Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:16])[NH:7][C:8](=[O:15])[C:9]3[C:14]=2[C:13]=1[CH:12]=[CH:11][CH:10]=3.[H-].[Na+].[Br:19][CH2:20][CH2:21][CH2:22][CH2:23]Br.O>CN(C)C=O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:16])[N:7]([CH2:23][CH2:22][CH2:21][CH2:20][Br:19])[C:8](=[O:15])[C:9]3[C:14]=2[C:13]=1[CH:12]=[CH:11][CH:10]=3
Reactant: Nc1ccc2c3c(cccc13)C(=O)NC2=O
Reactant: BrCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc2c3c(cccc13)C(=O)N(CCCCBr)C2=O
Temperature: 25 °C

Procedure:
A suspension of 10.6 g of 6-amino-1H-benz[de]-isoquinoline-1,3(2H)-dione in 250 ml of dimetnylformamide was stirred as 2.6 g of 50% sodium hydride in mineral oil was added. The initial orange suspension turned deep red in color. After ten minutes, a solution of 27 g of 1,4-dibromobutane in 50 ml of dimethylformamide was added. A slightly exothermic reaction was noted, and a deep red solution resulted. The mixture was then stirred at room temperature for sixteen hours, and drowned into 600 ml of cold water. A tarry brown precipitate was obtained, and on standing, bright yellow crystals developed in the supernatant. These were collected and recrystallized from aqueous alcohol to yield the pure title compound mp 175°-176° C. The brown precipitate required several recrystallizations from aqueous alcohol to afford more of the pure title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[F:23][C:24]([C:27]1[CH:31]=[C:30]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[O:29][N:28]=1)([CH3:26])[CH3:25].COC1C=C2C(=CC=1OC)N=CN=C2OC1C=C(NC(NC2ON=C(C(C)C)C=2)=O)C=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([NH:19][C:33]([NH:32][C:30]2[O:29][N:28]=[C:27]([C:24]([F:23])([CH3:25])[CH3:26])[CH:31]=2)=[O:34])[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: CC(C)(F)c1cc(NC(=O)Oc2ccccc2)on1
Agent: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)C)no4)c3)c2cc1OC
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)F)no4)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 46 %

Procedure:
3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (200 mg, 0.639 mmol) was reacted with phenyl 3-(2-fluoropropan-2-yl)isoxazol-5-ylcarbamate from Example 42A (253 mg, 0.959 mmol) according to the method described for 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropylisoxazol-5-yl)urea in Example 122B, except the reaction mixture was stirred at room temperature for 72 h. Purification via trituration with methanol afforded 1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)urea as a colorless solid (142 mg, 46%). 1H NMR (300 MHz, DMSO-d6) δ 10.43 (brs, 1H), 9.13 (brs, 1H), 8.70 (s, 1H), 7.84 (s, 1H), 7.57 (m, 1H), 7.46 (m, 1H), 7.30-7.35 (m, 3H), 6.16 (s, 1H), 3.99 (s, 6H), 1.67 (d, J=21 Hz, 6H); LC-MS (ESI) m/z 484 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=[C:4]2[C:3]=1[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1.[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:3]2[C:4]3[N:5]([C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=3)[CH:6]=[CH:7][C:2]=2[C:27]2[CH:26]=[CH:25][C:24]([Cl:23])=[CH:29][C:28]=2[Cl:30])=[CH:17][CH:18]=1
Reactant: CC(C)Cn1nc2c(-c3ccc(Cl)cc3)c(Br)ccn2c1=O
Reactant: OB(O)c1ccc(Cl)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)Cn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)ccn2c1=O
Temperature: 200 °C
Yield: 32 %

Procedure:
To a stirring, degassed mixture of 7-bromo-8-(4-chlorophenyl)-2-isobutyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (20 mg, 0.05 mmol), 2,4-dichlorophenylboronic acid (38 mg, 0.20 mmol), and tetrakis(triphenylphosphine)palladium (3 mg, 0.002 mmol) in dioxane (0.4 mL) at 20° C. was added K2CO3 (30 mg, 0.2 mmol) in water (0.13 mL). The resulting reaction mixture was heated in a microwave reactor at 200° C. for 10 min under argon. Analysis by HPLC/MS indicated that starting material had been consumed. The reaction mixture was brought to room temperature and was concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC (acetonitrile-water-TFA) to isolate the title compound (7 mg, 0.016 mmol) as a yellow oil. MS: [M+H]+=446.
Reaction SMILES: P(Br)(Br)Br.Br[CH2:6][C:7]1[N:11]([CH3:12])[N:10]=[CH:9][CH:8]=1.[CH3:13][C:14]1[N:19]=[C:18]([SH:20])[N:17]=[C:16]([OH:21])[CH:15]=1>>[CH3:13][C:14]1[N:19]=[C:18]([S:20][CH2:6][C:7]2[N:11]([CH3:12])[N:10]=[CH:9][CH:8]=2)[N:17]=[C:16]([OH:21])[CH:15]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: Cn1nccc1CBr
Agent: BrP(Br)Br
Product: Cc1cc(O)nc(SCc2ccnn2C)n1
Yield: 55 %

Procedure:
The title compound was prepared by following the procedure described for Example 55 from 1-methyl-1H-pyrazole-5-carbaldehyde to provide (1-methyl-1H-pyrazol-5-yl)methanol, which gave 5-(bromomethyl)-1-methyl-1H-pyrazole upon reaction with phosphorous tribromide. The reaction of 5-(bromomethyl)-1-methyl-1H-pyrazole and 6-methyl-2-sulfanylpyrimidin-4-ol provided 6-methyl-2-{[(1-methyl-1H-pyrazol-5-yl)methyl]sulfanyl}pyrimidin-4-ol as a white solid (0.742 g, 55% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.21 (s, 3H), 3.82 (s, 3H), 4.47 (s, 2H), 6.04 (bs, 1H), 6.23 (d, J=1.7 Hz, 1H), 7.29 (d, J=1.7 Hz, 1H), 8.19 (s, 1H); M+236.3.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[OH:13])[C:6]3[CH2:20][CH2:21][NH:22][CH2:23][C:5]=3[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:31][C:32]([CH3:35])([OH:34])[CH3:33]>C(#N)C.O>[OH:13][CH:12]([C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)[CH2:11][N:7]1[C:8]2[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=2[C:5]2[CH2:23][N:22]([CH2:31][C:32]([CH3:35])([OH:34])[CH3:33])[CH2:21][CH2:20][C:6]1=2
Reactant: CC(C)(O)CCl
Reactant: Cc1ccc2c(c1)c1c(n2CC(O)c2ccncc2)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1ccc2c(c1)c1c(n2CC(O)c2ccncc2)CCN(CC(C)(C)O)C1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
To a solution of 2-(8-methyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethanol (200 mg, 0.651 mmol) in acetonitrile (4 mL), potassium carbonate (270 mg, 1.95 mmol) and 1-chloro-2-methyl-propan-2-ol (105 mg, 0.977 mmol) were added and the reaction mixture was stirred at 100° C. for 12 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3×20 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (Neutral alumina, 1% MeOH-DCM), to yield 1-[5-(2-hydroxy-2-pyridin-4-yl-ethyl)-8-methyl-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl]-2-methyl-propan-2-ol. 1H NMR (CDCl3, freebase) δ (ppm): 8.6 (d, 2H), 7.27 (m, 2H), 7.2 (m, 2H), 7.0 (d, 1H), 5.08 (t, 1H), 4.19 (m, 2H), 3.9 (bs, 2H), 3.0-3.1 (m, 2H), 2.9 (m, 1H), 2.6 (s, 2H), 2.56 (m, 1H), 2.21 (s, 3H), 1.21 (s, 6H). Separation by chiral HPLC provides enantiomers II-84a-b.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]=[C:8]([Cl:19])[N:9]=[C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[CH3:20][C:21]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([CH3:25])[C:22]([NH2:24])=[O:23]>>[Cl:19][C:8]1[N:9]=[C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:11]2[N:12]=[C:3]([CH2:2][N:29]3[CH2:28][CH2:27][N:26]([C:21]([CH3:25])([CH3:20])[C:22]([NH2:24])=[O:23])[CH2:31][CH2:30]3)[CH:4]=[CH:5][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2nc(CBr)ccc2n1
Reactant: CC(C)(C(N)=O)N1CCNCC1
Product: CC(C)(C(N)=O)N1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1

Procedure:
4-(6-(Bromomethyl)-2-chloropyrido[3,2-d]pyrimidin-4-yl)morpholine 7 (0.1 g) was reacted with 2-methyl-2-(piperazin-1-yl)propanamide via General Procedure B to give 123 mg of 2-(4-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-methylpropanamide.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13]C)(=[O:12])[CH:10]=[CH2:11].[OH-].[K+]>Cl>[CH2:1]([O:8][CH2:11][CH2:10][C:9]([OH:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: C=CC(=O)OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: O=C(O)CCOCc1ccccc1
Reaction time: 0.33 h

Procedure:
A mixture of benzyl alcohol (84 ml) and methyl acrylate (80.6 ml) is then added drop by drop to the stirred solution over a period of 20-30 minutes, and stirring is continued for additional 20 minutes. Once the reaction, which is monitored by gas chromatography, is completed, 4N KOH (500 ml) is added and the mixture is stirred at room temperature for 2 hours. Then, 8% HCl (420 ml) is added keeping the temperature at about 20°-25° C. and the mixture is extracted with methylene chloride (200 ml plus four 50-ml portions). The mother liquors are acidified with 37% HCl (102 ml) to reach a pH of about 2.5 and extracted again with toluene (200 ml plus three 100 ml portions) The toluene extracts are combined, dried over Na2SO4, and concentrated to dryness yielding an oily residue of 3-benzyloxypropionic acid (100 g) which is employed as such in the next step.
Reaction SMILES: C1C(C(CBr)=[O:8])=CC=C(Br)C=1.[Cl:12][C:13]1[CH:14]=[C:15]([NH:20][C:21]2[C:22]3[CH:29]=[CH:28][N:27]([CH3:30])[C:23]=3[N:24]=[CH:25][N:26]=2)[CH:16]=[CH:17][C:18]=1[F:19]>C(O)(C)(C)C.C(O)(=O)C.[Zn]>[Cl:12][C:13]1[CH:14]=[C:15]([NH:20][C:21]2[C:22]3[CH2:29][C:28](=[O:8])[N:27]([CH3:30])[C:23]=3[N:24]=[CH:25][N:26]=2)[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: Cn1ccc2c(Nc3ccc(F)c(Cl)c3)ncnc21
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Product: CN1C(=O)Cc2c(Nc3ccc(F)c(Cl)c3)ncnc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.1 %

Procedure:
PBPB (2.8 g, 7.8 mmol) was added portionwise to the (3-chloro-4-fluoro-phenyl)-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine (1.08 g, 3.9 mmol) suspended in tert-butanol (20 mL) and acetic acid (10 mL). After stirring at room temperature for 18 hours, to the mixture was added zinc dust (760 mg, 11.7 mmol) portionwise and stirring was continued for overnight. The precipitate was filtered off and the filtrate was concentrated. The residue was triturated with little water and the precipitate was collected by vacuum filtration, washed with little ethyl acetate and dried to give 1.12 g (98%) of 4-(3-chloro-4-fluoro-phenylamino)-7-methyl-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one as a tan colored solid. 1H NMR (DMSO-d6) 9.07 (s, 1H, NH), 8.42 (s, 1H), 8.01 (d, J=2.6 & 7.2 Hz, 1H) 7.56 (m, 1H), 7.34 (t,J=9.1 Hz, 1H), 3.48 (s, 2H, CH2), 3.07 (s, 3H, CH3).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][CH:10]=[N:9]1.C([Li])CCC.[S:18](Cl)([Cl:21])(=[O:20])=[O:19]>C(OCC)C.CCCCCC>[N:8]1([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[S:18]([Cl:21])(=[O:20])=[O:19])[CH:12]=[CH:11][CH:10]=[N:9]1
Reactant: O=S(=O)(Cl)Cl
Reactant: Brc1ccccc1-n1cccn1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: O=S(=O)(Cl)c1ccccc1-n1cccn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 52 g of 1-(2-bromophenyl)pyrazole in 230 ml of diethyl ether under a nitrogen atmosphere and cooled at -70° C. was added dropwise 175 ml of a 1.6M solution of n-butyl lithium in hexane. The suspension was allowed to warm from -70° C. to -25° C. on its own, then a solution of 37 ml of sulfuryl chloride in 69 ml of hexane was added dropwise at -25° to -20° C. After allowing the suspension to warm to room temperature, the suspension was stirred for 5 hours, then filtered to yield 38 g of crude 2-(1H-pyrazol-1-yl)benzenesulfonyl chloride which was contaminated with inorganic salts.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][OH:5].[CH2:6]([NH:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([O-:29])=[O:28])=[CH:25][CH:24]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[Na+]>>[CH2:6]([NH:22][C:23]1[CH:24]=[CH:25][C:26]([C:27]([O:29][CH2:2][CH2:3][CH2:4][OH:5])=[O:28])=[CH:30][CH:31]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)[O-])cc1
Reactant: OCCCBr
Agent: [Na+]
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCCCO)cc1

Procedure:
In the manner described in Example 19, treatment of 3-bromopropanol with sodium 4-(n-hexadecylamino)benzoate affords 3-hydroxypropyl 4-(n-hexadecylamino)benzoate, mp 67°-69° C.
Reaction SMILES: [I-].[K+].[CH3:3][S:4][C:5]1[CH:6]=[CH:7][C:8]2[N:14]3[C:15]([CH2:18]Cl)=[N:16][N:17]=[C:13]3[CH2:12][N:11]=[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:9]=2[CH:26]=1.[CH:27]1([NH2:30])[CH2:29][CH2:28]1>O1CCCC1>[CH3:3][S:4][C:5]1[CH:6]=[CH:7][C:8]2[N:14]3[C:15]([CH2:18][NH:30][CH:27]4[CH2:29][CH2:28]4)=[N:16][N:17]=[C:13]3[CH2:12][N:11]=[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:9]=2[CH:26]=1
Reactant: NC1CC1
Reactant: CSc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CCl)n1-2
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: CSc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CNC3CC3)n1-2

Procedure:
In the manner given in Example 1, potassium iodide and 8-(methylthio)-1-(chloromethyl)-6-phenyl-4H-s-triazolo-[4,3-a][1,4]benzodiazepine in tetrahydrofuran is treated with cyclopropylamine to give 8-(methylthio)-1-[(cyclopropylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]-benzodiazepine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH2:11].[OH-].[Na+].[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cc([N+](=O)[O-])ccc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1cc([N+](=O)[O-])ccc1Br)c1ccccc1
Yield: 51.9 %

Procedure:
To a solution of 3-nitroaniline (0.5 g, 3.6 mmol) in 10 ml acetic acid added bromine (0.2 ml, 4.0 mmol) and stirred at 0° C. for 1 hour. The solution was filtered after recovering to room temperature to obtain 2-bromo-5-nitrobenzenamine (0.32 g, 40%) as a powder. A solution of 2-bromo-5-nitrobenzenamine (0.4 g, 1.8 mmol), sodium hydroxide (0.14 g, 3.6 mmol) and benzoyl chloride (0.24 ml, 2.0 mmol) in 20 ml THF was stirred for 2 hours in icy water bath. The reaction was quenched and washed with water (3×20 ml). The mixture was dried over anhydrous sodium sulfate. The crude N-(2-bromo-5-nitrophenyl)benzamide (0.3 g, 50%) was obtained after evaporation of the solvents. 1H NMR (500 MHz, CDCl3) δ (ppm) 7.65 (m, 2H), 7.68 (m, 1H), 7.80 (d, J=8.8 Hz, 1H), 7.94 (dd, J=8.8, 2.7 Hz, 1H), 8.00 (m, 2H), 8.62 (s, 1H), 9.55 (d, J=2.7 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].Br[C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:20]/[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27])/[C:13](=[O:19])[NH:14]2>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[CH3:27][O:26][C:25]1[CH:24]=[CH:23][NH:22][C:21]=1/[CH:20]=[C:12]1\[C:13](=[O:19])[NH:14][C:15]2[C:11]\1=[C:10]([C:2]#[C:1][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)[CH:18]=[CH:17][CH:16]=2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Reactant: C#Cc1cccnc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#Cc3cccnc3)c21

Procedure:
Using Method D above, 3-ethynyl pyridine (60.6 mg, 0.59 mmol) (see below) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (75 mg, 0.23 mmol) (Starting Material 1) using (Ph3P)4Pd (13.3 mg) (Aldrich) and CuI (3 mg) (Aldrich) as catalyst in DMF (4 mL) and Et3N (4 mL) as solvent at 100° C. for 18 h, to yield (Z)-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-4-[(3-pyridinyl)ethynyl]-2H-indol-2-one. (Yield 52 mg, 66%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[C:13](=[O:19])[NH:14][CH:15]=[CH:16][C:17]=3[CH3:18])[CH2:9][CH2:8][C:6]=2[N:7]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN1CCCC1=O.[Cu](I)I>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[C:13](=[O:19])[N:14]([C:25]4[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=4)[CH:15]=[CH:16][C:17]=3[CH3:18])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Cc1cc[nH]c(=O)c1N1CCc2nc(N)ncc2C1
Reactant: COc1ccc(I)cc1
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ccc(-n2ccc(C)c(N3CCc4nc(N)ncc4C3)c2=O)cc1
Temperature: 70 °C
Reaction time: 19 h

Procedure:
A degassed solution of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-4-methylpyridin-2(1H)-one (25 mg, 0.097 mmol), 4-methoxy-iodobenzene (23 mg, 97 mmol) N1,N2-dimethylethane-1,2-diamine (5 mg, 0.049 mmol), copper iodide (5 mg, 22 mmol), and potassium phosphate (41 mg, 0.194 mmol) in 2 mL of N-methylpyrrolidone was heated to 70° C. After allowing the reaction to stir overnight (19 h) at 70° C., the reaction was complete and allowed to cool to room temperature. The reaction was extracted with EtOAc (3×5 mL) and NaHCO3 (2×10 mL). The crude organic layers were combined, dried over anhydrous Na2SO4 (s), filtered and then concentrated in vacuo. The crude mixture was purified using the ISCO flash chromatography system using a 0-100% EtOAc gradient/100-0% Hexane gradient mixture. Following concentration of the appropriate fractions the crude solid collected was further purified by recrystallization using an Et2O/Hexane solvent mixture to give the title compound as an off white solid (13 mg, 37%). 1H NMR (DMSO) δ: 7.92 (s, 1H), 7.45-7.52 (m, 2H), 7.61 (d, J=6.7 Hz, 1H), 7.24-7.31 (m, 2H), 6.28 (s, 2H), 6.37 (d, J=7.0 Hz, 1H), 3.96 (br. S, H), 3.72 (s, 3H), 3.29 (s, 2H), 2.66(t, j=5.3 Hz, 2H), 2.18 (s, 3H).
Reaction SMILES: O[CH2:2][CH2:3][C@H:4]1[CH2:6][C@H:5]1[CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:39]I.N1C=CN=C1>ClCCl.C(OCC)C>[I:39][CH2:2][CH2:3][C@H:4]1[CH2:6][C@H:5]1[CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CCC([C@@H]2C[C@@H]2CCO)CC1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC([C@@H]2C[C@@H]2CCI)CC1
Reaction time: 0.33 h

Procedure:
rac-cis-tert-butyl 4-[2-(2-hydroxyethyl)cyclopropyl]piperidine-1-carboxylate (100 mg, 0.37 mmol) from step 2 of this example was dissolved in dichloromethane (3.7 mL), triphenylphosphine (195 mg, 0.74 mmol), iodine (94 mg, 0.37 mmol) and imidazole (51 mg, 0.74 mmol) were added. After 20 minutes, diethyl ether (10 mL) was added, filtered through a silica gel pad (0.5 inch), concentrated and purified by column chromatography through a 24 gram AnaLogix™ silica gel cartridge eluting with 10% ethyl acetate/hexanes to give the title compound as a white solid.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C@H:2]([CH3:4])[OH:3].C(N(CC)CC)C.[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[C:15]1([S:21]([O:3][C@@H:2]([CH3:4])[C:1]([O:6][CH3:7])=[O:5])(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)[C@H](C)O
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](C)OS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a solution of 200g (1.92 mol) of methyl (2S)-lactate (5) and 295 g (2.11 mol) of triethylamine in toluene (1 L) at 0° C. was added 270 mL, 2.11 mol) of benzenesulfonyl chloride dropwise over a 2 hour period under a nitrogen atmosphere. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature and stir there overnight. The reaction was worked-up by washing with water (3×1 L) and dried (MgSO4). Filtration, concentration and purification by vacuum distillation afforded 440 g (94%) of methyl (2S)-2-(phenylsulfonyl)oxypropanate (12) as a pale yellow liquid: bp 140°-142° C. (0.1 mm Hg); 1H NMR (CDCl3) δ1.51-1.56 (d, 3 H), 3.66 (s, 3 H), 4.95-5.01 (q, 1 H), 7.54-7.59 (m, 2 H), 7.65-7.70 (m, 1 H), 7.93-7.95 (d, 2 H); 13C NMR (CDCl3) δ169.3, 133.9, 129.1, 127.7, 112.3, 74.2, 52.5, 18.3; IR (neat) 2958 (w), 1762 (s), 1586 (m), 1451 (s), 1190 (vs), 1084 (s), 926 (m), 753 (m) cm-1.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[S:5][C:4]2[CH:13]=[C:14]([C:17]([OH:19])=O)[CH:15]=[CH:16][C:3]1=2.S(Cl)([Cl:22])=O>>[Cl:22][C:17]([C:14]1[CH:15]=[CH:16][C:3]2[C:2](=[O:1])[CH2:8][C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[S:5][C:4]=2[CH:13]=1)=[O:19]
Reactant: O=C(O)c1ccc2c(c1)Sc1ccccc1CC2=O
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc2c(c1)Sc1ccccc1CC2=O

Procedure:
Heat a solution of 5 g. of 10,11-dihydro-11-oxodibenzo[b,f]thiepin-3-carboxylic acid and 40 ml. of thionyl chloride under reflux for 20 minutes. Evaporate the reaction mixture under vacuum to dryness. Repeat the evaporation with two 30 ml. portions of carbon tetrachloride. Crystallize the residue from diisopropyl ether to obtain the title product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]([CH2:17][C:18]2[C:19]([CH3:24])=[N:20][NH:21][C:22]=2[CH3:23])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N12CCCN=C1CCCCC2.[CH2:36]([N:43]=[C:44]=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>ClCCl>[C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]([CH2:17][C:18]2[C:19]([CH3:24])=[N:20][N:21]([C:44](=[O:45])[NH:43][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:22]=2[CH3:23])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C=NCc1ccccc1
Reactant: Cc1n[nH]c(C)c1Cc1cn(C(=O)OC(C)(C)C)c2ncccc12
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: Cc1nn(C(=O)NCc2ccccc2)c(C)c1Cc1cn(C(=O)OC(C)(C)C)c2ncccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.4 %

Procedure:
To 3-(3,5-dimethyl-1H-pyrazol-4-ylmethyl)-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (514, 60.0 mg, 0.18 mmol) in dichloromethane (6.0 mL) were added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.033 mL, 0.220 mmol) and benzyl isocyanate (29.4 mg, 0.220 mmol) under an atmosphere of nitrogen. The reaction was stirred at room temperature for 2 hours. The reaction was concentrated and purified by silica gel column chromatography eluting with 30% ethyl acetate in hexane to give crude compound (515, approx. 50 mg) that was used in the next step directly. MS (ESI) [M+H+]+=460.5.