Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:13]([NH:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31](O)=[O:32])[CH2:14][CH2:15][CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].S(Cl)(Cl)=O>C(COC)OC.C(Cl)Cl.CC(N(C)C)=O>[CH2:13]([NH:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31]([NH:10][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])=[O:32])[CH2:14][CH2:15][CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: NS(=O)(=O)c1ccccc1
Reactant: CCCCCCCCCCC=CCCCNc1ccccc1C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCCCCCCCCC=CCCCNc1ccccc1C(=O)NS(=O)(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of 31.4 g. of benzenesulfonamide in 250 ml. of dry dimethylacetamide is added dropwise, with stirring and cooling, to a suspension of 5.5 g. of sodium hydride in 100 ml. of dry dimethylacetamide over 30 minutes at room temperature. Stirring is continued for a further 30 minutes. In the meantime, a mixture of 36.2 g. of 2-(4-pentadecenylamino)benzoic acid in 1200 ml. of methylene chloride, 300 ml. of dimethoxyethane, and 40 ml. of thionyl chloride is refluxed for 1 hour and 15 minutes. The solution is evaporated to an oil which is co-evaporated twice with added dioxane to remove excess thionyl chloride. To the resulting oily residue of 2-(4-pentadecenylamino)benzoyl chloride hydrochloride is added, in one portion, the previously prepared mixture of sodium benzenesulfonamide in dimethylacetamide. The mixture is stirred for 30 minutes, without cooling, and is then filtered through a bed of diatomaceous earth. The filtrate is poured into 2 l. of water, and 250 ml. of saturated sodium chloride solution is added to coagulate the precipitate. The mixture is filtered and the product is washed with water and partially air dried. The product is dissolved in methylene chloride, the mixture is filtered through diatomaceous earth, and brine is added to break the emulsion. The layers are separated, the organic phase is dried over anhydrous sodium sulfate and filtered through a bed of 300 g. of hydrous magnesium silicate. The product is eluted with an additional 3 l. of methylene chloride. The first approximately 1 l. of filtrate is set aside and the remainder is evaporated to dryness. The residue is crystallized three times from toluene and the product is dried in the Abderhalden at 65° C. to provide the title compound as colorless crystals.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[S:18][C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[F:25][P-:26]([F:31])([F:30])([F:29])([F:28])[F:27].[C:32]1([I+]C2C=CC=CC=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C([O-])(=O)C1C=CC=CC=1.[Cu+].CCOCC>[F:25][P-:26]([F:31])([F:30])([F:29])([F:28])[F:27].[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[S+:18]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: c1ccc([I+]c2ccccc2)cc1
Reactant: CCCCc1ccc(N2c3ccccc3Sc3ccccc32)cc1
Agent: [Cu+]
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])c1ccccc1
Solvent: CCOCC
Product: CCCCc1ccc(N2c3ccccc3[S+](c3ccccc3)c3ccccc32)cc1
Temperature: 120 °C

Procedure:
A mixture of 10-(4-butylphenyl)-10H-phenothiazine (83) (1.44 g, 4.34 mmol), diphenyliodonium hexafluorophosphate (1.85 g, 4.34 mmol) and copper (I) benzoate (0.10 g) was heated at 120° C. for 3 hours under nitrogen. Upon cooling to ambient temperature, the mixture was transferred to a mortar-and-pestle and 50 ml of ether was added. The solid was finely powdered, washed with ether, collected by filtration and washed three times with ether. Without further purification, it was isolated in 98.2% (2.36 g) yield as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([SH:12])[N:11]=[C:4]2[N:3]=1.[OH-].[Na+].Cl[CH2:16][C:17]([OH:19])=[O:18].Cl>O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([S:12][CH2:16][C:17]([OH:19])=[O:18])[N:11]=[C:4]2[N:3]=1
Reactant: Cc1cc(C)n2nc(S)nc2n1
Reactant: O=C(O)CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(C)n2nc(SCC(=O)O)nc2n1
Temperature: 120 °C
Reaction time: 6 h

Procedure:
A mixture of 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-thiol (1.0 g, 5.6 mmol), sodium hydroxide (0.44 g, 11.1 mmol), and water (22 mL) was added to a 100 mL RBF with a magnetic stirring bar. The flask was fitted with a condenser, and the mixture was warmed to reflux in a 120° C. oil bath for 30 min. The mixture was removed from the oil bath and allowed to cool, and chloroacetic acid (0.525 g, 5.6 mmol) was added. Warming to reflux was continued for 6 h. The mixture was allowed to cool to ambient temperature, and the pH was adjusted to 2 with 1 M aqueous hydrochloric acid (5 mL). A solid precipitate was isolated by filtration, rinsed with 1 M hydrochloric acid (2 mL) and water (5 mL), and allowed to dry. The title compound was obtained as a tan solid (1.16 g, 88% yield). 1H NMR (DMSO-d6, 400 MHz) δ ppm: 12.85 (br s, 1H), 7.12 (s, 1H), 4.08 (s, 2H), 2.66 (s, 3H), 2.54 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[S:23](=[O:24])[CH2:22][CH2:21][C:11]=3[N:12]=[C:13]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[N:14]=2)[CH:5]=[CH:6][CH:7]=1.Br[C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[S:23](=[O:24])[CH2:22][CH2:21][C:11]=3[N:12]=[C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:26]4[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=4)[CH2:17][CH2:16]3)[N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(Br)cc1
Reactant: O=S1CCc2nc(N3CCNCC3)nc(Nc3cccc(F)c3)c21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Product: N#Cc1ccc(N2CCN(c3nc4c(c(Nc5cccc(F)c5)n3)S(=O)CC4)CC2)cc1
Yield: 35.9 %

Procedure:
Under an argon atmosphere 315 mg (3-fluoro-phenyl)-(5-oxo-2-piperazin-1-yl-6,7-dihydro-5H-5λ4-thieno[3,2-d]pyrimidin-4-yl)-amine, 165 mg 4-bromo-benzonitrile, 21 mg palladium(II)acetate, 80 mg Xantphos and 415 mg caesium carbonate are stirred in 2.50 ml degassed toluene for 24 hours at 80° C. After cooling the reaction mixture is extracted with ethyl acetate and saturated sodium chloride solution. The organic phase is dried and evaporated to dryness. The residue is purified by preparative HPLC (method A). 146 mg of the product (36%) are obtained. HPLC (method A):RT=3.83 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[N:13]=[CH:12][CH:11]=1>C(O)C>[Cl:20][C:16]1[CH:15]=[C:14]2[C:19]([C:10]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=3)=[CH:11][CH:12]=[N:13]2)=[CH:18][CH:17]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: Nc1ccc(O)cc1
Solvent: CCO
Product: Oc1ccc(Nc2ccnc3cc(Cl)ccc23)cc1
Temperature: 25 °C
Yield: 95 %

Procedure:
4-aminophenol (1.09 g, 10 mmol) and 4,7-dichloroquinoline (1.98 g, 1 eq) were refluxed in 50 mL of ethanol for 2 h. The reaction mixture was then cooled to room temperature and the precipitate was removed by filtration and washed successively with a saturated aqueous solution of NaHCO3, water, methanol and then petroleum ether to yield expected compound as a yellow powder (2.57 g, 95% yield). LC-MS: m/z (ESI) 271.1 [M+H]+.
Reaction SMILES: [CH:1]1([NH2+]C2CCCCC2)CCCCC1.[C:14]([O:18][C:19]([NH:21][C@@H:22]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([Cl:34])[CH:28]=1)[C:23]([O-:25])=[O:24])=[O:20])([CH3:17])([CH3:16])[CH3:15].O[Li].O.COS(OC)(=O)=O.C(C)(C)C.C(OC(C)(C)C)=O>C1COCC1>[CH3:1][O:24][C:23](=[O:25])[C@@H:22]([NH:21][C:19]([O:18][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:20])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([Cl:34])[CH:28]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)c(Cl)c1)C(=O)[O-]
Reactant: C1CCC([NH2+]C2CCCCC2)CC1
Agent: CC(C)(C)OC=O
Agent: CC(C)C
Agent: [Li]O
Solvent: COS(=O)(=O)OC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccc(O)c(Cl)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 10 mL round-bottomed flask, (S)-2-(tert-butoxycarbonylamino)-3-(3-chloro-4-hydroxyphenyl)propanoate dicyclohexylammonium salt (300 mg, 604 μmol, Eq: 1.00) was combined with dry THF (2 mL) to give a white suspension. LiOH hydrate (38.4 mg, 905 μmol, Eq: 1.50) was added and the mixture was stirred for 30 min at 25° C. Then Me2SO4 (80.1 mg, 60.7 μL, 604 μmol, Eq: 1.00) was added. The reaction mixture was heated to 80° C. and stirred for 2 h. After that the mixture was stirred for 18 h at 50° C. The crude reaction mixture was concentrated in vacuo. The reaction mixture was poured into saturated aqueous NaHCO3 solution and extracted with AcOEt (2×). The organic layers were combined and washed with brine (1×). The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 20 g, n-heptane/AcOEt 4/1, 3/1) to yield a colorless oil (132 mg; 66%). m/z=330.2 [M+H]+; 274.1 [M+H-tBu]+; 230.2 [M+H-Boc]+.
Reaction SMILES: Br[C:2]1[C:3]([CH2:10][N:11]2[C@@H:15]([CH3:16])[C@@H:14]([C:17]3[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([F:27])[CH:18]=3)[O:13][C:12]2=[O:28])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.[Cl:29][C:30]1[CH:31]=[C:32](B2OC(C)(C)C(C)(C)O2)[C:33]([O:36][CH3:37])=[N:34][CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[Cl:29][C:30]1[CH:31]=[C:32]([C:2]2[C:3]([CH2:10][N:11]3[C@@H:15]([CH3:16])[C@@H:14]([C:17]4[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([F:27])[CH:18]=4)[O:13][C:12]3=[O:28])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=2)[C:33]([O:36][CH3:37])=[N:34][CH:35]=1
Reactant: COc1ncc(Cl)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CSc1ncc(Br)c(CN2C(=O)O[C@H](c3cc(F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: C1CCOC1
Product: COc1ncc(Cl)cc1-c1cnc(SC)nc1CN1C(=O)O[C@H](c2cc(F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 40 °C
Yield: 71 %

Procedure:
To a solution of (4S,5R)-3-{[5-bromo-2-(methylsulfanyl)pyrimidin-4-yl]methyl}-5-[3-fluoro-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 10, 263 mg, 0.548 mmol) in THF (3.0 mL) was added 5-chloro-2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (221 mg, 0.821 mmol), 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (17.8 mg, 0.027 mmol), and aqueous potassium carbonate (0.821 mL, 2.0 M). The mixture was degassed, flushed with nitrogen and heated to 40° C. for 18 hours. The reaction was diluted with ethyl acetate, washed with water, brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography to afford (4S,5R)-3-{[5-(5-chloro-2-methoxypyridin-3-yl)-2-(methylsulfanyl)pyrimidin-4-yl]methyl}-5-[3-fluoro-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (211 mg, 0.389 mmol). LCMS (M+H)+: 543.0.
Reaction SMILES: [Br-].[C:2]1([C:8]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:12][CH2:11][O:10][C:9]2=[N+:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]1([C:30]2([OH:36])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[OH:36][C:30]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:35][CH2:34][N:33]([CH2:11][CH2:12][C:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]([N:13]2[CH2:14][CH2:15][CH2:16][CH2:17]2)=[O:10])[CH2:32][CH2:31]1
Reactant: c1ccc(C2(c3ccccc3)CCOC2=[N+]2CCCC2)cc1
Reactant: OC1(c2ccccc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [I-]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: O=C(N1CCCC1)C(CCN1CCC(O)(c2ccccc2)CC1)(c1ccccc1)c1ccccc1

Procedure:
A mixture of 13 parts of 1-(tetrahydro-3,3-diphenyl-2-furylidene) pyrrolidinium bromide, 5.3 parts of 4-phenyl-4-piperidinol 8 parts of sodium carbonate, 0.2 parts of potassium iodide and 200 parts of 4-methyl-2-pentanone is stirred and refluxed for 5 hours with water separator. The reaction mixture is cooled and water is added. The organic layer s separated, washed with diluted sodium hydroxide solution, dried, filtered, and while stirring the filtrate, the product is crystallized. It is filtered off and dried, yielding 1-[4-(4-hydroxy-4-phenylpiperidino)-2,2-diphenylbutyryl]pyrrolidine; m.p. 187.5° C.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:6][N:7]([C:24]1[N:25]=[N:26][N:27]([CH3:29])[N:28]=1)[C@H:8]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[CH:15]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:17]([CH3:19])=[CH:18][C:9]1=2.Br[CH2:40][C:41]#[N:42].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O.C(OCC)(=O)C>[F:38][C:2]([F:37])([F:1])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:32]=1)[CH2:6][N:7]([C:24]1[N:25]=[N:26][N:27]([CH3:29])[N:28]=1)[C@H:8]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:40][C:41]#[N:42])[C:10]2[CH:15]=[C:16]([C:20]([F:21])([F:22])[F:23])[C:17]([CH3:19])=[CH:18][C:9]1=2
Reactant: Cc1cc2c(cc1C(F)(F)F)NCCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2c(cc1C(F)(F)F)N(CC#N)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Temperature: 25 °C

Procedure:
To a solution of (S)-(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amine (Example 3, Step 18) (0.09 mmol) in dimethylformamide (3 mL), add bromoacetonitrile (0.36 mmol) and cesium carbonate (0.36 mmol). After stirring the reaction at 60° C. for 6 h, cool to room temperature and dilute with water (20 mL) and ethyl acetate (30 mL). Separate the organic phase and wash the aqueous with ethyl acetate (2×10 mL). Dry the combined organics over sodium sulfate, filter, and remove solvent under vacuum. Chromatograph the product over silica gel, eluting with ethyl acetate/hexane (5-40%), to afford the title compound as a colorless foam. MS (ES+): 592 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:27]=[C:26]4[C:22]([CH2:23][CH2:24][N:25]4[C:28](=[O:32])[CH2:29][NH:30][CH3:31])=[CH:21][C:20]=3[O:33][CH3:34])[NH:15][C:14]3=[N:35][CH:36]=[CH:37][C:13]=23)[C:3]=1[C:4]([NH2:6])=[O:5].CN[O:40][CH3:41]>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:27]=[C:26]4[C:22]([CH2:23][CH2:24][N:25]4[C:28](=[O:32])[CH2:29][N:30]([CH3:31])[O:40][CH3:41])=[CH:21][C:20]=3[O:33][CH3:34])[NH:15][C:14]3=[N:35][CH:36]=[CH:37][C:13]=23)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: CNOC
Reactant: CNCC(=O)N1CCc2cc(OC)c(Nc3nc(Nc4cccc(F)c4C(N)=O)c4ccnc-4[nH]3)cc21
Product: COc1cc2c(cc1Nc1nc(Nc3cccc(F)c3C(N)=O)c3ccnc-3[nH]1)N(C(=O)CN(C)OC)CC2

Procedure:
One third of the reaction mixture from the preparation of 2-fluoro-6-[(2-{[1-(N-methylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]benzamide was treated with N,O-dimethylhydroxylamine (145 mg, 2.37 mmol) and KI (90 mg, 0.54 mmol). After 1 h the resulting mixture was concentrated onto Celite and purified by silica gel chromatography using 1-10% MeOH (containing 0.2% NH3)/CH2Cl2 to obtain 2-fluoro-6-[(2-{[1-[N-methyl-N-(methyloxy)glycyl]-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]benzamide as a yellow solid (43 mg 42%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.59 (s, 3H), 3.08-3.20 (m, 2H), 3.43 (s, 3H), 3.60 (s, 2H), 3.78 (s, 3H), 4.22 (t, J=8.26 Hz, 2H), 6.23 (s, 1H), 6.81-6.92 (m, 1H), 6.95 (s, 1H), 6.97 (s, 1H), 7.28-7.40 (m, 1H), 7.61 (s, 1H), 8.02 (s, 1H), 8.10 (s, 1H), 8.51 (d, J=8.42 Hz, 1H), 8.63 (s, 1H), 10.54 (s, 1H), 11.31 (s, 1H); ESIMS (M+H)+=535.18.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([S:9][C:10]2[N:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH:6]=[CH:7][CH:8]=1.CC(C)=[O:21].ClC1C=C(C=CC=1)C(OO)=O>C(OCC)(=O)C>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[C:5]([S:9]([C:10]2[N:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)=[O:21])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)=O
Reactant: Nc1ccc(Sc2cccc(C(F)(F)F)c2)nc1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Product: Nc1ccc(S(=O)c2cccc(C(F)(F)F)c2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-(3-(Trifluoromethyl)phenylthio)-3-aminopyridine (4.0 grams) was dissolved in 50 ml. of acetone and m-chloroperoxybenzoic acid (4.0 grams) added. The solution was allowed to stir at room temperature for 2 hours, and an additional 1.0 gram of m-chloroperoxybenzoic acid was added. The reaction mixture was passed over a column of silica gel with ethyl acetate, and the fraction corresponding to the product collected and crystallized from ethyl acetate-hexanes, yield, 4.0 grams m.p. 74°-76° C.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[CH2:38]([NH2:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[CH2:38]([NH:45][C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: COc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1ccccc1C
Reactant: NCc1ccccc1
Product: COc1cc(C(=O)N2Cc3ccc(C(=O)NCc4ccccc4)n3Cc3ccccc32)ccc1-c1ccccc1C
Yield: 78 %

Procedure:
The title compound was prepared in 78% yield in the manner of Example 36 from 2,2,2-trichloro-1-{10-[(2-methoxy-2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 35 and benzylamine, m.p. m.p. 170-174° C. MS [(+)ESI, m/z]: 542 [M+H]+ Anal. Calcd for C35H31N3O3: C, 77.61; H, 5.77; N, 7.76. Found: C, 77.51; H, 5.74; N, 7.58.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:27])[NH:9][NH:10][C:11](=O)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C>C(OCC)(=O)C.O1CCCC1.C(Cl)Cl>[C:1]1([NH:7][C:8]2[O:27][C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][CH2:19][C:20]3[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=3)=[N:10][N:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(NNC(=O)c1ccccc1OCc1ccncc1)Nc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: c1ccc(Nc2nnc(-c3ccccc3OCc3ccncc3)o2)cc1
Temperature: 25 °C
Yield: 40 %

Procedure:
To a solution of 4-phenyl-1-(2-(pyridin-4-yl) methoxybenzoyl) semicarbazide (110 mg, 0.47 mmol; Reference Compound 6-(1) and triphenylphosphine (190 mg, 0.71 mmol) in a mixed solvent of methylene chloride (3.0 mL) and tetrahydrofuran (3.0 mL) were added carbon tetrachloride (290 mg, 1.9 mmol) and triethylamine (70 mg, 0.71 mmol), and then the mixture was refluxed overnight. The reaction solution was cooled to room temperature and ethyl acetate was added thereto. The ethyl acetate solution was washed with a saturated brine solution. To the solution was added a 1M hydrochloric acid and then the aqueous layer was taken out. To the aqueous layer was added a 1 M aqueous sodium hydroxide solution. The solid which precipitated at pH 8 was filtered off and dried under a reduced pressure to give 65 mg (40%) of the titled compound as a colorless solid.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][NH:5][C:6](=[NH:13])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH3:15][C:16](=O)[CH2:17][C:18](=O)[CH3:19]>C1C=CC=CC=1>[CH3:14][N:2]([CH3:1])[CH2:3][CH2:4][NH:5][C:6]1[N:13]=[C:18]([CH3:19])[CH:17]=[C:16]([CH3:15])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)CC(=N)NCCN(C)C
Reactant: CC(=O)CC(C)=O
Solvent: c1ccccc1
Product: CCOC(=O)c1c(C)cc(C)nc1NCCN(C)C

Procedure:
A solution of crude ethyl 3-(2-dimethylamino-ethylamino)-3-iminopropionate (15.3 g, 50 mmol) and pentane-2,4-dione (7.7 ml, 75 mmol) in dry benzene (80 ml) is refluxed for 18 hours. This solution is dried over anhydrous sodium sulfate and evaporated to give 18.4 g of crude title B product.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[CH:2]=1.S(Cl)([Cl:16])=O>C1(C)C=CC=CC=1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([Cl:16])=[O:13])[CH:2]=1
Reactant: O=C(O)c1cnc2ccccc2c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cnc2ccccc2c1
Yield: 90 %

Procedure:
10 g of 3-quinoline carboxylic acid was mixed with 8.5 ml of thionyl chloride and 150 ml of toluene, and allowed to react at 100° C. for 12 hours. The reaction mixture was condensed under a reduced pressure, to obtain a residue that gave 10 g of the title compound (yield 90%).
Reaction SMILES: [N+:1]([CH2:4][CH2:5][C:6]1[CH:18]=[CH:17][C:9]([O:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:8][CH:7]=1)([O-:3])=O.C[O-].[Li+].C(=O)(O)[O-].[Na+].[C:27]([C:29]1[C:30]([NH2:36])=[N:31][C:32]([NH2:35])=[CH:33][CH:34]=1)#[CH:28].C(N(CC)CC)C>[Ti](Cl)(Cl)(Cl)Cl.O.O1CCCC1.C(OCC)(=O)C.CO>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([O:10][C:9]2[CH:17]=[CH:18][C:6]([CH2:5][C:4]3[CH:28]=[C:27]([C:29]4[C:30]([NH2:36])=[N:31][C:32]([NH2:35])=[CH:33][CH:34]=4)[O:3][N:1]=3)=[CH:7][CH:8]=2)[CH:12]=1
Reactant: C#Cc1ccc(N)nc1N
Reactant: O=[N+]([O-])CCc1ccc(Oc2cccnc2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C[O-]
Agent: O=C([O-])O
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ccc(-c2cc(Cc3ccc(Oc4cccnc4)cc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15.8 %

Procedure:
To a methanol (10.0 mL) solution of 3-(4-(2-nitro-ethyl)-phenoxy)-pyridine (819 mg, 3.35 mmol) described in Manufacturing Example 76-1-3 was added lithium methoxide (254 mg, 6.70 mmol), which was stirred for 30 minutes at room temperature. The reaction mixture was concentrated under a reduced pressure, and anhydrous dichloromethane (15.0 mL) and anhydrous tetrahydrofuran (7.00 mL) were added to the residue. Titanium (IV) chloride (1.18 mL, 10.7 mmol) was added dropwise to the reaction mixture on a dry ice-ethanol bath (−78° C.), after which the system was stirred for 30 minutes at room temperature. Aqueous sodium bicarbonate and ethyl acetate were added to the reaction mixture on an ice bath (0° C.), and the mixture was filtered through a Celite pad. The organic layer of the filtrate was extracted with ethyl acetate, and this organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and the filtrate was concentrated under a reduced pressure, which gave a crude product (400 mg). To a tetrahydrofuran (5.00 mL) solution of 3-ethynyl-pyridin-2,6-diamine (40.0 mg, 0.300 mmol) described in Manufacturing Example 13-1-3 and this crude product (150 mg) was added triethylamine (125 μL, 0.900 mmol), which was stirred for 3 hours at 60° C. Water was added to the reaction solution at room temperature, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=3:1→5:1) to obtain the title compound (17.0 mg, 15.8%).