Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[C:16]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]([CH3:30])[CH3:29])=[C:23]([Cl:31])[CH:22]=3)[O:18][N:17]=2)[C:9]([CH2:32][CH2:33][C:34]([O:36]CCC)=[O:35])=[CH:8]1)[CH2:4][CH2:5][CH3:6].Cl>O1CCCC1.C(O)(C)C.O>[CH2:3]([N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[C:16]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]([CH3:30])[CH3:29])=[C:23]([Cl:31])[CH:22]=3)[O:18][N:17]=2)[C:9]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[CH:8]1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCn1cc(CCC(=O)OCCC)c2cccc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)c21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CCCCn1cc(CCC(=O)O)c2cccc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
Sodium hydroxide (94 mg) was added to a solution of propyl 3-[1-butyl-7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoate (D123) (61 mg) in tetrahydrofuran (5 mL), isopropanol (4 mL) and water (2 mL). The reaction mixture was stirred at room temperature overnight. The mixture was neutralized with 2 M HCl till pH ˜6.0. The solvent was concentrated, and the residue was dissolved in water. The precipitated solid was purified by Mass Directed Auto Prep to afford 3-[1-butyl-7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoic acid (E29) (30 mg). δH (DMSO-d6, 400 MHz): 0.65 (3H, t), 0.96 (2H, m), 1.37 (8H, m), 2.62 (2H, t), 2.98 (2H, t), 4.10 (2H, t), 4.88 (1H, m), 7.17 (1H, t), 7.25 (1H, s), 7.44 (2H, m), 7.81 (1H, dd), 8.13 (1H, dd), 8.19 (1H, d), 12.05 (1H, br s); MS (ES): C26H28ClN3O4 requires 481; found 482.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[C:6](=[O:19])[N:5]([CH2:20][CH2:21][CH3:22])[C:4](=[O:23])[CH:3]=1.O.C(O)C.[N:28]([O-])=[O:29].[Na+]>C(O)(=O)C>[NH2:1][C:2]1[N:7]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=2)[C:6](=[O:19])[N:5]([CH2:20][CH2:21][CH3:22])[C:4](=[O:23])[C:3]=1[N:28]=[O:29]
Reactant: CCCn1c(=O)cc(N)n(CCc2ccc([N+](=O)[O-])cc2)c1=O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CCCn1c(=O)c(N=O)c(N)n(CCc2ccc([N+](=O)[O-])cc2)c1=O
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 96.4 %

Procedure:
To a solution of 232 gm of crude 6-amino-1-[2-(4-nitrophenyl)ethyl]-3-propyluracil (4), 4.0 L of water and ca. 2.0 L of ethanol at 80 degrees C. was added 55.3 gm of sodium nitrite in one portion, followed by the dropwise addition of 100 mL of glacial acetic acid. After stirring at 80 degrees C. for 20 minutes the mixture was allowed to cool to near room temperature, then was chilled in an ice bath to effect crystallization. The solids were isolated by filtration, washed with two 1.0 L portions of water and dried under vacuum to yield 244 gm of purple colored 6-amino-5-nitroso-1-[2-(4-nitrophenyl)ethyl]-3-propyluracil (5).
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[CH3:7][Si:8]([CH3:11])([CH3:10])Cl>[Br-].C([P+](CCCC)(CCCC)CCCCCCCCCCCCCCCC)CCC>[CH3:7][Si:8]([CH3:11])([CH3:10])[O:5][CH2:4][CH2:3][CH2:2][CH2:1][O:6][Si:8]([CH3:11])([CH3:10])[CH3:7]
Reactant: C[Si](C)(C)Cl
Reactant: OCCCCO
Agent: CCCCCCCCCCCCCCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Product: C[Si](C)(C)OCCCCO[Si](C)(C)C

Procedure:
1 mole of butane-1,4-diol, 3 moles of trimethylchlorosilane and 0.002 moles of tributyl-hexadecyl phosphonium bromide were reacted at the reflux temperature (56°-96° C.) as in Example 1. The product was worked up by fractional distillation.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=2)[C:10]([CH2:20][Cl:21])=[CH:9]1)=O)(C)(C)C>Cl>[Cl:21][CH2:20][CH:10]1[C:11]2[C:16](=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)n1cc(CCl)c2ccc([N+](=O)[O-])cc21
Agent: Cl
Product: O=[N+]([O-])c1ccc2c(c1)NCC2CCl

Procedure:
1-(tert-Butyloxycarbonyl)-3-chloromethyl-6-nitroindole (156 mg, 0.50 mmol) was stirred in HCl-saturated dioxane (5 mL) at 20° C. for 2 h, and the mixture was then evaporated to dryness under high vacuum below 25° C. to give crude 3-chloromethyl-6-nitroindoline (6). Acid 11 (135 mg, 0.50 mmol), EDCI.HCl (240 mg, 1.25 mmol) and DMA (1.5 mL) were then added in sequential fashion and the mixture was stirred at 20° C. for 2 h. Dilution with water provided the crude product which was recrystallised twice from EtOAc to give 1-[(E)-3-(1-methylpyrrole-2-carboxamido)-cinnamoyl]-3-chloromethyl-6-nitroindole (12) (166 mg, 72%), mp 215° C. 1H NMR [(CD3)2SO] δ9.86 (s, 1 H, NH), 8.97 (s, 1 H, H-7), 8.03-7.96 (m, 1 H, H-5), 8.00 (s, 1 H, H-2′), 7.80 (d, J=8.0 Hz, 1 H, H-4′), 7.70 (d, J=8.3 Hz, 1 H, H-4), 7.69 (d, J=15.4 Hz, 1 H, PhCH═CH), 7.54 (d, J=7.4 Hz, 1 H, H-6′), 7.41 (t, J=7.9 Hz, 1 H, H-5′), 7.11 (d, J=15.4 Hz, 1 H, PhCH═CH), 7.1-7.04 (m, 2 H, H-pyrrole), 6.12 (t, J=3.1 Hz, 1 H, H-pyrrole), 4.66 (t, J=10.0 Hz, 1 H, H-2), 4.34 (dd, J=10.6, 5.1 Hz, 1 H, H-2), 4.15-3.99 (m, 3 H, H-3, CH2Cl ), 3.90 (s, 3 H, NCH3).
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:26][CH2:27][CH2:28][N:29]([CH2:40][CH2:41][OH:42])[S:30]([C:33]1[S:37][C:36]([NH2:38])=[N:35][C:34]=1[CH3:39])(=[O:32])=[O:31]>>[OH:26][CH2:27][CH2:28][N:29]([CH2:40][CH2:41][OH:42])[S:30]([C:33]1[S:37][C:36]([NH:38][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])=[N:35][C:34]=1[CH3:39])(=[O:31])=[O:32]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Cc1nc(N)sc1S(=O)(=O)N(CCO)CCO
Product: Cc1nc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)sc1S(=O)(=O)N(CCO)CCO

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C. 1) and 2-amino-4-methyl-thiazole-5-sulfonic acid bis-(2-hydroxy-ethyl)-amide (example B.8) according to general procedure II. Light yellow solid. MS (ISP) 621.1 [(M+H)+]; mp 191° C.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[C:10]1([C@H:16]2[CH2:21][CH2:20][C@H:19]([C:22]([OH:24])=[O:23])[CH2:18][CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>[N+](C1C=CC=CC=1)([O-])=O>[N+:6]([C:13]1[CH:14]=[CH:15][C:10]([C@H:16]2[CH2:17][CH2:18][C@H:19]([C:22]([OH:24])=[O:23])[CH2:20][CH2:21]2)=[CH:11][CH:12]=1)([O-:9])=[O:7]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)[C@H]1CC[C@H](c2ccccc2)CC1
Agent: O=S(=O)(O)O
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(O)[C@H]1CC[C@H](c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of concentrated sulphuric acid (1.5 mL) and concentrated nitric acid (0.9 mL) was added dropwise to a vigorously stirred solution of trans-4-phenylcyclohexanecarboxylic acid (1.7 g. 8.3 mmol) in nitrobenzene (4 mL) at 5° C. The reaction mixture was warmed to room temperature and stirred for 2.5 h and then poured onto ice. The aqueous mixture was extracted with DCM and the organic layer was concentrated in vacuo to leave a yellow oil, which crystallised to a white solid upon standing. The solid was triturated with toluene and filtered to give the title compound (600 mg, 60%) as a solid; 1H NMR δ 1.4-1.6 (4H, m), 1.75-1.9 (2H, m), 1.95-2.1 (2H, m), 2.2-2.38 (1H, m), 2.64-2.77 (1H, m), 7.52 (2H, d), 8.15 (2H, d); MS m/e (M−H)− 248.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:20][CH:19]([O:21][CH3:22])[CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:23]([O:26][CH2:27][C:28]1[C:29]([N:43]2[CH2:54][CH2:53][N:52]3[C:45](=[CH:46][C:47]4[CH2:48][C:49]([CH3:56])([CH3:55])[CH2:50][C:51]=43)[C:44]2=[O:57])=[N:30][CH:31]=[CH:32][C:33]=1B1OC(C)(C)C(C)(C)O1)(=[O:25])[CH3:24].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[C:23]([O:26][CH2:27][C:28]1[C:29]([N:43]2[CH2:54][CH2:53][N:52]3[C:45](=[CH:46][C:47]4[CH2:48][C:49]([CH3:56])([CH3:55])[CH2:50][C:51]=43)[C:44]2=[O:57])=[N:30][CH:31]=[CH:32][C:33]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:20][CH:19]([O:21][CH3:22])[CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: COC1CN(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: COC1CN(c2ccc(Nc3cc(-c4ccnc(N5CCn6c(cc7c6CC(C)(C)C7)C5=O)c4COC(C)=O)cn(C)c3=O)nc2)C1
Temperature: 100 °C
Yield: 68.7 %

Procedure:
A 50-mL round bottomed flask was equipped with a reflux condenser was charged with 323c (150 mg, 0.411 mmol), {3-[(acetoxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (326.5 mg, 0.822 mmol), Pd(dppf)Cl2 (16.8 mg, 0.0205 mmol), K3PO4 (174.3 mg, 0.822 mmol), sodium acetate (67.5 mg, 0.822 mmol), acetonitrile (10 mL), and water (5 drops). After bubbling nitrogen through the reaction mixture for 20 minutes, it was heated 100° C. under N2 protection for 1 h. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. It was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 40:1 dichloromethane/methanol to afford 323d as a yellow oil (180 mg, 68.7%). MS-ESI: [M+H]+ 637.8
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:11]=[CH:10][C:9]2[CH:12]=[N:13][N:14]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:8]=2[CH:7]=1)CCC.Cl[C:30]1[CH:35]=[N:34][CH:33]=[C:32]([CH3:36])[N:31]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>CN(C)C(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:36][C:32]1[N:31]=[C:30]([C:6]2[N:11]=[CH:10][C:9]3[CH:12]=[N:13][N:14]([CH:15]4[CH2:20][CH2:19][CH2:18][CH2:17][O:16]4)[C:8]=3[CH:7]=2)[CH:35]=[N:34][CH:33]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2c(cn1)cnn2C1CCCCO1
Reactant: Cc1cncc(Cl)n1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Product: Cc1cncc(-c2cc3c(cn2)cnn3C2CCCCO2)n1
Temperature: 130 °C
Yield: 64.5 %

Procedure:
A mixture of tributyl-(1-tetrahydropyran-2-ylpyrazolo[4,3-c]pyridin-6-yl)stannane (7.139 mmol; 3514.5 mg), 2-chloro-6-methyl-pyrazine (10.71 mmol; 1377 mg), tricyclohexylphosphine; (0.5140 mmol; 144.1 mg) and tris(dibenzylideneacetone)dipalladium (0) (0.2142 mmol; 196.1 mg) in N,N-Dimethylacetamide (15 mL) was purged with Argon for 1 min. The reaction mixture was sealed in a pressure vial and heated at 130° C. overnight. The mixture was partitioned between EtOAc and water. The organic layer was concentrated and the residue was purified on silica eluted with 0 to 100% EtOAc in DCM to afford 6-(6-methylpyrazin-2-yl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridine as a clear oil (1.3608 g, 60%).
Reaction SMILES: C([C:5]1[C:6](=[O:26])[CH2:7][CH:8]([C:12]2[CH:17]=[CH:16][C:15](OCC3C=CC=CC=3)=[CH:14][CH:13]=2)[CH2:9][C:10]=1[OH:11])(=O)CC.C([OH:29])C>[Pd]>[OH:11][C:10]1[CH2:9][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:29])[CH:13]=2)[CH2:7][C:6](=[O:26])[CH:5]=1
Reactant: CCC(=O)C1=C(O)CC(c2ccc(OCc3ccccc3)cc2)CC1=O
Reactant: CCO
Agent: [Pd]
Product: O=C1C=C(O)CC(c2cccc(O)c2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 20 g (0.068 mol) of 2-propionyl-3-hydroxy-5-(4-benzyloxyphenyl)cyclohex-2-en-1-one in 250 mL of absolute ethanol was treated with 7.5 g of 5 percent palladium on carbon and shaken in a Parr® hydrogenator under 50 pounds of hydrogen pressure for 2 hours at room temperature. The reaction mixture was filtered through diatomaceous earth, diluted with 1 liter of water and extracted thrice with 100 mL portions of ethyl acetate. The combined extracts were washed with an aqueous saturated NaCl solution, dried over MgSO4, filtered, concentrated and cooled to precipitate the desired above named product as a greyish-white solid in a yield of 9.8 g (71 percent of theoretical). The product melted at 140°-150° C./ dec.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)=[C:15]3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.C([O:38][CH2:39][C:40](Cl)=[O:41])(=O)C>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:39](=[O:38])[CH2:40][OH:41])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:34])[NH:14][C:15]=23)[CH2:32][CH2:33]1
Reactant: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)CO)CC4)c(C)[nH]c23)c1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f16) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].Cl.[N+:19]([C:22]1[C:27]2[N:28]=[C:29]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[S:30][C:26]=2[CH:25]=[CH:24][CH:23]=1)([O-:21])=[O:20]>O1CCCC1>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:34]1[CH2:35][CH2:36][N:31]([C:29]2[S:30][C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([N+:19]([O-:21])=[O:20])[C:27]=3[N:28]=2)[CH2:32][CH2:33]1)=[O:9])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1cccc2sc(N3CCNCC3)nc12
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2nc3c([N+](=O)[O-])cccc3s2)CC1

Procedure:
Prepared in analogy to example 1.1 b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.2) and 4-Nitro-2-piperazin-1-yl-benzothiazole hydrochloride in tetrahydrofuran. The crude material was purified by chromatography (SiO2, heptane/ethyl acetate), and the residue was then triturated in ether to yield the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:18][CH:17]([CH2:19][OH:20])[N:8]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]([F:16])[C:14]=4[CH:15]=[C:7]3[C:6]=2[N:21]=1.[CH3:22][O:23][C:24]1[N:29]=[CH:28][C:27]([C:30]2[O:31][C:32]3[CH:42]=[C:41]([N:43]([CH3:48])[S:44]([CH3:47])(=[O:46])=[O:45])[C:40](B4OC(C)(C)C(C)(C)O4)=[CH:39][C:33]=3[C:34]=2[C:35]([NH:37][CH3:38])=[O:36])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:16][C:13]1[C:14]2[CH:15]=[C:7]3[C:6]4[N:21]=[C:2]([C:40]5[C:41]([N:43]([CH3:48])[S:44]([CH3:47])(=[O:46])=[O:45])=[CH:42][C:32]6[O:31][C:30]([C:27]7[CH:28]=[N:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=7)=[C:34]([C:35]([NH:37][CH3:38])=[O:36])[C:33]=6[CH:39]=5)[CH:3]=[CH:4][C:5]=4[O:18][CH:17]([CH2:19][OH:20])[N:8]3[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: CNC(=O)c1c(-c2ccc(OC)nc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: OCC1Oc2ccc(Cl)nc2-c2cc3c(F)cccc3n21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(OC)nc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3C(CO)O4)cc12
Temperature: 70 °C
Yield: 47 %

Procedure:
To a solution of (S or R)-(2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-6-yl)methanol (35 mg, 0.115 mmol), 2-(6-methoxypyridin-3-yl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (50 mg, 0.097 mmol) and sodium carbonate (20 mg, 0.188 mmol) in 2 mL of 1,4-dioxane and 0.2 mL of water was added Pd2(dba)3 (10 mg) and X-Phos (10 mg) under nitrogen. The reaction mixture was heated at 70° C. for 16 hours and concentrated in vacuo to remove 1,4-dioxane. And then the residue was suspended in water and extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by prep-HPLC to give the product of (S or R)-5-(11-fluoro-6-(hydroxymethyl)-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(6-methoxypyridin-3-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (30 mg, yield: 47%). 1H-NMR (CDCl3, 400 MHz) δ 8.72 (d, J=2.4 Hz, 1H), 8.14˜8.17 (m, 1H), 7.99 (s, 1H), 7.64 (s, 1H), 7.43˜7.48 (m, 2H), 7.14˜7.23 (m, 3H), 6.81˜6.86 (m, 2H), 6.42˜6.45 (m, 1H), 6.06 (brs, 1H), 4.01 (s, 3H), 3.98˜4.00 (m, 1H), 3.85˜3.88 (m, 1H), 3.37 (s, 3H), 2.96 (d, J=4.8 Hz, 3H), 2.72 (s, 3H), 2.27 (s, 1H). MS (M+H)+: 658.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1.[OH:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[CH:24]2.C([O-])([O-])=O.[K+].[K+]>CC#N.O>[CH3:19][O:18][C:12]1[CH:11]=[C:10]([C:3]2[CH:4]=[N:5][CH:6]=[C:7]([C:2]=2[O:20][C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[NH:26][CH:25]=[CH:24]3)[C:8]#[N:9])[CH:15]=[CH:14][C:13]=1[O:16][CH3:17]
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: COc1ccc(-c2cncc(C#N)c2Cl)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(-c2cncc(C#N)c2Oc2ccc3[nH]ccc3c2)cc1OC
Temperature: 80 °C
Yield: 74 %

Procedure:
A mixture of 4-chloro-5-(3,4-dimethoxyphenyl)nicotinonitrile (120 mg, 0.44 mmol), 5-hydroxyindole (71 mg, 0.53 mmol) and K2CO3 (91 mg, 0.66 mmol) in CH3CN (4.0 mL) was heated at 80° C. for 4 h. After cooling to r.t., the reaction mixture was diluted with water (20 mL) and the precipitate was collected by filtration and washed with ether containing MeOH to give 121 mg (74%) of 5-(3,4-dimethoxyphenyl)-4-(1H-indol-5-yloxy)nicotinonitrile 220 as a tan solid. MS: 372.2; melting range: 192-194° C.
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:14][NH2:15]>C(Cl)Cl>[CH3:14][NH:15][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CN
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc(C(=O)O)cc1
Reaction time: 8 h

Procedure:
To a solution of 4-chlorosulfonylbenzoic acid (5.8 g, 25.2 mmol) in DCM (200 mL), a solution of methylamine (52.15 mL, 2 M in THF) is added. The mixture is stirred overnight at it before the solvent is evaporated. The residue is dissolved in sat. aq. NH4Cl solution and extracted with EA. The organic extract is washed with water, dried over MgSO4, filtered and the solvent of the filtrate is evaporated to give 4-methylsulfamoyl-benzoic acid (3.77 g) as a white solid; LC-MS: tR=0.64 min.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C@@H:9]([N:11]2[CH2:16][CH2:15][C:14]([CH3:23])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:13][C:12]2=[O:24])[CH3:10])[CH:6]=[CH:7][CH:8]=1>CN(C=O)C.CCOC(C)=O>[OH:2][C:3]1[CH:4]=[C:5]([C@@H:9]([N:11]2[CH2:16][CH2:15][C:14]([CH3:23])([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[O:13][C:12]2=[O:24])[CH3:10])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc([C@H](C)N2CCC(C)(c3ccccc3)OC2=O)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](c1cccc(O)c1)N1CCC(C)(c2ccccc2)OC1=O
Temperature: 170 °C
Yield: 87 %

Procedure:
A mixture of 3-((S)-1-(3-methoxyphenyl)ethyl)-6-methyl-6-phenyl-1,3-oxazinan-2-one Isomer 1 (0.1240 g, 0.381 mmol) and EtSNa (0.2115 g, 2.51 mmol) in DMF (2 mL) was heated at 170° C. for 2.5 h under nitrogen. The mixture was diluted with EtOAc, washed with 1 N aq HCl. The aqueous phase was extracted with EtOAc (2×). The combined organic phase was dried over Na2SO4. After the solvents were evaporated, the residue was purified by chromatography on silica gel eluted with hexanes/EtOAc to afford of 3-((S)-1-(3-hydroxyphenyl)ethyl)-6-methyl-6-phenyl-1,3-oxazinan-2-one (0.1036 g, 87%). LC-MS Method 1 tR=1.49 min, m/z 312 (MH+); 1H NMR (400 MHz, CDCl3) δ 7.59-7.53 (m, 1H), 7.40-7.28 (m, 5H), 7.19-7.15 (m, 1H), 6.98 (m, 1H), 6.83-6.75 (m, 2H), 5.74 (q, J=7.1 Hz, 1H), 2.80-2.67 (m, 2H), 2.30-2.25 (m, 1H), 2.09-2.01 (m, 1H), 1.62 (s, 3H), 1.25 (d, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[C:4]([O:25][CH3:26])=[CH:5][C:6]([CH:9]([OH:24])[CH2:10][N:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)=[N:7][CH:8]=1)#[N:2]>C(O)(C(F)(F)F)=O>[OH:24][CH:9]([C:6]1[N:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([O:25][CH3:26])[CH:5]=1)[CH2:10][N:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]1
Reactant: COc1cc(C(O)CN2CCN(C(=O)OC(C)(C)C)CC2)ncc1C#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(O)CN2CCNCC2)ncc1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Enantiomer A of tert-Butyl 4-[2-(5-cyano-4-methoxy-2-pyridyl)-2-hydroxy-ethyl]piperazine-1-carboxylate (1.30 g, 3.59 mmol) was dissolved in 5 mL of TFA and stirred at room temperature for 2 h. The mixture was concentrated to ¼ the original volume and diluted with 10 mL of diethyl ether. The precipitate was filtered and dried under high vacuum to offer amine TFA salt. This intermediate was diluted with 5% aqueous sodium bicarbonate with follow up addition of 10 N NaOH to bring the pH of extraction above 10. The aqueous layer was extracted with ethyl acetate. The organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to provide the product. LC/MS: (IE, m/z) tR=0.39 min; [M+1]+=263.12 Enantiomer B of tert-Butyl 4-[2-(5-cyano-4-methoxy-2-pyridyl)-2-hydroxy-ethyl]piperazine-1-carboxylate (1.0 g, 2.76 mmol) was dissolved in 5 mL of TFA and stirred at room temperature for 2 h. The mixture was concentrated to ¼ the original volume and diluted with 10 mL of diethyl ether. The precipitate was filtered and dried under high vacuum to offer amine TFA salt. This intermediate was diluted with 5% aqueous sodium bicarbonate with follow up addition of 10 N NaOH to bring the pH of extraction above 10. The aqueous layer was extracted with ethyl acetate. The organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to provide the product. LC/MS: (IE, m/z) tR=0.62 min; [M+1]+=263.09
Reaction SMILES: Cl.Cl.[NH2:3][C:4]([CH3:10])([C:6]([NH2:9])([CH3:8])[CH3:7])[CH3:5].[OH-].[Na+].[C:13]1(=O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C1C=CC=CC=1>[CH3:5][C:4]1([CH3:10])[C:6]([CH3:8])([CH3:7])[NH:9][C:13]2([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[NH:3]1
Reactant: CC(C)(N)C(C)(C)N
Reactant: O=C1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CC1(C)NC2(CCCCC2)NC1(C)C

Procedure:
2,3-Diamino-2,3-dimethylbutane dihydrochloride is neutralized with aqueous caustic soda and the diamine is recovered. The wet diamine (15.3 grams) is then heated with benzene (150 mls) to azeotrope off about 2.2 mls of water. The benzene, containing 13.1 grams (0.113 mole) of the diamine, is then treated with cyclohexanone (11.0 grams 0.112 mole) and p-toluenesulfonic acid (50 mgs) and the reaction mixture is refluxed for 40 hours in a flask fitted with a Dean-Stark water separator. The benzene is then removed by distillation and the reddish liquid residue is fractionally distilled. The main fraction, b.p 82°-84° C. at 1 mm pressure, has a nuclear magnetic resonance spectrum identical to that reported in the literature [Keana et al., J. Am. Chem. Soc. 100, pg. 934 (1978)]. On standing the liquid solidifies to a crystalline solid, m.p. 31°-32° C., which contains 9.95% water.