol). The reaction mixture is stirred at 0° C. for 5 h. After that the solution of the title F compound, 5-methoxy-thiazolo[5,4-b]pyridin-2-ylamine (2.36 g, 0.013 mol) and D1EA (8 mL, 0.046 mol) in a mixture of DCM (60 mL) and DMF (20 mL) is added dropwise over 30 min. Reaction temperature is maintained at 0° C. for 3 h, then at RT (28° C.) for 3 days. Reaction is diluted with (60 mL) of water and the organic layer is separated and washed with saturated sodium bicarbonate solution (2×50 mL) followed by water washing (2×50 mL) and saturated sodium chloride aqueous solution (1×150 mL). Finally the organic layer is dried over sodium sulfate, filtered, and evaporated under vacuo. The crude product is purified using column chromatography over silica gel (60-120 mesh), using 40% ethyl acetate in hexane as an eluent to afford 3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide as a white solid: 1H NMR (400 MHz, CDCl3) δ 0.9-2.1 (m, 11H), 2.2 (s, 3H), 2.5 (br s, 4H), 3.1 (br s, 4H), 3.7 (m, 1H), 4.0 (s, 3H), 6.8 (d, J=8.8, 1H), 7.5 (d, J=8.3, 2H), 7.7 (d, J=8.3, 2H), 7.8 (d, J=8.8, 1H), 8.6 (s, 1H); MS 617 [M+1]+.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:10]([O:14][C:15]([NH:17][CH2:18][CH:19](O)C)=[O:16])([CH3:13])([CH3:12])[CH3:11].O.[CH2:23]1COCC1>>[C:10]([O:14][C:15]([NH:17][C@H:18]([CH3:19])[CH2:23][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:16])([CH3:11])([CH3:12])[CH3:13]
Reactant: CC(O)CNC(=O)OC(C)(C)C
Reactant: Sc1ccccc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: C[C@H](CSc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85 %

Procedure:
Thiophenol (1.5 g, 14 mmol) was dissolved in dry THF (100 ml) and a 60% oil dispersion of sodium hydride (0.30 g, 14 mmol) was added in portions under nitrogen. After stirring for 15 min. at room temperature, the mesylate ester of N-tert-butoxycarbonyl-2-hydroxypropylamine (3.2 g, 14 mmol) was added in three portions and the reaction mixture was heated at 70° C. for 18 h. After cooling, water (30 ml) was added, the aqueous phase was separated and washed with dichloromethane (50 ml). The combined organic phases were dried (MgSO4) and evaporated to give (R)- N-tertbutyloxycarbonyl-1-phenylthio-2-propylamine as a fawn oil (3.2 g, 85%), TLC Rf 0.64 [SiO2 : heptanethyl acetate (1:1)].
Reaction SMILES: C(=O)(O)O.[NH2:5][C:6]([NH2:8])=[NH:7].[CH2:9]([O:11][C:12](=[O:23])[C:13](=[CH:19]OCC)[C:14](OCC)=[O:15])[CH3:10].O.Cl>C(O)C>[CH2:9]([O:11][C:12]([C:13]1[C:14]([OH:15])=[N:7][C:6]([NH2:8])=[N:5][CH:19]=1)=[O:23])[CH3:10]
Reactant: N=C(N)N
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: Cl
Agent: O=C(O)O
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cnc(N)nc1O
Temperature: 25 °C
Reaction time: 96 h
Yield: 83.3 %

Procedure:
Guanidine carbonate (18.0 g, 200 mmol) is dissolved in ethanol (300 ml), and then sodium alcoholate (13.6 g) and ethoxymethylenemalonic acid diethyl ester (43.2 g, 200 mmol) are added at room temperature. After stirring at room temperature for 4 days, the mixture is concentrated to dryness under reduced pressure. To the residue obtained, water (500 ml) is added and neutralized with hydrochloric acid, and then the crystal precipitated is collected by filtration and recrystallized, to yield a white crystal (30.5 g, 83%).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[CH:25]([C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:28]=1B(O)O)=[O:26]>>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[N:14]=[C:10]([C:8]3[CH:9]=[C:4]([C:3]([OH:2])=[O:24])[C:5]([C:28]4[CH:29]=[C:30]([CH3:33])[CH:31]=[CH:32][C:27]=4[CH:25]=[O:26])=[CH:6][CH:7]=3)[S:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: Cc1ccc(C=O)c(B(O)O)c1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: Cc1ccc(C=O)c(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)c1
Yield: 19.2 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with 2-formyl-5-methylphenylboronic acid (available from Frontier Scientific, Inc.; 66 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-2′-formyl-5′-methyl-biphenyl-2-carboxylic acid (18 mg, 19%). 1H NMR (400 MHz, DMSO-d6) δ 13.10 (br s, 1H), 9.72 (s, 1H), 8.52 (d, J=1.8 Hz, 1H), 8.49 (s, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.26 (dd, J=8.0, 2.0 Hz, 1H), 8.10 (dd, J=8.5, 2.0 Hz, 1H), 7.83 (d, J=8.0 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.17 (s, 1H), 2.43 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]1[C:11](=[O:17])[NH:12][C:13](=[O:16])[NH:14][CH:15]=1.[CH3:18][Si](C([Si](C)(C)C)C(N)=O)(C)C.[F:30][C:31]1[C:38]([C:39]([F:42])([F:41])[F:40])=[CH:37][CH:36]=[CH:35][C:32]=1CBr>C(#N)C>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]1[C:11](=[O:17])[NH:12][C:13](=[O:16])[N:14]([CH2:18][C:31]2([F:30])[C:38]([C:39]([F:40])([F:41])[F:42])=[CH:37][CH:36]=[CH:35][CH2:32]2)[CH:15]=1
Reactant: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Reactant: COc1cccc(-c2c[nH]c(=O)[nH]c2=O)c1Cl
Reactant: Fc1c(CBr)cccc1C(F)(F)F
Solvent: CC#N
Product: COc1cccc(-c2cn(CC3(F)CC=CC=C3C(F)(F)F)c(=O)[nH]c2=O)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.1 %

Procedure:
To a suspension of 5-(2-chloro-3-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione 7e (2.2 g, 8.7 mmol) in acetonitrile (25 mL) was added bis(trimethylsilyl)acetamide (4.3 mL, 17.4 mmol), and the resulting solution was refluxed for 1.5 hours. The mixture was cooled to room temperature, 2-fluoro-3-trifluoromethylbenzyl bromide (2.7 g, 10.5 mmol) was added, and reflux was resumed for 16 hours. The reaction was quenched by addition of MeOH (25 mL) and stirring for 2 hours. After concentration, the residue was purified by column chromatography on silica gel with ethyl acetate/hexanes 1/1 to afford 5-(2-chloro-3-methoxyphenyl)-1-[1-fluoro-6-(trifluoromethyl)benzyl]pyrimidine-2,4(1H,3H)-dione 7f (3.3 g, 88%) as a white solid. MS (CI) m/z 429.0, 431.0 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N:11]([O-])=O.[Na+].[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1>>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([N:8]=[N:11][C:18]2[CH:17]=[C:16]([CH3:15])[CH:21]=[CH:20][C:19]=2[SH:22])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccc(S)cc1
Reactant: O=N[O-]
Agent: [Na+]
Product: Cc1ccc(S)c(N=Nc2ccc([N+](=O)[O-])cc2)c1

Procedure:
This is prepared similarly to Example 1 using 19.6 g (142 mmoles) of 4-nitro-aniline, 10% sodium nitrite solution (103.5 ml), and 20 g (142 mmoles) of 4-methylthio-phenol.
Reaction SMILES: [CH:1]1([O:7][N:8]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.NN.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[CH:1]1([O:7][NH:8][S:29]([C:26]2[CH:25]=[CH:24][C:23]([O:22][CH3:21])=[CH:28][CH:27]=2)(=[O:31])=[O:30])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1c2ccccc2C(=O)N1OC1CCCCC1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: NN
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(S(=O)(=O)NOC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.6 %

Procedure:
2-(cyclohexyloxy)-1H-isoindole-1,3(2H)-dione (11.8 mmol, 2.89 g) was combined with hydrazine (13.0 mmol, 0.41 mL) in anhydrous THF (20 mL) under nitrogen. The reaction immediately formed a white suspension and was allowed to stir at room temperature for 18 hours. The suspension was filtered directly into a flask containing 4-methoxybenzenesulfonyl chloride (10.6 mmol, 2.20 g) and diisopropylethylamine (14.2 mmol, 2.47 mL) was added. After stirring at room temperature for 24 hours, the reaction was concentrated to a yellow solid and partitioned between ethyl acetate and 1N HCl. The organic layer was separated and washed with a saturated aqueous solution of sodium bicarbonate, and brine, and dried over magnesium sulfate. The product was concentrated to a yellow solid and purified by silica gel chromatography (1:1 hexanes/ethyl acetate) providing 2.53 g (83%) of a white solid. Rf: 0.2 (2:1 hexanes/ethyl acetate); H1-NMR (CDCl3): δ 7.86 (2H,d), 7.00 (2H,d), 6.67 (1H,s), 3.98-3.95 (1H,m), 3.88 (3H,s), 2.00-1.94 (2H,m), 1.75-1.55 (2H,m), 1.35-1.17 (6H,m).
Reaction SMILES: C(ON=O)CC(C)C.I[CH2:10][I:11].NC1[CH:22]=[C:21]2[C:16]([CH2:17][CH2:18][N:19]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][C:29]=3[C:30]([F:33])([F:32])[F:31])[C:20]2=[O:23])=[CH:15][C:14]=1[F:34].C(OCC)(=O)C>C1COCC1.CCCCCC.[Cu]I>[F:34][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:10]=1[I:11])[C:20](=[O:23])[N:19]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][C:29]=1[C:30]([F:31])([F:33])[F:32])[CH2:18][CH2:17]2
Reactant: Nc1cc2c(cc1F)CCN(c1cnccc1C(F)(F)F)C2=O
Reactant: ICI
Agent: [Cu]I
Agent: CC(C)CCON=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1c2cc(I)c(F)cc2CCN1c1cnccc1C(F)(F)F
Temperature: 70 °C
Reaction time: 1 h
Yield: 3.2 %

Procedure:
Isoamylnitrite (0.4 mL, 3.2198 mmol), diiodomethane (0.4 mL, 5.36 mmol) and CuI (203.9 mg, 1.07 mmol) were added to a stirred solution of 7-amino-6-fluoro-2-(4-(trifluoromethyl)pyridin-3-yl)-3,4-dihydroisoquinolin-1(2H)-one (I-79b: 350 mg, 1.07 mmol) in dry THF (10 mL). The resulting mixture was stirred for 1 hour at 70° C. The reaction was monitored by TLC (40% ethyl acetate in hexane). The reaction mixture was concentrated to yield the crude product. Purification by column chromatography on silica gel (30% ethyl acetate in hexane), followed by preparative HPLC afforded 15 mg of the product (10% yield).
Reaction SMILES: B(F)(F)F.C[CH2:6][O:7]CC.[CH3:10][O:11][C:12]1[CH:28]=[CH:27][C:15]([CH2:16][CH:17]2[C:22]([CH3:24])([CH3:23])[C:21](=[O:25])[CH2:20][CH2:19][N:18]2[CH3:26])=[CH:14][CH:13]=1.[OH-].[Na+].[CH3:31]O>>[CH3:31][O:25][C:21]1([O:7][CH3:6])[CH2:20][CH2:19][N:18]([CH3:26])[CH:17]([CH2:16][C:15]2[CH:14]=[CH:13][C:12]([O:11][CH3:10])=[CH:28][CH:27]=2)[C:22]1([CH3:24])[CH3:23]
Reactant: CO
Reactant: COc1ccc(CC2N(C)CCC(=O)C2(C)C)cc1
Reactant: CCOCC
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(CC2N(C)CCC(OC)(OC)C2(C)C)cc1
Reaction time: 16 h

Procedure:
40 ml of borontrifluoride etherate are added drop-wise over 20 minutes and with stirring to a solution of 52.2 g (0.2 Mol) 2-(4-methoxybenzyl)-1,3,3-trimethyl-4-piperidone in 500 ml methanol, the temperature being maintained below 35° C. After stirring for 16 hours at room-temperature 40 g pulverized sodium hydroxide are added. After stirring for a further 30 minutes the obtained sodium salts are filtered off and washed with methanol. The filtrate is evaporated under reduced pressure and after addition of 500 ml water, extracted 3 times with 150 ml of chloroform. The chloroform phases are dried over sodium sulphate and evaporated under reduced pressure. After crystallization from 200 ml petrol ether (b.p.: 60°-80° C.) and further recrystallization there are obtained 25.4 g 4,4-dimethoxy-2-(4-methoxybenzyl)-1,3,3-trimethylpiperidine, m.p.: 91°-92.5° C.
Reaction SMILES: [N+:1](=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12])=[N-:2].[CH2:13]([OH:16])[C:14]#[CH:15]>C(OCC)C>[OH:16][CH2:13][C:14]1[CH:15]=[C:3]2[N:1]([C:4](=[O:12])[NH:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=32)[N:2]=1
Reactant: [N-]=[N+]=C1C(=O)Nc2ccccc21
Reactant: C#CCO
Solvent: CCOCC
Product: O=c1[nH]c2ccccc2c2cc(CO)nn12
Temperature: 25 °C
Yield: 73.8 %

Procedure:
2.0 g (0.0126 mole) of 3-diazooxindole is dissolved in 22 ml of propargyl alcohol (0.378 mole) and refluxed under nitrogen for 3 hours. The reaction mixture is cooled to room temperature and diluted with 10 volumes of ethyl ether. The solid is filtered, washed with ethyl ether and dried to give 2.0 g of product (75% direct yield). Recrystallization from methanol gives 1.5 g of title compound, m.p. 286°-288° (sl. dec.).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([Cl:7])=[O:6].FC1C=CC(C=O)=CC=1>>[F:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([Cl:7])=[O:6])=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccc(F)c(Cl)c1
Agent: O=Cc1ccc(F)cc1
Product: O=C(Cl)c1ccc(F)cc1

Procedure:
A process for the preparation of 3-chloro-4-fluorobenzoyl chloride, which comprises reacting 4-fluorobenzaldehyde with a chlorinating agent in the presence of a free-radical initiator in the presence or absence of a solvent at from −20 to 200° C. to give 4-fluorobenzoyl chloride, and reacting the 4-fluorobenzoyl chloride with a chlorinating agent in the presence of a chlorination catalyst in the presence or absence of a solvent at from −20 to 200° C. to give 3-chloro-4-fluorobenzoyl chloride.
Reaction SMILES: [C:1]([O-:4])([O-])=O.[K+].[K+].Br[CH2:8][C:9]1[O:14][C:13](=[O:15])[C:12]([CH3:16])=[C:11]([O:17]COC)[C:10]=1[CH3:21].Cl.CN([CH:26]=[O:27])C>>[CH3:16][C:12]1[C:13](=[O:15])[O:14][C:9]([C:8]2[O:27][C:26]3[CH:13]=[CH:12][C:11]([O:4][CH3:1])=[CH:10][C:9]=3[CH:8]=2)=[C:10]([CH3:21])[C:11]=1[OH:17]
Reactant: CN(C)C=O
Reactant: COCOc1c(C)c(CBr)oc(=O)c1C
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Product: COc1ccc2oc(-c3oc(=O)c(C)c(O)c3C)cc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
K2CO3 (138 mg) was added to a solution of 5-methoxysalicyl aldehyde (152 mg) and 6-bromomethyl-3,5-dimethyl-4-methoxymethoxy-2H-pyran-2-one (277 mg) in DMF (5 ml), and the mixture was stirred at room temperature for 16 hours. A 6 N hydrochloric acid aqueous solution was slowly added to the reaction solution, and after stirring for one hour, extraction was performed with AcOEt and the organic layer was dried with MgSO4 and then filtered and concentrated. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=1/1) to obtain 3,5-dimethyl-4-hydroxy-6-(5-methoxybenzofuran-2-yl)-2H-pyran-2-one.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25](O)=[O:26])=[N:23][CH:24]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:15])([F:14])[C@:8]([C:4]2[CH:3]=[C:2]([NH:1][C:25]([C:22]3[CH:21]=[CH:20][C:19]([Cl:18])=[CH:24][N:23]=3)=[O:26])[CH:7]=[CH:6][CH:5]=2)([CH3:17])[N:9]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: C[C@]1(c2cccc(N)c2)N=C(N)OCC1(F)F
Product: C[C@]1(c2cccc(NC(=O)c3ccc(Cl)cn3)c2)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(3-amino-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-4) and 5-chloro-pyridine-2-carboxylic acid following procedure I yielded the title compound as an off-white solid. MS (ISP): m/z=381.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]1[C:20](O)=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>CN(C=O)C.CCOC(C)=O>[CH2:23]([NH:30][C:20]([CH:9]1[CH:10]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:11][CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2ccccc2)C1C(=O)O
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(c2ccccc2)C1C(=O)NCc1ccccc1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-3-phenylpiperidine-2-carboxylic acid (1.03 g, 3.36 mmol) in DMF (5 ml) were added benzyl amine (0.4 ml, 3.70 mmol), 1-hydroxybenzotriazole (567 mg, 3.70 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (949 mg, 4.70 mmol). The reaction was adjusted to pH 7 with the addition of diisopropylethylamine and allowed to stir for 1 h. The reaction mixture was diluted with EtOAc, washed with saturated sodium bicarbonate (3×) and brine (2×), dried over sodium sulfate, filtered, and concentrated in vacuo to yield tert-butyl 2-[(benzylamino)carbonyl]-3-phenylpiperidine-1-carboxylate (100%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[O:20])[C:10]3[N:14]=[C:13]([O:15][CH2:16][CH3:17])[NH:12][C:11]=3[CH:18]=2)=[C:5]([CH3:27])[O:4][N:3]=1.[CH:28]([Mg]Br)([CH2:30][CH3:31])[CH3:29]>C1COCC1>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)([OH:20])[CH:28]([CH3:29])[CH2:30][CH3:31])[C:10]3[N:14]=[C:13]([O:15][CH2:16][CH3:17])[NH:12][C:11]=3[CH:18]=2)=[C:5]([CH3:27])[O:4][N:3]=1
Reactant: CCOc1nc2c(C(=O)c3ccccn3)cc(-c3c(C)noc3C)cc2[nH]1
Reactant: CCC(C)[Mg]Br
Solvent: C1CCOC1
Product: CCOc1nc2c(C(O)(c3ccccn3)C(C)CC)cc(-c3c(C)noc3C)cc2[nH]1
Reaction time: 0.17 h

Procedure:
(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)methanone (20 mg, 0.055 mmol) was dissolved in dry THF (0.55 mL) under argon. Sec-butylmagnesium bromide (1.0 M in THF, 0.27 mL, 0.28 mmol) was added dropwise and the reaction was allowed to stir for 10 minutes. The reaction was quenched with water, concentrated and purified by reverse-phase HPLC to give 1-(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)-2-methyl-1-(pyridin-2-yl)butan-1-ol intermediate. Intermediate was taken up in 0.5 mL EtOH and 0.3 mL 4.0M HCl/dioxane and heated to 65° C. for 1 hr. Reaction was concentrated and purified by reverse phase HPLC to afford the desired product
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([S:11][CH3:12])=[N:9]2)=[CH:4][CH:3]=1.[N+:13]([C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1B(O)O)([O-:15])=[O:14].C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.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>[CH3:22][C:20]1[CH:19]=[CH:18][C:17]([C:2]2[N:10]3[C:5]([CH:6]=[N:7][C:8]([S:11][CH3:12])=[N:9]3)=[CH:4][CH:3]=2)=[C:16]([N+:13]([O-:15])=[O:14])[CH:21]=1
Reactant: CSc1ncc2ccc(Br)n2n1
Reactant: Cc1ccc(B(O)O)c([N+](=O)[O-])c1
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: C1COCCO1
Solvent: O
Product: CSc1ncc2ccc(-c3ccc(C)cc3[N+](=O)[O-])n2n1
Temperature: 95 °C

Procedure:
7-Bromo-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (600 mg, 2 mmol), 2-nitro-4-methyl-phenylboronic acid (500 mg, 3 mmol) 1.50 M of Sodium carbonate in Water (5 mL, 8 mmol) and dioxane (10 mL) were added to a RB flask. The reaction mixture was degassed with nitrogen for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (100 mg, 0.1 mmol) was added and the reaction mixture was degassed again. The reaction mixture was heated at 95° C. overnight under argon. MS showed product formation. The mixture was cooled to RT, concentrated, filtered through a pad of celite, and partitioned with water and EtOAc. The organic phase was separated, washed with brine, and dried over magnesium sulfate. After solvent evaporation, the product, 7-(4-Methyl-2-nitro-phenyl)-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine, was obtained as a solid which was further purified by taking in ether followed by filtration and washing with ether (628 mg, 80%). LCMS (E/I+) 301 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[N:13]1[CH:21]=[C:20]2[C:15]([CH2:16][CH2:17][CH:18]([NH2:22])[CH2:19]2)=[N:14]1.Cl[CH2:24][C:25]([C:27]1[CH:28]=[CH:29][C:30]2[O:35][CH2:34][C:33](=[O:36])[NH:32][C:31]=2[CH:37]=1)=[O:26].CCN(CC)CC>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[N:13]1[CH:21]=[C:20]2[C:15]([CH2:16][CH2:17][CH:18]([NH:22][CH2:24][C:25]([C:27]3[CH:28]=[CH:29][C:30]4[O:35][CH2:34][C:33](=[O:36])[NH:32][C:31]=4[CH:37]=3)=[O:26])[CH2:19]2)=[N:14]1
Reactant: O=C1COc2ccc(C(=O)CCl)cc2N1
Reactant: COc1ccc2nccc(-n3cc4c(n3)CCC(N)C4)c2c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc2nccc(-n3cc4c(n3)CCC(NCC(=O)c3ccc5c(c3)NC(=O)CO5)C4)c2c1
Temperature: 50 °C
Reaction time: 12 h
Yield: 0.8 %

Procedure:
To a solution of 2-(6-methoxy-quinolin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamine (50 mg, 0.2 mmol) in DMF (0.5 mL) was added 6-(2-chloro-acetyl)-4H-benzo[1,4]oxazin-3-one (0.05 g, 0.22 mmol) and Et3N (0.033 mL, 0.22 mmol). The reaction was heated to 50° C. and stirred for 12 h. The crude was purified directly by basic reverse phase HPLC to afford 0.8 mg (10%) of the title compound. HPLC: Rt=5.50 min. MS (ESI): exact mass calculated for C27H25N5O4, 483.19; m/z found, 484.5 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.78 (d, J=4.7, 1H), 8.06 (d, J=9.1, 1H), 7.69-7.61 (m, 3H), 7.42 (d, J=2.6, 1H), 7.40 (dd, J=9.1, 2.6, 1H), 7.32 (d, J=4.7, 1H), 7.04 (d, J=8.9, 1H), 4.70 (s, 2H), 4.21 (s, 1H), 3.89 (s, 3H), 3.11-2.80 (m, 5H), 2.62-2.58 (m, 1H), 2.26-2.17 (m, 1H), 1.93-1.86 (m, 1H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][C:14]([NH2:16])=[N:13][C:12]=2[CH3:17])=[CH:7][CH:6]=1)(=[O:4])=[O:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:42]1([CH2:47][C:48](O)=[O:49])[CH:46]=[N:45][N:44]=[N:43]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[S:15][C:14]([NH:16][C:48](=[O:49])[CH2:47][N:42]3[CH:46]=[N:45][N:44]=[N:43]3)=[N:13][C:12]=2[CH3:17])=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: Cc1nc(N)sc1-c1ccc(S(C)(=O)=O)cc1
Reactant: O=C(O)Cn1cnnn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(NC(=O)Cn2cnnn2)sc1-c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(4-Methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 58) (0.08 g, 0.3 mmol) is added to a solution of HATU (0.113 g, 0.3 mmol) and 1-tetrazole acetic acid (0.039 g, 0.31 mmol) in DCM. Triethylamine (0.104 ml, 0.75 mmol) is then added and the reaction mixture is left to stir at room temperature overnight. The product is purified by chromatography on silica eluting with methanol—DCM (96:4) to give the titled compound.