Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:25]=[CH:24][C:9]([C:10]([O:12][CH2:13][C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])=[O:11])=[CH:8][C:7]=2[CH:26]=O)[CH2:3][CH2:2]1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:25]=[CH:24][C:9]([C:10]([O:12][CH2:13][C:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:15])=[O:11])=[CH:8][C:7]=2[CH2:26][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH2:2][CH2:3]1
Reactant: C1COCCN1
Reactant: O=Cc1cc(C(=O)OCC(=O)OCc2ccccc2)ccc1OCC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(COC(=O)c1ccc(OCC2CC2)c(CN2CCOCC2)c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
A solution of 2-(benzyloxy)-2-oxoethyl 4-(cyclopropylmethoxy)-3-formylbenzoate (3.73 g, 10.13 mmol) and morpholine (1.15 g, 13.17 mmol) in dry THF (50 ml), under argon atmosphere, was stirred for 15 minutes at RT. Na(OAc)3BH (2.79 g, 13.17 mmol) and CH3COOH (754 μl, 13.17 mmol) were added. CH3COOH was added to reach a pH between 5 and 6. The mixture stirred at RT for 24 hours. The solvent was removed, and the crude was dissolved in EtOAc and washed with NaHCO3 sat. sol. and brine. The organic phase was dried over Na2SO4, and the solvent was removed to give 2-(benzyloxy)-2-oxoethyl 4-(cyclopropylmethoxy)-3-(morpholinomethyl)benzoate (4.45 g, quantitative yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:12]2[CH:13]=[C:14]([NH2:17])[CH:15]=[CH:16][C:11]=2[O:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])[C:22]([Cl:37])=[CH:21][N:20]=1.C(O)(C)C.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>>[CH2:1]([O:3][C:4]([N:6]1[C:12]2[CH:13]=[C:14]([NH:17][C:19]3[N:24]=[C:23]([NH:25][C:26]4[C:27]([C:28](=[O:29])[NH:30][CH3:31])=[CH:32][CH:33]=[CH:34][C:35]=4[F:36])[C:22]([Cl:37])=[CH:21][N:20]=3)[CH:15]=[CH:16][C:11]=2[O:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CCOC(=O)N1CCCOc2ccc(N)cc21
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CCOC(=O)N1CCCOc2ccc(Nc3ncc(Cl)c(Nc4c(F)cccc4C(=O)NC)n3)cc21
Yield: 51.6 %

Procedure:
2-Amino-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid ethyl ester (102 mg, 0.433 mmol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide (150 mg, 0.476 mmol) were placed in isopropyl alcohol (3.00 mL, 39.2 mmol) and 10-camphorsulfonic acid (10.0 mg, 0.0433 mmol) was added. The reaction was microwaved on 300 watts, 120° C. for 20 minutes and then concentrated under reduced pressure. The residue was taken up in DCM (20 mL) and washed with sat. NaHCO3 (20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-100% EtOAc/hex as the eluting solvent to obtain 2-[5-Chloro-4-(2-fluoro-6-methylcarbamoyl-phenylamino)-pyrimidin-2-ylamino]-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid ethyl ester as a yellow foam (115 mg, 52%). LCMS (m/e) 515 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 9.37 (bs, 1H), 8.56-8.47 (m, 1H), 8.17 (s, 1H), 7.52-7.36 (m, 4H), 7.28-7.17 (m, 1H), 6.79 (d, 1H, J=8.7 Hz), 4.20-3.81 (m, 4H), 3.70-2.42 (m, 1H), 2.73 (d, 3H, J=4.5 Hz), 1.95-1.80 (m, 2H), 1.36-0.98 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]2[C:7]([S:8][C:9]3[C:14]([N:15]=2)=[CH:13][CH:12]=[C:11]([O:17][CH3:18])[CH:10]=3)=[CH:6][C:5](=[O:19])[CH:4]=1.[Cl:20]Cl.CO>C(O)(=O)C>[Cl:20][C:6]1[C:5](=[O:19])[CH:4]=[C:3]([O:2][CH3:1])[C:16]2[C:7]=1[S:8][C:9]1[C:14](=[CH:13][CH:12]=[C:11]([O:17][CH3:18])[CH:10]=1)[N:15]=2
Reactant: COc1ccc2nc3c(OC)cc(=O)cc-3sc2c1
Reactant: ClCl
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc2nc3c(OC)cc(=O)c(Cl)c-3sc2c1
Reaction time: 0.25 h

Procedure:
To a suspension of 1,7-dimethoxy-3H-phenothiazin-3-one (800 mg) in acetic acid (24 ml) was added a 1.15M solution of Cl2 in acetic acid (3.1 ml). After 15 minutes, methanol was added and the mixture was filtered, washed with ether and air dried to afford a mixture of the two title compounds (700 mg), which were separated on a silica gel column (EtOAc:CH2Cl2, 1:9), affording 4-chloro-1,7-dimethoxy-3H-phenothiazin-3-one, m.p. 278°-280° C. (dec.)
Reaction SMILES: C([N:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]1=[O:41])(=O)C1C=CC=CC=1>[OH-].[Na+].O1CCOCC1.[Cl-].[Na+].O>[C:22]([O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:11]1[CH:12]=[CH:13][C:14](=[O:15])[NH:9][C:10]1=[O:41])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C(c1ccccc1)n1c(=O)ccn(CCCCCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c1=O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=c1ccn(CCCCCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c(=O)[nH]1
Reaction time: 48 h

Procedure:
Compound (15) (231 mg; 0.42 mmol) was stirred for 48 hours at room temperature in a mixture of NaOH 1M and Dioxane 1:1 (8 ml). After 48 hours, Brine (8 ml) was added to the solution, and then extracted with EtOAc (3×8 ml). The organic phase was dried over MgSO4; the solvent was removed in vacuo and the crude residue was purified by flash chromatography using DCM/MeOH 90:10 as eluent. The title compound was obtained as a colourless oil which precipitated after treatment with a mixture of Water/EtOH 1:1 which gave the title compound as a white solid (112 mg, 60%). Rf: 0.64 in DCM/MeOH 90:10.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([CH3:17])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].CN([CH:27]=[O:28])C.P(Cl)(Cl)(Cl)=O>O>[CH3:17][C:12]1[CH:11]=[C:10]([N:9]([C:18]2[CH:23]=[CH:22][C:21]([CH:27]=[O:28])=[CH:20][CH:19]=2)[C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=2)[CH:15]=[CH:14][C:13]=1[CH3:16]
Reactant: Cc1ccc(N(c2ccccc2)c2ccc(C)c(C)c2)cc1C
Reactant: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(N(c2ccc(C=O)cc2)c2ccc(C)c(C)c2)cc1C
Temperature: 0 °C

Procedure:
124.6 g of [N,N-bis-(3,4-dimethylphenyl)amino]benzene and 35.5 mL of DMF were placed in a three-neck flask. While stirring and cooling in ice water, 84.4 mL of phosphorus oxychloride was dropped into the flask. Upon completion of addition of drops, the mixture solution was reacted for 5 hours at 95° C., poured into 4 L of warm water, and stirred for 1 hour. The precipitate was collected and washed in a :1:1 mixture solution of ethanol/water. 4-[N,N-bis-(3,4-dimethylphenyl)amino]benzaldehyde was obtained. The yield was 107.6 g (yield rate of 79.0%).
Reaction SMILES: C(O)(=O)C.[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[C:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14](=O)[CH:15]([CH3:17])[CH3:16])=[CH:8][CH:7]=1.[NH2:25][C:26]([CH:33]([CH3:35])[CH3:34])=[CH:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>C(O)CO>[CH:33]([C:26]1[NH:25][C:14]([CH:15]([CH3:17])[CH3:16])=[C:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]([C:9]2[CH:10]=[CH:11][C:6]([F:5])=[CH:7][CH:8]=2)[C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29])([CH3:35])[CH3:34]
Reactant: CC(C)C(=O)C(=Cc1ccc(F)cc1)c1ccccc1
Reactant: CCOC(=O)C=C(N)C(C)C
Solvent: OCCO
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(C(C)C)NC(C(C)C)=C(c2ccccc2)C1c1ccc(F)cc1
Temperature: 25 °C

Procedure:
2.86 ml (50 mmol) of glacial acetic acid are added to 13.45 g (50 mmol) of the compound from Example 97 and 17.4 g (100 ml) of ethyl 3-amino-4-methyl-pent-2-enoate in 80 ml of ethylene glycol and the mixture is heated to reflux overnight. After cooling to room temperature, it is concentrated in vacuo and the residue is dissolved in dichloromethane and extracted several times using water. The organic phase is dried over magnesium sulphate and concentrated in vacuo, and the residue is taken up in ethyl acetate. After extracting using 10% strength hydrochloric acid, water and saturated sodium hydrogen carbonate solution, the organic phase is dried again and concentrated, and the residue is chromatographed on a column (silica gel 70-230 mesh, using ethyl acetate/petroleum ether)).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C([O:7][C:8]([C:10]1[C:11]2[S:19][CH:18]=[C:17]([CH2:20][O:21][C:22]3[CH:27]=[C:26]([C:28]4[NH:32][C:31]([CH3:33])=[N:30][N:29]=4)[CH:25]=[CH:24][C:23]=3[CH3:34])[C:12]=2[C:13]([NH2:16])=[N:14][CH:15]=1)=O)C>CS(C)=O>[OH:2][CH2:1][CH2:3][NH:4][C:8]([C:10]1[C:11]2[S:19][CH:18]=[C:17]([CH2:20][O:21][C:22]3[CH:27]=[C:26]([C:28]4[NH:32][C:31]([CH3:33])=[N:30][N:29]=4)[CH:25]=[CH:24][C:23]=3[CH3:34])[C:12]=2[C:13]([NH2:16])=[N:14][CH:15]=1)=[O:7]
Reactant: CCOC(=O)c1cnc(N)c2c(COc3cc(-c4nnc(C)[nH]4)ccc3C)csc12
Reactant: NCCO
Solvent: CS(C)=O
Product: Cc1nnc(-c2ccc(C)c(OCc3csc4c(C(=O)NCCO)cnc(N)c34)c2)[nH]1
Temperature: 135 °C
Reaction time: 1 h

Procedure:
Ethanolamine (1.5 mL; 24.9 mmol) (Aldrich) was added to a suspension of 4-amino-3-[2-methyl-5-(5-methyl-4H-[1,2,4]triazol-3-yl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (68.4 mg; 0.162 mmol) (from Example 62 supra) in dimethylsulfoxide (0.5 mL). The mixture was heated in a microwave reactor at 135° C. for 90 minutes and then for 1 hour at 140° C. The crude reaction mixture was concentrated under high vacuum with heat to remove most of the ethanolamine and DMSO. The residue was diluted with water, causing a milky precipitate to drop out of solution. The solid was collected by filtration, washed with water and dried. The material was then triturated with hot methanol to give 4-amino-3-[2-methyl-5-(5-methyl-4H-[1,2,4]triazol-3-yl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide as an off-white solid. (Yield 48 mg, 67.8%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([CH2:7][C:8]#[N:9])=[O:6].[C:13]1([N:19](C2C=CC=CC=2)[CH:20]=N)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C(C)=CC=CC=1.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([C:7](=[CH:20][NH:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]#[N:9])=[O:6]
Reactant: N=CN(c1ccccc1)c1ccccc1
Reactant: N#CCC(=O)c1cccc(Br)c1
Solvent: CCOCC
Solvent: Cc1ccccc1C
Product: N#CC(=CNc1ccccc1)C(=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.3 %

Procedure:
A mixture of 2-(3-bromobenzoyl)acetonitrile (16.5 g, 73.6 mmol) and N,N-diphenylformamidine (14.5 g, 73.6 mmol) in xylene (100 ml) was heated at reflux under a nitrogen atmosphere. After 3 h, the reaction mixture was cooled to room temperature and diluted with ether to give 2-(3-bromobenzoyl)-3-phenylaminoacrylonitrile (17.9 g) as a solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]3[CH:34]=[CH:33][C:23]([CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])=[CH:22][CH:21]=3)[N:10]=2)=[C:4]([C:35](=[O:38])[NH:36][CH3:37])[CH:3]=1.[CH2:39]([N:41]([CH2:58][CH3:59])[CH2:42][CH2:43][N:44]1[CH:48]=[C:47](B2OC(C)(C)C(C)(C)O2)[CH:46]=[N:45]1)[CH3:40]>>[CH2:27]([O:26][P:25]([CH2:24][C:23]1[CH:33]=[CH:34][C:20]([NH:19][C:11]2[N:10]=[C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([C:47]4[CH:46]=[N:45][N:44]([CH2:43][CH2:42][N:41]([CH2:58][CH3:59])[CH2:39][CH3:40])[CH:48]=4)=[CH:3][C:4]=3[C:35](=[O:38])[NH:36][CH3:37])[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=2)=[CH:21][CH:22]=1)(=[O:32])[O:29][CH2:30][CH3:31])[CH3:28]
Reactant: CCN(CC)CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)cc3C(=O)NC)n2)cc1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCN(CC)CC)c4)cc3C(=O)NC)n2)cc1)OCC

Procedure:
The title compound was prepared according to the procedure of Example 97 using Diethyl(4-{[4-{[4-bromo-2-(methylcarbamoyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (Example 106) and N,N-diethyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]ethanamine (Compound 175A). MS (ES+): m/z 703.45 (100) [MH+]; HPLC: tR=0.73 min (UPLC, purity).
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:31])[C:4]([C@@H:6]1[CH2:10][C@@H:9]([S:11][C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][NH:7]1)=[O:5].N1C=CC=CC=1.[CH2:38]([O:42][C:43](Cl)=[O:44])[CH2:39][CH2:40][CH3:41]>C1COCC1>[CH2:38]([O:42][C:43]([N:7]1[CH2:8][C@H:9]([S:11][C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:10][C@H:6]1[C:4](=[O:5])[N:3]([O:2][CH3:1])[CH3:31])=[O:44])[CH2:39][CH2:40][CH3:41]
Reactant: CON(C)C(=O)[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1
Reactant: CCCCOC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCCOC(=O)N1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1C(=O)N(C)OC
Temperature: 25 °C
Yield: 95.7 %

Procedure:
A solution of 17.3 g (40 mmol) (2S,4R)-4-Tritylsulfanyl-pyrrolidine-2-carboxylic acid methoxy-methyl-amide in 120 ml THF was treated at 0° C. with 4 ml (50 mmol) pyridine and 5.59 ml (42 mmol) butylchloroformate. The reaction was warmed up to RT over night, evaporated and partitioned between aqueous 10% KHSO4/Et2O (3×). The organic phases were washed with aqueous saturated NaHCO3, 10% NaCl and dried over Na2SO4. Purification by flash-chromatography on silicagel (Hexane/EtOAc 4:1) gave 20.4 g (96%) of (2S,4R)-2-(Methoxy-methyl-carbamoyl)-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid butyl ester, MS: 533 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:41]=[CH:40][C:17]([C:18]([N:20]3[CH2:25][CH2:24][N:23]([S:26]([C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[C:34]([Cl:39])[CH:35]=5)[CH:30]=4)(=[O:28])=[O:27])[CH2:22][CH2:21]3)=[O:19])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(OCC)(=O)C.CCOCC>[ClH:39].[Cl:39][C:34]1[CH:35]=[C:36]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[C:29]([S:26]([N:23]1[CH2:22][CH2:21][N:20]([C:18](=[O:19])[C:17]3[CH:40]=[CH:41][C:14]([CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[CH:15][CH:16]=3)[CH2:25][CH2:24]1)(=[O:28])=[O:27])[CH:38]=[CH:37]2
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=C(c1ccc(C2CCNCC2)cc1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 188 %

Procedure:
To a solution of 1-[4-(N-tert-butoxycarbonylpiperidin-4-yl)benzoyl]-4-(6-chloronaphthalene-2-sulfonyl)piperazine (125 mg) in ethyl acetate (0.5 ml) was added 4 N hydrochloric acid in ethyl acetate solution (4 ml) and the solution was stirred at room temperature for 1 hour, and diluted with ether. The precipitate was filtered, washed with ether and dried to give a colorless solid of the title compound (105 mg).
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[N+]([O-])(O)=O.[O:14]([CH2:18][CH2:19][NH2:20])[N+:15]([O-:17])=[O:16].C(OC(C)C)(C)C>>[O:14]([CH2:18][CH2:19][NH:20][C:7]([C:5]1[O:6][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:9])[N+:15]([O-:17])=[O:16]
Reactant: NCCO[N+](=O)[O-]
Reactant: O=C(O)c1ccc(Br)o1
Solvent: O=[N+]([O-])O
Solvent: CC(C)OC(C)C
Product: O=C(NCCO[N+](=O)[O-])c1ccc(Br)o1
Yield: 22.2 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.68 g of 5-bromo-2-furancarboxylic acid and 0.60 g of nitroxyethylamine nitrate, 0.22 g of the title compound was obtained as pale yellow acicular prisms (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: C([O:3][CH2:4][C:5]1[N:6]([CH2:19][C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:21]=2)[C:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)C.B(Br)(Br)Br.CO>ClCCl>[NH2:17][C:9]1[C:8]2[N:18]=[C:5]([CH2:4][OH:3])[N:6]([CH2:19][C:20]3[O:24][N:23]=[C:22]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[CH:21]=3)[C:7]=2[C:16]2[N:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CCOCc1nc2c(N)nc3cccnc3c2n1Cc1cc(-c2ccc(F)cc2)no1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: Nc1nc2cccnc2c2c1nc(CO)n2Cc1cc(-c2ccc(F)cc2)no1
Reaction time: 17 h
Yield: 37.4 %

Procedure:
Under a nitrogen atmosphere, a solution of 2-(ethoxymethyl)-1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine (0.40 g, 0.96 mmol) in dichloromethane (25 mL) was cooled on an ice bath, and boron tribromide (2.4 mL of a 1 M solution in dichloromethane) was added. The reaction was stirred for 17 hours, and an analysis by HPLC indicated the presence of starting material. Additional boron tribromide (1 mL) was added after 17 hours and then again after 32 hours of reaction time. After 32 hours of reaction time, methanol was added, and the solvents were removed under reduced pressure. The residue was triturated with water, isolated by filtration, washed with diethyl ether, recrystallized from methanol, and dried under high vacuum at 100° C. to provide 0.14 g of (4-amino-1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-1H-imidazo[4,5-c][1,5]naphthyridin-2-yl)methanol as a white solid, mp 247.0-248.0° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[CH3:18][Mg]Br.C(OCC)C>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)([OH:11])[CH3:18])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: O=C(c1ccccc1)c1ccc2occc2c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)(c1ccccc1)c1ccc2occc2c1
Temperature: 25 °C

Procedure:
To a solution of benzofuran-5-yl(phenyl)methanone (1.0 g, 4.5 mmol) in 20 mL THF under nitrogen at 0° C. was added methylmagnesium bromide 3.0M in diethyl ether (2.2 mL, 6.7 mmol) dropwise via syringe. The reaction was allowed to warm to ambient temperature slowly. The reaction was quenched with sat'd aq. NH4Cl and DCM. The aqueous layer was extracted 2×DCM, and the combined organics were dried over anhyd sodium sulfate, filtered, and concentrated in vacuo to give 1-(benzofuran-5-yl)-1-phenylethanol as an oil, which was used without further purification. MS (ESI) m/z: Calculated: 238.1; Observed: 238.8 (M++1).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][NH2:16])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17](N1C=CN=C1)(N1C=CN=C1)=[S:18]>CC#N>[N:16]([CH2:15][CH2:14][CH2:13][N:10]1[CH2:9][CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:12][CH2:11]1)=[C:17]=[S:18]
Reactant: NCCCN1CCC(c2ccccc2)CC1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: S=C=NCCCN1CCC(c2ccccc2)CC1

Procedure:
A solution of 4-phenyl-1-piperidinepropanamine (Example 5 intermediate) (3.2 g, 14.7 mmol) and 1,1'-thiocarbonyldiimidazole (2.8 g, 15.7 mmol) in MeCN (100 mL) was stirred for 2 h. The reaction mixture was chromatographed by vacuum filtration over silica (MeCN) to furnish 1-(3-isothiocyanatopropyl)-4-phenylpiperidine as an amber oil which crystallized upon standing (1.25 g, 33%). mp 50-55° C.; MS (ESI) m/z 261 (MH+); IR (KBr) 2113 cm-1. 1H NMR (CDCl3) δ 7.23 (m, 5H), 3.63 (t, 2 H, J=6.3 Hz), 3.08 (m, 2H), 2.55 (t, 2H, J=7.2 Hz), 2.50 (m, 1H), 2.15 (m, 2H), 1.95 (t, 2H, J=6.9 Hz), 1.86 (m, 4H). Anal. Calcd. for C15H20N2S.0.5 C2H3N: C, 66.28; H, 7.82; N, 12.08. Found: C, 66.68; H, 7.75; N, 12.22.
Reaction SMILES: Br[CH:2]([CH2:7][CH2:8][CH3:9])[C:3]([O:5][CH3:6])=[O:4].[CH2:10]([CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:6][O:5][C:3]([CH2:2][CH2:7][CH2:8][CH2:9][N:20]1[CH2:21][CH2:22][CH:17]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:18][CH2:19]1)=[O:4]
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: CCCC(Br)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)CCCCN1CCC(Cc2ccccc2)CC1
Yield: 77.7 %

Procedure:
A mixture of methyl bromovalerate (1.56 g, 8.0 mmol), 4-benzylpiperidine (1.49 g, 8.5 mmol) and potassium carbonate (2.93 g, 21.25 mmol) in 30 mL of acetonitrile was refluxed under N2 for 12 hr. The inorganic salt was removed through a short column of silica gel and washed with ethyl acetate (3×30 mL). The filtrate was evaporated in vacuo to give a residue, which was purified by flash chromatography, giving 1.8 g (78%) of the product as a pale yellow oil. 1H NMR (CHCl3), 1.312 (m, 2 H), 1.505-1.593 (m, 7 H), 1.831 (m, 2 H), 2.292 (m, 4 H), 2.505 (d, J=6.9 Hz, 2H), 2.860 (d, J=11.4 Hz, 2 H), 3.647 (s, 3 H), 7.136 (m, 5 H).
Reaction SMILES: [CH2:1]([N:5]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:6][C:7]#[C:8][C:9]#[N:10])[CH2:2][CH2:3][CH3:4].Cl.Cl.[CH2:17]([NH:24][NH2:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH-].[Na+]>C(O)C>[NH2:10][C:9]1[N:24]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:25]=[C:7]([CH2:6][N:5]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:1][CH2:2][CH2:3][CH3:4])[CH:8]=1
Reactant: CCCCN(CC#CC#N)CCCC
Reactant: NNCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCN(CCCC)Cc1cc(N)n(Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.5 %

Procedure:
A solution of 4-dibutylamino-2-butynenitrile in ethanol (10 mL) was added to a stirring solution of benzylhydrazine dihydrochloride (3.0 g, 15.4 mmol) and 3.0 N NaOH (5.00 mL, 15.4 mmol) in ethanol (50 mL). The resulting solution as stirred (2 hours, 25° C.), then concentrated. The residue was taken up in ethyl acetate (250 mL), washed with brine (3×90 mL), then dried (MgSO4) and concentrated in vacuo. The resulting oil was chromatographed on silica (80:20 hexane:ethyl acetate) to yield 0.70 g (14.5%) of 5-amino-3-[(dibutylamino)methyl]-1-(phenylmethyl)-1H-pyrazole as an orange oil. 1H NMR (250 MHz, CDCl3 δ 7.22 (m, 6H), 4.56 (s, 2H), 4.00 (br s, 2H), 2.30 (m, 4H), 1.34 (m, 8H), 0.90 (t, 6H).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[NH2:21][C:22]1[C:27]([C:28]([OH:30])=[O:29])=[C:26](Cl)[N:25]=[CH:24][N:23]=1.CCN(C(C)C)C(C)C.[F-].[Cs+]>C(O)C>[NH2:21][C:22]1[C:27]([C:28]([OH:30])=[O:29])=[C:26]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:16])[C:7]3=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[N:25]=[CH:24][N:23]=1
Reactant: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Reactant: Nc1ncnc(Cl)c1C(=O)O
Agent: [Cs+]
Agent: [F-]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3C(=O)O)n(-c3ccccc3)c(=O)c12
Yield: 29.7 %

Procedure:
(S)-2-(1-Aminoethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (270 mg, 0.89 mmol), 4-amino-6-chloropyrimidine-5-carboxylic acid (190 mg, 0.88 mmol, prepared according to Lan, Ruoxi et al from PCT Int. Appl. (2013), WO 2013040059 A1 20130321), DIEA (1.54 ml, 8.84 mmol) and cesium fluoride (403 mg, 2.65 mmol) were suspended in ethanol (10 ml) and the mixture was heated to reflux for 72 h. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography using SP1® Purification System (0% to 70%, ethyl acetate-methanol) to obtain 106 mg (27% yield) of the title compound. Purity: 90%.
Reaction SMILES: [CH3:1][C:2]1([C:5](=O)[CH2:6][C:7]#[N:8])[CH2:4][CH2:3]1.[CH3:10][NH:11][NH2:12]>CO>[CH3:10][N:11]1[C:7]([NH2:8])=[CH:6][C:5]([C:2]2([CH3:1])[CH2:4][CH2:3]2)=[N:12]1
Reactant: CNN
Reactant: CC1(C(=O)CC#N)CC1
Solvent: CO
Product: Cn1nc(C2(C)CC2)cc1N

Procedure:
A solution of 3-(1-methyl-cyclopropyl)-3-oxo-propionitrile (1.0 g, 8.1 mmol), methylhydrazine (0.56 g, 12.2 mmol) and MeOH (40 mL) is heated at 80° C. for 16 h. The solution is then concentrated in vacuo and the residue is suspended in 5 mL DCM and 20 mL heptane, filtered to give product. MS (ESI) m/z 152.3 (M+1).