Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1C(O)=O.C(OC(C)C)(C)C>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[OH:1]
Reactant: COc1cc2ncc(C(=O)O)c(O)c2cc1OC
Solvent: CC(C)OC(C)C
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1cc2nccc(O)c2cc1OC
Temperature: 250 °C
Reaction time: 8 h
Yield: 104.6 %

Procedure:
A mixture of 9.24 g of 4-hydroxy-6,7-dimethoxyquinoline-3-carboxylic acid in 185 cm3 of diphenyl ether was maintained, with mechanical stirring, at a temperature in the region of 250° C. for 1.3 hours. After cooling the reaction mixture to about 20° C., 100 cm3 of diisopropyl ether were added. The suspension was stirred for 8 hours and filtered, and the filter cake was washed with 3 times 100 cm3 of diisopropyl ether. 7.96 g of 6,7-dimethoxyquinolin-4-ol were obtained in the form of a brown solid.
Reaction SMILES: Cl.[C:2]1([CH2:8][N:9]2[CH2:14][CH2:13][C:12]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)([C:15](N)=[O:16])[CH2:11][CH2:10]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:29].[Na+]>O>[C:2]1([CH2:8][N:9]2[CH2:10][CH2:11][C:12]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)([C:15]([OH:16])=[O:29])[CH2:13][CH2:14]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: NC(=O)C1(Nc2cccc(C(F)(F)F)c2)CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)C1(Nc2cccc(C(F)(F)F)c2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To 792 parts of concentrated hydrochloric acid solution are added 100 parts of 1-(phenylmethyl)-4-{[3-(trifluoromethyl)phenyl]amino}-4-piperidinecarboxamide. The whole is heated to reflux temperature while stirring. 230 Parts of water are added followed by the addition of anti-foam. Stirring at reflux is continued for 3.50 h. After cooling to room temperature, the reaction mixture is poured into a vessel and 200 parts of water are added. The whole is strongly alkalized with sodium hydroxide while stirring vigorously: a precipitate is formed. The supernatant aqueous phase is decanted and the residual precipitate is dissolved in water. The resulting solution is cooled and acidified with acetic acid (pH=about 7), whereupon the product is precipitated. It is filtered off and boiled in N,N-dimethylformamide. After cooling, the product is filtered off again, washed successively with ethanol and 2,2'-oxybispropane and dried. The less pure fraction is crystallized from N,N-dimethylformamide. The pure product is filtered off, washed successively with ethanol and with N,N-dimethylformamide, and dried at 140° C., yielding 1-(phenylmethyl)-4-[3-(trifluoromethyl)phenylamino] -4-piperidinecarboxylic acid; mp. 264.3° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[CH2:19]=O.C[O-].[Na+].[BH4-].[Na+]>CO>[CH3:19][NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc2nc(-c3ccc(N)cc3)sc2c1
Reactant: C=O
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNc1ccc(-c2nc3ccc(OC)cc3s2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.5 %

Procedure:
2-(4-Aminophenyl)-6-methoxybenzothiazole (43, 779 mg, 3.04 mmol) and paraformaldehyde (487 mg, 15.2 mmol) were dissolved in methanol and then added to 0.5 M NaOMe in methanol (30 mL, 15.2 mmol). The resulting reaction mixture was agitated for 4 hours at room temperature and, after adding NaBH4 (1.0 g, 26.5 mmol), heated for 1.5 hours under reflux. After removing methanol by distilling under reduced pressure, the residue was dissolved in ethyl acetate (100 mL) and water was added thereto. After extracting the organic compound with ethyl acetate, removing water using sodium sulfate and removing the solvent under reduced pressure, column chromatography yielded the target compound 2-[4-(N-monomethyl)aminophenyl)-6-methoxybenzothiazole (44, 588 mg, 72%) as yellow solid.
Reaction SMILES: [Na].C(=O)(O)O.[NH2:6][C:7]([NH2:9])=[NH:8].[CH2:10]([O:12][C:13](=[O:37])[NH:14][C:15]1[C:20]([O:21][CH3:22])=[CH:19][C:18]([CH2:23][C:24]([C:33]#N)=[CH:25][NH:26]C2C=CC=CC=2)=[CH:17][C:16]=1[O:35][CH3:36])[CH3:11]>C(O)C>[CH2:10]([O:12][C:13](=[O:37])[NH:14][C:15]1[C:20]([O:21][CH3:22])=[CH:19][C:18]([CH2:23][C:24]2[C:25]([NH2:26])=[N:8][C:7]([NH2:9])=[N:6][CH:33]=2)=[CH:17][C:16]=1[O:35][CH3:36])[CH3:11]
Reactant: N=C(N)N
Reactant: CCOC(=O)Nc1c(OC)cc(CC(C#N)=CNc2ccccc2)cc1OC
Agent: O=C(O)O
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)Nc1c(OC)cc(Cc2cnc(N)nc2N)cc1OC
Reaction time: 1 h

Procedure:
A solution of 360 mg. of sodium in 100 ml. of absolute ethanol was treated with 2.8 g. of guanidine carbonate and 2.0 g. of 4-(3-anilino-2-cyano-allyl)-2,6-dimethoxy carbanilic acid ethyl ester and boiled under reflux for 20 hours. The solution was diluted with 100 ml. of water and the alcohol removed under vacuum. After standing at room temperature for 1 hour, the precipitate was removed by filtration with suction, washed with water and dissolved in about 200 ml. of boiling ethanol. The solution was chromatographed on 100 g. of silica gel using ethanol/ethyl acetate (1:1) and there was obtained 4-[(2,4-diamino-5-pyrimidinyl)-methyl]-2,6-dimethoxy-carbanilic acid ethyl ester which, after recrystallization from ethanol, had a melting point of 228° C. (decomposition).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH:12]=O.CC(O)=O.[BH3-]C#N.[Na+]>CO.C([O-])(O)=O.[Na+]>[CH2:16]([O:15][C:11](=[O:14])[CH2:12][NH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[CH3:17]
Reactant: NCCCN1CCOCC1
Reactant: CCOC(=O)C=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)CNCCCN1CCOCC1
Reaction time: 0.25 h
Yield: 47.2 %

Procedure:
A solution of 4-(3-aminopropyl)morpholine (10.0 mL, 68.4 mmol) in MeOH (180 mL) was cooled in an ice bath and treated with ethyl glyoxylate (50% solution in toluene, 20.0 mL, 98.0 mmol) and HOAc (12 mL). After stirring for 15 min, NaBH3CN (4.81 g, 76.5 mmol) was added and the mixture was allowed to stir at 0° C. for 2 h. The mixture was diluted with saturated aqueous NaHCO3 (500 mL) and then extracted with EtOAc (5×300 mL) followed by CH2Cl2 (9×200 mL). The combined CH2Cl2 layers were dried over Na2SO4, filtered and the solvent was removed in vacuo to give the title compound (7.44 g, 47%) as a colorless oil: MS (ESI) m/e 231 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([CH:12]2[CH2:14][CH2:13]2)[CH:5]=1.[OH-].[Na+]>C1COCC1.C(O)C>[CH:12]1([C:6]2[CH:5]=[C:4]([CH:9]=[C:8]([O:10][CH3:11])[CH:7]=2)[C:3]([OH:15])=[O:2])[CH2:13][CH2:14]1
Reactant: COC(=O)c1cc(OC)cc(C2CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(C(=O)O)cc(C2CC2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.2 %

Procedure:
The above prepared 3-cyclopropyl-5-methoxy-benzoic acid methyl ester (0.221 g, 1.07 mmol) was dissolved in 3.6 ml of THF/ethanol=1/1 and treated with 1.79 ml of aq. NaOH (3M, 5 eq.). The mixture was stirred for 1.5 h at ambient temperature and was then poured onto crashed ice/AcOEt/HCl dil.; the organic layer was washed with water, dried over sodium sulfate, and evaporated to dryness to leave 0.202 g of the title compound as white solid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1.Br[CH2:30][C:31]([CH3:33])=[CH2:32]>C1COCC1>[CH3:32][C:31](=[CH2:30])[CH2:33][CH:19]([C:16]1[CH:15]=[CH:14][C:13]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:18][CH:17]=1)[C:20]([OH:22])=[O:21]
Reactant: C=C(C)CBr
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C=C(C)CC(C(=O)O)c1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 71.4 %

Procedure:
To a stirring solution of diisopropylamine (0.537 g, 5.31 mmol) in THF (5.2 mL) at 0° C. was added n-butyllithium (2.1 mL, 5.22 mmol, 2.5M in hexane) dropwise. After stirring for 15 min at 0° C., the mixture was cooled to -78° C. and a solution of 4-biphenylacetic acid (0.500 g, 2.36 mmol) in THF (2 mL) was added dropwise. After again warming to 0° C. and cooling to -78° C., 3-bromo-2-methylpropene (0.485 g, 3.54 mmol) was added to the mixture in one portion. After stirring at -78° C. for 1h, the reaction was quenched with 2 mL of water then concentrated. The residue was redissolved in water and extracted with ether (100 mL). The aqueous layer was acidified (3N HCl) and extracted with ether (3×100 mL). The organic layers were combined, dried (MgSO4), filtered and concentrated to yield a white solid (0.449 g, 72%). MS(ESI): 265.3 (M+H)-.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([N:15]([S:23]([CH3:26])(=[O:25])=[O:24])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=[CH:13][CH:14]=1)[C:2]1C=CC=C[CH:3]=1.C1CCCCC=1.C([OH:35])C>[Pd]>[CH3:26][S:23]([N:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C@@H:2]2[CH2:3][O:35]2)[CH:10]=1)[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:19])[CH3:20])(=[O:25])=[O:24]
Reactant: CCO
Reactant: CC(C)(C)OC(=O)N(c1cccc(OCc2ccccc2)c1)S(C)(=O)=O
Agent: [Pd]
Solvent: C1=CCCCC1
Product: CC(C)(C)OC(=O)N(c1cccc(OC[C@@H]2CO2)c1)S(C)(=O)=O

Procedure:
tert-Butyl 3-(benzyloxy)phenyl(methylsulfonyl)carbamate (2.6 g, 6.88 mmol) was dissolved in ethanol (25 mL), 10% palladium on carbon (0.75 g) and cyclohexene (1.5 mL) were added. The solution was heated to reflux for 3 hours. The solution was cooled and filtered through Celite. The solvent was removed in vacuo to yield crude title compound (1.93 g, 6.7 mmol).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=2)[C:6](=[C:18](OCC)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]1=[O:28])(=O)C.[CH3:29][N:30]([CH2:32][C:33]1[CH:34]=[C:35]([CH:37]=[CH:38][CH:39]=1)[NH2:36])[CH3:31]>>[CH3:31][N:30]([CH2:32][C:33]1[CH:34]=[C:35]([CH:37]=[CH:38][CH:39]=1)[NH:36]/[C:18](=[C:6]1\[C:5](=[O:28])[NH:4][C:12]2[C:7]\1=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=2)/[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH3:29]
Reactant: CN(C)Cc1cccc(N)c1
Reactant: CCOC(=O)c1ccc2c(c1)N(C(C)=O)C(=O)C2=C(OCC)c1ccccc1
Product: CCOC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1cccc(CN(C)C)c1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-ethoxycarbonyl-2-indolinone and 3-(dimethylaminomethyl)-aniline Rf value: 0.5 (aluminium oxide, methylene chloride/ethanol=30:1) C27H27N3O3
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][P:11]([OH:13])[OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si](Cl)(C)C.[C:19](#[N:22])[CH:20]=[CH2:21].Cl>C(Cl)(Cl)Cl.C(N(CC)CC)C>[OH:12][P:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH2:21][CH2:20][C:19]#[N:22])=[O:13]
Reactant: OP(O)CCCCc1ccccc1
Reactant: C=CC#N
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: N#CCCP(=O)(O)CCCCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-phenylbutyl phosphonous acid (0.44 g, 0.0022 mole) in chloroform (15 ml) was added triethylamine (0.68 ml), trimethyl silylchloride (0.61 ml) and acrylonitrile (0.17 ml) and the reaction mixture was stirred at room temperature for 18 hours; the mixture was poured into crushed ice (15 gm) containing 10 ml 10% HCl acid. It was shaken in a separatory funnel; a chloroform layer was evaporated, and the aqueous layer extracted once with 20 ml chloroform. The combined organic phase was washed with water, dried over anhydrous sodium sulphate and the organic solvent removed on a rotavap to produce the title compound as a highly crystalline solid 0.5 gm (90% yield), m.p. 80°-82° C.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[CH2:8][CH2:9][CH2:10][C:11](=[O:13])[NH:12][C:6]=2[CH:5]=1)([O-:3])=[O:2].CN(C)CCN(C)C.[I:24][Si](C)(C)C.II>C(Cl)Cl>[I:24][CH:10]1[C:11](=[O:13])[NH:12][C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:15]=[CH:14][C:7]=2[CH2:8][CH2:9]1
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc2N1
Reactant: C[Si](C)(C)I
Agent: CN(C)CCN(C)C
Agent: II
Solvent: ClCCl
Product: O=C1Nc2cc([N+](=O)[O-])ccc2CCC1I
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
A mixture of 8-nitro-1,3,4,5-tetrahydro-1-benzazepin-2-one (1.72 g, 8.34 mmol) and N,N,N′,N′-Tetramethylethylenediamine (5.02 mL, 33.3 mmol) in methylene chloride (25 mL) was chilled to −20° C. and iodotrimethylsilane (5.32 g, 26.6 mmol) was added. The mixture became homogeneous and was stirred for 30 min before adding iodine (3.17 g, 12.5 mol). After stirring for 2 h at 0° C., the reaction was quenched with 10% aqueous Na2S2O3 and the mixture was filtered. The solid residue was washed with water (10×5 mL) and then with ether (2×2 mL) to yield 2.345 g of 3-iodo-8-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (contaminated with ˜8% starting material) that was used as such in the next reaction.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@@H:9]1[CH2:13][NH:12][C@H:11]([C:14]([OH:16])=[O:15])[CH2:10]1.[Br:17][C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.CN(C=O)C>[Br:17][C:18]1[CH:19]=[C:20]([N:12]2[CH2:13][C@@H:9]([CH3:8])[CH2:10][C@H:11]2[C:14]([OH:16])=[O:15])[CH:21]=[CH:22][CH:23]=1
Reactant: C[C@@H]1CN[C@H](C(=O)O)C1
Reactant: Brc1ccc(Br)cc1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1C[C@@H](C(=O)O)N(c2cccc(Br)c2)C1
Temperature: 95 °C

Procedure:
To (4S)-4-methyl-L-proline trifluoroacetate (2.92 g, 8.17 mmol), 1,4-dibromobenzene (2.9 g, 12.27 mmol), potassium carbonate (3.95 g, 28.6 mmol), and copper iodide (315 mg, 1.64 mmol) was added dry DMF (30 mL) under dry nitrogen. The reaction flask was thoroughly degassed with dry nitrogen and heated at 95° C. for 3 days. Water and hexane were added and the organic phase was separated and discarded (to remove excess 1,4-dibromobenzene). The pH of the aqueous phase was adjusted to 3 with aqueous 10% HCl and the product extracted with EtOAc (2×), dried over Na2SO4, concentrated in vacuo and purified by flash chromatography over silica gel (AcOH/EtOAc/Hex, 0.5/49.5/50) to afford (4S)-1-(3-bromophenyl)-4-methyl-L-proline.
Reaction SMILES: [C:1]1([CH2:9][OH:10])[CH:6]=[CH:5][C:4]([CH2:7][OH:8])=[CH:3][CH:2]=1.F[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.[H-].[Na+]>CN(C=O)C>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[O:8][CH2:7][C:4]1[CH:5]=[CH:6][C:1]([CH2:9][OH:10])=[CH:2][CH:3]=1
Reactant: OCc1ccc(CO)cc1
Reactant: Fc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OCc1ccc(COc2ccccn2)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 65.9 %

Procedure:
To a solution of 1,4-benzenedimethanol (5.5 g) and DMF (15 mL) of 2-fluoropyridine (1.3 g) was added NaH (1.4 g/66% in oil) at 0° C., which was stirred for 1 hour at 70° C. The reaction mixture was cooled to room temperature and extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:1) to obtain the titled compound (1.9 g).
Reaction SMILES: Br[C:2]1[C:3]([F:20])=[CH:4][C:5]2[CH:17]3[CH2:18][CH:15]([CH2:16]3)[C:8]3[S:9][C:10]([C:12]([NH2:14])=[O:13])=[CH:11][C:7]=3[C:6]=2[CH:19]=1.[CH3:21][C:22]([OH:26])([C:24]#[CH:25])[CH3:23]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C)C=O.C(N(CC)CC)C>[F:20][C:3]1[C:2]([C:25]#[C:24][C:22]([OH:26])([CH3:23])[CH3:21])=[CH:19][C:6]2[C:7]3[CH:11]=[C:10]([C:12]([NH2:14])=[O:13])[S:9][C:8]=3[CH:15]3[CH2:16][CH:17]([C:5]=2[CH:4]=1)[CH2:18]3
Reactant: C#CC(C)(C)O
Reactant: NC(=O)c1cc2c(s1)C1CC(C1)c1cc(F)c(Br)cc1-2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(O)C#Cc1cc2c(cc1F)C1CC(C1)c1sc(C(N)=O)cc1-2
Temperature: 80 °C
Reaction time: 0.03 h
Yield: 62.5 %

Procedure:
Into a pressure tube containing a solution of 9-bromo-8-fluoro-5,6-dihydro-4H-4,6-methanobenzo[3,4]cyclohepta[1,2-b]thiophene-2-carboxamide (31 mg, 0.08 mmol) in 1:1 N,N-dimethylformamide/triethylamine (0.8 mL) was introduced 2-methyl-3-butyn-2-ol (181 mg, 2.16 mmol), copper(I) iodide (2 mg, 0.01) and nitrogen gas bubbled through the solution for 3 minutes. Bis(triphenylphosphine)palladium(II) chloride (8 mg, 0.01 mmol) was added and nitrogen bubbling continued a further two minutes before the pressure tube was closed under nitrogen. The reaction mixture was warmed to 80° C. for 20 hr, re-treated with 2-methyl-3-butyn-2-ol (181 mg, 2.16 mmol), copper(I) iodide (2 mg, 0.01) and bis(triphenylphosphine)palladium(II) chloride (8 mg, 0.01 mmol) and warmed to 100° C. for an additional 7 hr. After cooling to room temperature, the reaction mixture was evaporated in vacuo and the residue re-dissolved in ethyl acetate (20 mL). This solution was washed with saturated aqueous sodium bicarbonate (10 mL), water (10 mL) and brine (5 mL). The organic extract was dried over sodium sulfate, filtered and the filtrate absorbed onto silica gel. Purification by silica gel flash column chromatography (eluent:heptane/ethyl acetate) furnished partially purified product as a brown solid. After several acetonitile solubilisation-evaporation (in vacuo) cycles, the resulting solid residue was slurried in acetonitrile (1.0 mL) and collected by filtration to furnish the title compound (17 mg, 0.05 mmol, 62%) as a pale-brown solid: 1H NMR (500 MHz, CDCl3) δ1.68 (s, 6H), 1.71-1.73 (m, 2H), 2.87-2.96 (m, 2H), 3.53-3.62 (m, 2H), 6.87 (d, J=10.09 Hz, 1H), 7.92 (d, J=6.94 Hz, 1H), 8.06 (s, 1H); M+H=356.
Reaction SMILES: [Cl:1][CH:2]([Cl:6])[C:3](Cl)=[O:4].[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1)([O-:9])=[O:8].C(N(CC)CC)C>C1(C)C=CC=CC=1>[N+:7]([C:10]1[CH:11]=[CH:12][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C:3](=[O:4])[CH:2]([Cl:6])[Cl:1])[CH2:18][CH2:17]2)=[CH:14][CH:15]=1)([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: O=C(Cl)C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(C(Cl)Cl)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Yield: 45.8 %

Procedure:
7.1 g (0.048 mol) of dichloroacetyl chloride were added dropwise to a solution of 10 g (0.048 mol) of 1-(4-nitrophenyl)-piperazine and 5 g (0.495 mol) of triethylamine in 100 ml of toluene at room temperature, while stirring. The mixture was subsequently stirred at 20° C. for 3 hours. Working up was then effected by a procedure in which the reaction mixture was washed twice with 100 ml of water each time and the organic phase was separated off, dried and evaporated under reduced pressure. The residue was recrystallized from toluene. 7 g (46% of theory) of 1-(4-nitrophenyl)-4-dichloroacetyl-piperazine were obtained in the form of light yellow crystals of melting point 155° C.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[C:8]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][S:18]3(=[O:24])=[O:23])[CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[CH2:6][CH2:5]1)(=O)[CH3:2].CCO>C1COCC1>[O:24]=[S:18]1(=[O:23])[CH2:19][CH2:20][CH2:21][CH2:22][N:17]1[C:8]1[CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=[C:12]2[C:7]=1[CH2:6][CH2:5][N:4]2[CH2:1][CH3:2]
Reactant: COC(=O)c1cc2c(c(N3CCCCS3(=O)=O)c1)CCN2C(C)=O
Solvent: C1CCOC1
Solvent: CCO
Product: CCN1CCc2c1cc(C(=O)OC)cc2N1CCCCS1(=O)=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 69.5 %

Procedure:
To a solution of methyl 1-acetyl-4-(1,1-dioxidotetrahydro-2H-1,2-thiazin-2-yl)-2,3-dihydro-1H-indole-6-carboxylate (D235) (300 mg, 0.85 mmol, 1 equiv) in THF (20 ml) at room temperature was added BH3 (1.5 M in THF, 2 ml, 3 mmol, 3.5 equiv) and the resulting mixture was stirred at room temperature for 15 h. EtOH (5 ml) was added and the resulting mixture was concentrated in vacuo after 5 min. The residue was partitioned between a 2N aqueous HCl solution (20 ml) and CH2Cl2 (20 ml) and the biphasic mixture was vigorously stirred for 3 h. The two layers were separated and the organic phase was dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (AcOEt/iso-hexane: 1/2) gave methyl 4-(1,1-dioxidotetrahydro-2H-1,2-thiazin-2-yl)-1-ethyl-2,3-dihydro-1H-indole-6-carboxylate (B145) (200 mg, 70%) as a very pale yellow solid. [M+H]+=339.2, RT=2.92 min.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=[C:3]1[C:12]([OH:14])=O.[C:15]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][C:27]=1[NH2:28])[NH:24][CH:23]=[CH:22]2)([CH3:18])([CH3:17])[CH3:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[C:15]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][C:27]=1[NH:28][C:12]([C:3]1[C:2](=[O:1])[C:11]3[C:6](=[CH:7][N:8]=[CH:9][CH:10]=3)[NH:5][CH:4]=1)=[O:14])[NH:24][CH:23]=[CH:22]2)([CH3:18])([CH3:16])[CH3:17]
Reactant: O=C(O)c1c[nH]c2cnccc2c1=O
Reactant: CC(C)(C)c1cc2cc[nH]c2cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc2cc[nH]c2cc1NC(=O)c1c[nH]c2cnccc2c1=O
Temperature: 80 °C

Procedure:
To 4-oxo-1,4-dihydro-1,7-naphthyridine-3-carboxylic acid (48 mg, 0.25 mmol), 5-tert-butyl-1H-indol-6-amine (48 mg, 0.25 mmol) in DMF (1 mL) was added HATU (106 mg, 0.28 mmol), followed by triethylamine (1064, 0.76 mmol) and the reaction mixture was heated at 80° C. for 16 h. The reaction mixture was then purified by reverse phase HPLC 10-99% ACN in water to give N-(5-tert-butyl-1H-indol-6-yl)-4-oxo-1,4-dihydro-1,7-naphthyridine-3-carboxamide. MS m/z: 361.5 [M+H]+
Reaction SMILES: [CH2:1]1[C@@H:5]2[CH2:6][NH:7][CH2:8][C@@H:4]2[CH2:3][N:2]1[C:9]1[N:14]=[N:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][NH:24][CH:25]=3)=[CH:17][C:16]=2[OH:26])=[CH:11][CH:10]=1.[Si:27]([O:34][CH2:35][CH:36]=O)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].[Na].C(O)(=O)C>C(Cl)Cl>[Si:27]([O:34][CH2:35][CH2:36][N:7]1[CH2:6][C@@H:5]2[CH2:1][N:2]([C:9]3[N:14]=[N:13][C:12]([C:15]4[CH:20]=[CH:19][C:18]([C:21]5[CH:22]=[N:23][NH:24][CH:25]=5)=[CH:17][C:16]=4[OH:26])=[CH:11][CH:10]=3)[CH2:3][C@@H:4]2[CH2:8]1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: Oc1cc(-c2cn[nH]c2)ccc1-c1ccc(N2C[C@H]3CNC[C@H]3C2)nn1
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: [Na]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)OCCN1C[C@@H]2CN(c3ccc(-c4ccc(-c5cn[nH]c5)cc4O)nn3)C[C@@H]2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.2 %

Procedure:
To a solution of 2-(6-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol (31.4 mg, 0.09 mmol), 2-((tert-butyldimethylsilyl)oxy)acetaldehyde (47.1 mg, 0.270 mmol), and sodium triacetoxyhydroborate (57.2 mg, 0.270 mmol) in CH2Cl2 (2 mL), was added acetic acid (0.013 mL, 0.225 mmol). The reaction mixture was stirred at RT overnight, then quenched with water and diluted with DCM. The organic layer was acidified with 1N HCl solution to pH˜3 and filtered to remove insoluble materials. The filtrate was loaded onto an SCX column, washed with MeOH, then eluted with 7N NH3 in MeOH. Concentration provided a brownish solid, 2-(6-((3a R,6aS)-5-(2-((tert-butyldimethylsilyl)oxy)ethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol (23 mg, 0.020 mmol, 51% yield), MS (M+1)=507.1.