Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:5]2[C:6](O)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.FC1C=CC(S(C)(=O)=O)=CC=1.CC(C)([O-])C.[K+]>CN(C)C(=O)C>[N:11]1[C:2]([NH2:1])=[N:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: Nc1nc2c(O)cccn2n1
Agent: CC(C)(C)[O-]
Agent: CS(=O)(=O)c1ccc(F)cc1
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Nc1nc2ccccn2n1
Temperature: 130 °C

Procedure:
A well stirred mixture of 2-amino-[1,2,4]triazolo[1,5-a]pyridine-8-ol (0.300 g, 2.00 mmol), 1-fluoro-4-methanesulfonyl-benzene (0.418 g, 2.40 mmol), N,N-dimethylacetamide (2 mL) and potassium tert-butoxide (0.448 g, 4.00 mmol) was heated at 130° C. for 18 h under an argon atmosphere. The reaction mixture was evaporated in vacuo and partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane and the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and evaporated in vacuo to furnish a crude product. The crude product was purified by preparative Gilson HPLC method to yield a pure product, which was triturated from a mixture of dichloromethane, methanol, ether and hexane. 8-(4-Methanesulfonyl-phenoxy)-[1,2,4-triazolo[1,5-a]pyridin-2-ylamine was isolated as a white solid (125 mg, 20%). MP=245-247° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.53 (d, J=6.56 Hz, 1H), 7.87 (d, J=8.77 Hz, 2H), 7.36 (d, J=7.73 Hz, 1H), 7.15 (d, J=8.76 Hz, 2H), 6.92 (t, J=7.28 Hz, 1H), 6.13 (s, 1H), 3.19 (s, 3H). MS=305 (MH)+. 211b) 2-Chloro-8-(4-methanesulfonyl-phenoxy)-[1,2,4]triazolo[1,5-a]pyridine was prepared in a manner analogous to Example 68a. Product was isolated as a yellow solid (0.455 g, 80%). MP=202-204° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.44 (d, J=6.77 Hz, 1H), 7.98 (d, J=8.08 Hz, 2H), 7.21 (t, J=7.76 Hz, 3H), 7.08 (t, J=7.52 Hz, 1H), 3.09 (s, 3H). MS=324 (MH)+. 211c) (1-Ethyl-1H-pyrazol-4-yl)-[8-(4-methanesulfonyl-phenoxy)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine was prepared from 2-chloro-8-(4-methanesulfonyl-phenoxy)-[1,2,4]triazolo[1,5-a]pyridine (0.065 g, 0.20 mmol) and 1-ethyl-1H-pyrazol-4-ylamine (0.029 g, 0.26 mmol) in a manner analogous to Example 2d. Product was isolated as a tan solid (45 mg, 56%). MP=183-185° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.27 (s, 1H), 8.67 (d, J=6.51 Hz, 1H), 7.89 (d, J=7.72 Hz, 2H), 7.68 (s, 1H), 7.45 (d, J=7.74 Hz, 1H), 7.35 (s, 1H), 7.22 (d, J=7.29 Hz, 2H), 7.00 (t, J=7.29 Hz, 1H), 4.055 (q, J=7.18 Hz, 2H), 3.20 (s, 3H), 1.32 (t, J=7.06 Hz, 3H). MS=399 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:12][CH2:11][CH2:10][NH:9]1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[F:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:9]2[CH2:10][CH2:11][CH2:12][CH:8]2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Fc1ccccc1C1CCCN1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: O=S(=O)(c1ccc(F)cc1)N1CCCC1c1ccccc1F

Procedure:
The title compound, white solid, m.p. 108° C. and MS: m/e=324.2 (M+H+) was prepared in accordance with the general method of example 1e from (RS)-2-(2-fluoro-phenyl)-pyrrolidine and 4-fluoro-benzenesulfonyl chloride.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH2:11]Br)=[C:9]([Br:13])[N:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:7]=1)=[O:5])[CH3:2].[SH:20][C:21]1[NH:22][CH:23]=[CH:24][N:25]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH2:11][S:20][C:21]2[NH:22][CH:23]=[CH:24][N:25]=2)=[C:9]([Br:13])[N:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: Sc1ncc[nH]1
Reactant: CCOC(=O)c1nn(-c2ccccc2)c(Br)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)c1nn(-c2ccccc2)c(Br)c1CSc1ncc[nH]1
Temperature: 85 °C

Procedure:
To a solution of ethyl-5-bromo-4-(bromomethyl)-1-phenyl-1H-pyrazole-3-carboxylate (2.1 g, 5.44 mmol, 1 eq) and 2-mercaptoimidazole (0.6 g, 5.98 mmol, 1.1 eq) in ACN (30 mL) is added dry K2CO3 (2.25 g, 16.32 mmol, 3 eq) and the reaction mixture is heated at 85° C. for 1 h. The reaction mixture is diluted with DCM and filtered. The filtrate is concentrated and the residue is partitioned between DCM/water. The organic layer is dried over Na2SO4 and concentrated to afford the title compound. 1H NMR (DMSO-d6, 400 MHz): δ 12.29 (bs, 1H), 7.59-7.53 (m, 5H), 7.16 (d, J=1.4 Hz, 1H), 6.94 (d, J=1.4 Hz, 1H), 4.28-4.26 (m, 2H), 4.19 (s, 2H), 1.29 (t, J=7.7 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15](Cl)=[O:16])[S:14][C:5]=3[C:4]=2[CH:3]=1.[Cl:18][C:19]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:20]=1[NH:21][CH3:22]>>[Cl:18][C:19]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:20]=1[N:21]([CH3:22])[C:15]([C:13]1[S:14][C:5]2[C:4]3[CH:3]=[C:2]([F:1])[CH:11]=[CH:10][C:9]=3[O:8][CH2:7][C:6]=2[CH:12]=1)=[O:16]
Reactant: CNc1ccc(Cl)cc1Cl
Reactant: O=C(Cl)c1cc2c(s1)-c1cc(F)ccc1OC2
Product: CN(C(=O)c1cc2c(s1)-c1cc(F)ccc1OC2)c1ccc(Cl)cc1Cl

Procedure:
Following Example 75, 8-fluoro-4H-thieno[3,2-c]chromene-2-carbonyl chloride and 2,4-dichloro-N-methylaniline gave 164bp. MS: (ESI+)=408.0
Reaction SMILES: [S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[Al+3:6].[S:7]([O-:11])([O-:10])(=[O:9])=[O:8].S([O-])([O-])(=O)=[O:13].[Al+3].S(O)(O)(=O)=[O:19].[NH2:23][C:24]([NH2:26])=[NH:25]>O>[OH2:2].[OH2:8].[OH2:13].[OH2:19].[OH2:2].[OH2:2].[S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[Al+3:6].[NH2:25][C:24]([NH2:26])=[NH2+:23].[S:7]([O-:11])([O-:10])(=[O:9])=[O:8]
Reactant: O=S(=O)(O)O
Reactant: N=C(N)N
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Solvent: O
Product: NC(N)=[NH2+]

Procedure:
Guanidinium aluminum sulfate hexahydrate is prepared by dissolving 342 grams of aluminum sulfate in 1,000 milliliters of water and adding 141 grams of guanidine sulfate to the solution. The solvent is evaporated by vacuum evaporation to yield a dried salt. Approximately 1 to 25 pounds of this salt are incorporated per barrel of drilling fluid to provide a shale-stabilizing drilling fluid with improved properties.
Reaction SMILES: C([S:4][CH:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])[CH2:7]/[C:6]/1=[CH:24]\[C:25]1[N:26]=[N:27][N:28]([CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[N:29]=1)(=O)C.[ClH:38]>C(O)C>[ClH:38].[CH:14]1([C:12](=[O:13])[CH:11]([N:8]2[CH2:9][CH2:10][CH:5]([SH:4])/[C:6](=[CH:24]/[C:25]3[N:26]=[N:27][N:28]([CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[N:29]=3)/[CH2:7]2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[CH2:15][CH2:16]1
Reactant: CCOC(=O)CCCn1nnc(/C=C2\CN(C(C(=O)C3CC3)c3ccccc3F)CCC2SC(C)=O)n1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CCCn1nnc(/C=C2\CN(C(C(=O)C3CC3)c3ccccc3F)CCC2S)n1
Yield: 91 %

Procedure:
(E)-4-(Acetylsulfanyl)-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-3-({2-[3-(ethoxycarbonyl)propyl]-2H-tetrazol-5-yl}methylidene}piperidine (1.08 g) was treated with hydrogen chloride in ethanol (20 ml) in a similar manner to that described in Example 133. The reaction mixture was concentrated in vacuo, and the residue was purified by chromatography on silica gel using a mixture of ethanol and dichloromethane (2:98 to 10:90) as the eluent to afford the title compound as a pale yellow amorphous solid (976 mg, yield: 91%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH:9]C(=O)C)=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1>Cl.C(O)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH2:9])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1
Reactant: CC(=O)Nc1cc(F)c(F)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Product: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 94.3 %

Procedure:
A solution of N-(4,5-difluoro-2-nitrophenyl)acetamide (70 g) in concentrated hydrochloric acid (110 ml) and ethanol (440 ml) was refluxed for 2 hours. The reaction mixture was poured into ice water (1.5 liter) and the resulting precipitate was collected by filtration and washed with chilled water sufficiently to give the title compound (53.2 g) as yellow prisms, mp 109°-109.5° C.
Reaction SMILES: [CH2:1]([CH:4]1[C:8](O)([CH3:9])[CH:7]=[CH:6][C:5]1=[O:11])[CH:2]=[CH2:3].[C:12]1([CH:19]=[CH:18][CH:17]=[C:15]([OH:16])[CH:14]=1)[OH:13].O1CCCC1.C(N(CC)CC)C>O.C1(C)C=CC=CC=1>[CH2:1]([C:4]1[C:5](=[O:11])[CH2:6][CH:7]([O:13][C:12]2[CH:19]=[CH:18][CH:17]=[C:15]([OH:16])[CH:14]=2)[C:8]=1[CH3:9])[CH:2]=[CH2:3]
Reactant: C=CCC1C(=O)C=CC1(C)O
Reactant: Oc1cccc(O)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: C=CCC1=C(C)C(Oc2cccc(O)c2)CC1=O
Reaction time: 2 h

Procedure:
Into the same flask as used in Example 1, 2-allyl-3-hydroxy-3-methyl-4-cyclopentenone (0.1 mol; 1 part), resorcinol (5 parts), tetrahydrofuran (1/2 part) and triethylamine (1/10 part) were charged, and the mixture was stirred at a temperature of 50° to 80° C. for 2 hours. After completion of the reaction, toluene (6 parts) and water (2 parts) were added thereto, and the separated organic layer was washed with a 5% aqueous solution of sodium carbonate. Toluene was evaporated off from the organic layer to give 2-allyl-3-methyl-4-(3-hydroxyphenoxy)-2-cyclopentenone. Yield, 95%. The product was purified by recrystallization from a mixture of chloroform and methanol (5:2 by volume). nD20 1.5707.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:14]([OH:16])=O)[C:10]([CH3:13])([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:38][N:39]1[CH2:44][CH2:43][CH:42]([N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:41][CH2:40]1>C(#N)C.C(N(CC)CC)C>[CH3:13][C:10]([CH3:11])([CH3:12])[C@@H:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[C:14]([N:48]1[CH2:47][CH2:46][N:45]([CH:42]2[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]2)[CH2:50][CH2:49]1)=[O:16]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(C)(C)C
Reactant: CN1CCC(N2CCNCC2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN1CCC(N2CCN(C(=O)[C@H](NC(=O)OC(C)(C)C)C(C)(C)C)CC2)CC1
Yield: 101.4 %

Procedure:
To a solution of Boc-D-tert-leucine (0.46 g) and HOBt (0.46 g) in acetonitrile (20 ml) was added WSC (0.58 g), and the reaction mixture was mixed at room temperature for 15 minutes. Then, 1-(1-methyl-4-piperidyl)piperazine (0.70 g) and triethylamine (0.61 g) were added, and the reaction mixture was mixed at room temperature for 15 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with an aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as a colorless oil (0.80 g, quantitative).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][C:13]=2[CH3:20])=[CH:8][CH:7]=1.[CH3:21][N:22]([CH3:28])[C@@H:23]1[CH2:27][CH2:26][NH:25][CH2:24]1>>[CH3:21][N:22]([CH3:28])[C@@H:23]1[CH2:27][CH2:26][N:25]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][C:13]=3[CH3:20])=[CH:8][CH:7]=2)[CH2:24]1
Reactant: Cc1cc(C#N)ccc1-c1ccc(OCCCCl)cc1
Reactant: CN(C)[C@@H]1CCNC1
Product: Cc1cc(C#N)ccc1-c1ccc(OCCCN2CC[C@@H](N(C)C)C2)cc1
Yield: 55 %

Procedure:
The product from Example 165C and (3R)-N,N-dimethyl-3-pyrrolidinamine were processed as described in Example 164D to provide the title compound (55% yield). 1HNMR (300 MHz, CDCl3) δ1.65 (m, 2H), 1.81 (bs, 2H), 2.00-2.85 (m, 15H), 3.0 (m, 1H), 4.13 (bs, 2H), 6.90-7.54 (m, 7H); MS (ESI) m/z 364 (M+H)+.
Reaction SMILES: P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].C1(C)C=CC=CC=1.Cl[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[C:23]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])#[N:24]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1([B-](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.O>[CH2:29]([O:28][C:26](=[O:27])[CH:25]([C:23]#[N:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:30]
Reactant: CCOC(=O)CC#N
Reactant: Clc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C(C#N)c1ccccc1
Yield: 53 %

Procedure:
A 30-ml four-necked flask was equipped with a stirrer, a thermometer and a reflux condenser. 0.022 g (0.1 mmol) of palladium (II) acetate, 2.459 g (15 mmol) of sodium phosphate and 15 ml of toluene were weighed in the flask, followed by stirring. Further, 0.105 g (0.2 mmol) of tri-tert-butylphosphonium tetraphenylborate obtained in Example A-1 was weighed in air and added into the flask. The flask was purged with argon, followed by stirring at 25° C. for 30 minutes. 0.563 g (5 mmol) of chlorobenzene was added, followed by stirring at 25° C. for 30 minutes. 0.622 g (5.5 mmol) of ethyl cyanoacetate was added, followed by stirring at 100° C. for 12 hours. After the completion of the reaction, 5 ml of water was added, followed by separation. The organic phase was purified by column chromatography to afford 0.501 g of ethyl-2-phenylcyanoacetate (yield: 53 mol % based on chlorobenzene). The identification of the product was made by mass spectroscopy, 1H-NMR and 13C-NMR.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:22]([O-:24])=[O:23])=[C:9]([CH:11]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[OH:12])[CH:10]=1)[CH:2]=[CH2:3].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.S(=O)(O)[O-].[Na+].[Cl-].[NH4+]>CC(C)=O.C(O)(C)C>[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:22]([O-:24])=[O:23])=[C:9]([C:11]([C:13]2[CH:14]=[CH:15][C:16]([CH:19]([CH3:20])[CH3:21])=[CH:17][CH:18]=2)=[O:12])[CH:10]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc([N+](=O)[O-])c(C(O)c2ccc(C(C)C)cc2)c1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Agent: O=S([O-])O
Solvent: CC(C)=O
Solvent: CC(C)O
Product: C=CCOc1ccc([N+](=O)[O-])c(C(=O)c2ccc(C(C)C)cc2)c1

Procedure:
A solution of 16.38 g (50 mmol) (5-allyloxy-2-nitro-phenyl)-(4-isopropyl-phenyl)-methanol in 60 ml acetone is treated at 0° C. with 20 ml (53.4 mmol) Jones reagent. After stirring for 2 h at r.t. isopropanol, an aqueous solution of sodium bisulphite and saturated aqueous ammonium chloride solution are added. Extraction with dichloromethane affords (5-allyloxy-2-nitro-phenyl)-(4-isopropyl-phenyl)-methanone.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][NH:8][C:9]1[S:10][CH2:11][C:12](=[O:14])[N:13]=1.C(O[Na])(C)=O.[CH:20]([C:22]1[N:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]=[CH:27][C:26]([C:32]#[N:33])=[C:25]2[O:34][CH:35]([CH3:37])[CH3:36])=O>CC(O)=O>[CH:35]([O:34][C:25]1[C:24]2[C:29](=[CH:30][CH:31]=[C:22]([CH:20]=[C:11]3[S:10][C:9]([NH:8][CH2:7][C:3]4[S:4][CH:5]=[CH:6][C:2]=4[CH3:1])=[N:13][C:12]3=[O:14])[N:23]=2)[N:28]=[CH:27][C:26]=1[C:32]#[N:33])([CH3:37])[CH3:36]
Reactant: CC(C)Oc1c(C#N)cnc2ccc(C=O)nc12
Reactant: Cc1ccsc1CNC1=NC(=O)CS1
Agent: CC(=O)O[Na]
Solvent: CC(=O)O
Product: Cc1ccsc1CNC1=NC(=O)C(=Cc2ccc3ncc(C#N)c(OC(C)C)c3n2)S1
Temperature: 80 °C
Yield: 31.4 %

Procedure:
To a mixture of 2-[(3-methyl-thiophen-2-ylmethyl)-amino]-thiazol-4-one (36.2 mg, 0.16 mmol) (prepared as described below), AcONa (160 mg, 1.95 mmol), and 6-formyl-4-isopropoxy-[1,5]naphthyridine-3-carbonitrile (50.2 mg, 0.21 mmol) (see Example 1) in a sealed tube was added AcOH (0.3 mL). The reaction mixture was heated to 80° C. (oil bath) for 5 hrs. The reaction mixture was then cooled to r.t. and triturated with water. The solid was collected by filtration and washed with water. The solid was then suspended in AcOEt (20 mL) and filtered through a glass. The solid was washed with AcOEt and dried to give 4-isopropoxy-6-{2-[(3-methyl-thiophen-2-ylmethyl)-amino]-4-oxo-4H-thiazol-5-ylidenemethyl}-[1,5]naphthyridine-3-carbonitrile as a light brown solid (22.6 mg, 32.4%). HR-ES (+) m/e calcd for C22H19N5O2S2 (M+H)+ 450.1053. found 450.1051.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:25][C:26]1[CH:27]=[CH:28][C:29](B2OC(C)(C)C(C)(C)O2)=[C:30]2[C:34]=1[NH:33][CH:32]=[CH:31]2.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O>[CH3:25][C:26]1[CH:27]=[CH:28][C:29]([C:2]2[N:3]=[C:4]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[C:30]2[C:34]=1[NH:33][CH:32]=[CH:31]2
Reactant: CN1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c2cc[nH]c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(-c2nc(N3CCOCC3)c3sc(CN4CCN(C)CC4)cc3n2)c2cc[nH]c12
Temperature: 130 °C
Yield: 70.5 %

Procedure:
To a mixture of 2-Chloro-6-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (0.23 mmol, 84 mg) and 7-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (0.46 mmol, 117 mg) in toluene (2 mL), ethanol (1 mL) and water (0.5 mL) was added sodium carbonate (0.69 mmol, 73 mg). Pd (PPh3)2Cl2 (0.012 mmol, 8 mg) was added and the mixture heated in a microwave reactor at 130° C. for 1.5 hours. The mixture was allowed to cool and partitioned between water and dichloromethane. The combined organic layers were washed with brine, separated and dried (MgSO4). The solvent was evaporated and the crude product purified by column chromatography to yield 2-(7-methyl-1H-indol-4-yl)-6-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine as a pale cream solid (75 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][C:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:18])[CH3:17])=[N:11][CH:10]=[CH:9][CH:8]=2)([O-])=O.[H][H]>C(#N)C.[Pt]>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][C:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:17])[CH3:18])=[N:11][CH:10]=[CH:9][CH:8]=2
Reactant: CC(C)(CNc1c([N+](=O)[O-])cnc2cccnc12)NC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pt]
Solvent: CC#N
Product: CC(C)(CNc1c(N)cnc2cccnc12)NC(=O)OC(C)(C)C
Yield: 95.7 %

Procedure:
A Parr vessel was charged with a solution of tert-butyl N-{2-[(3-nitro[1,5]naphthyridin-4-yl)amino]-1,1-dimethylethyl}carbamate (12.62 g, 34.9 mmol) in acetonitrile (100 mL) and 5% Pt/C (2.00 g). The vessel was placed under hydrogen pressure (50 psi, 3.4×105 Pa) until hydrogen uptake ceased. The reaction mixture was filtered through a layer of CELITE filter aid and the filter cake was rinsed with acetonitrile. The filtrate was concentrated under reduced pressure to provide 11.07 g of tert-butyl N-{2-[(3-amino[1,5]naphthyridin-4-yl)amino]-1,1-dimethylethyl]carbamate as a bright yellow foam.
Reaction SMILES: Cl.[C:2]([CH2:4][C:5](=[NH:8])[O:6][CH3:7])#[N:3].[N+:9]([C:12]1[CH:17]=C[C:15](O)=[C:14](N)[CH:13]=1)([O-:11])=[O:10]>CO>[N+:9]([C:12]1[C:17]2[N:8]=[C:5]([CH2:4][C:2]#[N:3])[O:6][C:7]=2[CH:15]=[CH:14][CH:13]=1)([O-:11])=[O:10]
Reactant: COC(=N)CC#N
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Agent: Cl
Solvent: CO
Product: N#CCc1nc2c([N+](=O)[O-])cccc2o1
Reaction time: 0.5 h
Yield: 84.2 %

Procedure:
The mixture of methyl cyanoacetimidate hydrochloride (43.47 g, 0.32 mole) and 4-nitro-2-aminophenol (24.9 g, 0.16 mole) in methanol (260 ml) was heated at reflux for 3 h. The mixture was placed in an ice bath for 30 minutes and was filtered. The solid material was suspended in water (300 ml), stirred for a few minutes and filtered. It was washed with water (200 ml) and air dried to give 4-nitro-2-benzoxazoleacetonitrile (27.38 g, 83%).
Reaction SMILES: FC(F)(F)C([O-])=O.[Tl+3].FC(F)(F)C([O-])=O.FC(F)(F)C([O-])=O.[CH3:23][C:24]1[CH:32]=[C:31]2[C:27]([C:28]([CH:33]=[O:34])=[CH:29][NH:30]2)=[CH:26][CH:25]=1.[I-:35].[K+].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].[OH-].[Na+]>FC(F)(F)C(O)=O>[CH3:23][C:24]1[CH:32]=[C:31]2[C:27]([C:28]([CH:33]=[O:34])=[CH:29][NH:30]2)=[C:26]([I:35])[CH:25]=1
Reactant: Cc1ccc2c(C=O)c[nH]c2c1
Reactant: [I-]
Agent: O=C([O-])C(F)(F)F
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(I)c2c(C=O)c[nH]c2c1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
A solution of thallium (III) trifluoroacetate (1 g 1.84 mmol) in trifluoroacetic acid (15 mL) was added to 6-methyl-indole-3-carboxaldehyde (200 mg, 1.25 mmol) and the resulting mixture was stirred at 30° C. for 2 h. The solvent was removed under vacuum (rotary evaporator). To the residue was added an aqueous solution of potassium iodide (2 g, 12 mmol, in 20 mL of water) and the mixture was stirred at room temperature overnight. Solid sodium meta-bisulfite was added to the reaction mixture until it turned yellow. The mixture was basified with aqueous NaOH solution and was extracted repeatedly from diethyl ether. The combined organic was washed with brine and was dried over magnesium sulfate. Evaporation of solvent gave the crude product, which was purified by flash chromatography by using EtOAc as eluent. The product, 6-methyl-4-iodo-indole-3-carboxaldehyde was isolated as solid to yield 283 mg (79%) of the desired product. MS: 286.
Reaction SMILES: [Cl:1]CCN1CCOCC1.[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][N:21]([C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[N:29]([CH2:33][C@H:34]2[CH2:38][CH2:37][CH2:36][N:35]2C(OC(C)(C)C)=O)[N:28]=[CH:27]3)[C:20](=[O:46])[CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.FC(F)(F)C(O)=O.Cl>C(Cl)Cl.CCOC(C)=O.CCOCC>[ClH:1].[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][N:21]([C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[N:29]([CH2:33][C@H:34]2[CH2:38][CH2:37][CH2:36][NH:35]2)[N:28]=[CH:27]3)[C:20](=[O:46])[CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ClCCN1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1Cn1ncc2cc(-n3ccc(OCc4ccccc4)cc3=O)ccc21
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCOCC
Product: O=c1cc(OCc2ccccc2)ccn1-c1ccc2c(cnn2C[C@H]2CCCN2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
Following the procedure of Example 2, but substituting (R)-tert-butyl 2-(bromomethyl)pyrrolidine-1-carboxylate for 4-(2-chloroethyl)morpholine, (R)-tert-butyl 2-((5-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-1H-indazol-1-yl)methyl)pyrrolidine-1-carboxylate (22 mg, 8%) was prepared as a yellow powder. A solution of this compound (22 mg, 0.044 mmol) in CH2Cl2 (2 mL) was treated with trifluoroacetic acid (25 mg, 0.22 mmol). After stirring at room temperature for 16 h, the reaction mixture was diluted with EtOAc (10 mL) and washed with 1N NaOH (10 mL). The organics were dried (Na2SO4), filtered and concentrated. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH/NH4OH, 40:1:0.1 to 20:1:0.2) provided the free base. This was dissolved in ethyl acetate (0.4 mL) and treated with 1 equivalent of 1 M HCl in Et2O and the mixture was filtered to provide the title compound (14.8 mg, 77%) as a yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 9.25 (s, 1H), 9.01 (s, 1H), 8.25 (s, 1H), 7.86 (d, J=8.9 Hz, 1H), 7.79 (d, J=17 Hz, 1H), 7.60 (d, J=7.6 Hz, 1H), 7.49-7.35 (m, 6H), 6.12 (dd, J=7.6, 2.6 Hz, 1H), 5.99 (d, J=2.7 Hz, 1H), 5.16 (s, 2H), 4.85-4.71 (m, 2H), 4.02-3.92 (m, 1H), 3.32-3.22 (m, 1H), 3.20-3.11 (m, 1H), 2.14-2.05 (m, 1H), 2.02-1.92 (m, 1H), 1.91-1.85 (m, 1H), 1.78-1.68 (m, 1H); ESI MS m/z 401 [M+H]+.
Reaction SMILES: B.CSC.[Br:5][C:6]1[CH:7]=[C:8]([NH:14][C:15](=O)[C:16]([F:19])([F:18])[F:17])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]>O1CCCC1>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]([NH:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:7][C:6]=1[Br:5]
Reactant: COc1ccc(NC(=O)C(F)(F)F)cc1Br
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: COc1ccc(NCC(F)(F)F)cc1Br
Yield: 110.3 %

Procedure:
Borane-dimethylsulfide complex (2M in THF, 6.7 ml, 13.4 mmol) was added to a solution of N-(3-Bromo-4-methoxyphenyl)trifluoroacetamide (Description 52, 2.0 g, 6.7 mmol) in tetrahydrofuran (20 ml) and the mixture was heated under reflux for 18 h. The mixture was cooled and the solvent was evaporated under reduced pressure to give the title compound as a yellow oil (2.1 g). 1H NMR (360 MHz, CDCl3) δ6.93 (1H, d, J 2.9 Hz), 6.80 (1H, d, J 8.8 Hz), 6.62 (1H, dd, J 8.8, 2.9 Hz), 3.82 (3H, s), and 3.71 (3H, m). m/z (ES+) 284, 286 (M+1).