Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.Cl.[OH-].[Na+].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6]2
Reactant: COc1ccc2[nH]ccc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCN2
Temperature: 20 °C
Reaction time: 0.75 h
Yield: 96 %

Procedure:
To 5-methoxy-indole (4.55 g, 31 mmol) suspended in THF (10 mL) at 0°-5° C. was added borane/pyridine complex (15.5 ml of 8M in BH3) followed by dropwise aqueous 6N HCl (50 mL) over 15 min. During the addition THF was added dropwise as required to control foaming. The mixture was stirred 45 min at 20° C., the pH was raised to ~10 by the addition of aqueous NaOH and Na2CO3, and the mixture was extracted with CHCl3. The organic extracts were washed with brine at pH 9-10 dried over MgSO4(s), filtered, and concentrated in vacuo to afford 5-methoxy-indoline (96%; GC-MS: RT=min, M+ =149) which was >97% purity by 1H NMR. This material could be used without further purification, or precipitated pure as its hydrochloride salt by the addition of 1 eq. of 1N HCl in Et2O to a solution of the free base in EtOAc or ether.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[C:4]([CH3:10])[C:3]=1[OH:11].[H-].[Na+].[CH3:14][O:15][CH2:16]Cl>CN(C)C=O.O>[Br:1][C:2]1[C:3]([O:11][CH2:14][O:15][CH3:16])=[C:4]([CH3:10])[C:5]([CH3:9])=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(C)c(Br)c(O)c1C
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1c(C)c(C)cc(C)c1Br
Reaction time: 0.17 h
Yield: 99 %

Procedure:
Under nitrogen gas, a solution of 2-bromo-3,5,6-trimethylphenol (10 g) in N,N-dimethylformamide (50 mL) was added dropwise to a suspension of 60% sodium hydride (2.1 g) in N,N-dimethylformamide (20 mL) under ice-cooling and the mixture was stirred for 10 minutes. To this mixture was further added a solution of chloromethyl methyl ether (3.9 mL) in N,N-dimethylformamide (5mL) dropwise and the mixture was stirred for another 30 minutes. This reaction mixture was diluted with iced water and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=97:3) to provide the title compound (12 g). Yield 99%.
Reaction SMILES: [OH:1][C@H:2]([CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)/[CH:3]=[CH:4]/[C:5]#[C:6]/[CH:7]=[CH:8]/[CH:9]=[CH:10]/[C@H:11]1[O:15]C(C)(C)[O:13][C@H:12]1[CH2:18][O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22].Cl>CO>[F:33][C:30]1[CH:31]=[CH:32][C:27]([O:26][CH2:25][C@@H:2]([OH:1])/[CH:3]=[CH:4]/[C:5]#[C:6]/[CH:7]=[CH:8]/[CH:9]=[CH:10]/[C@@H:11]([OH:15])[C@@H:12]([OH:13])[CH2:18][O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:28][CH:29]=1
Reactant: COC(=O)COC[C@@H]1OC(C)(C)O[C@@H]1/C=C/C=C/C#C/C=C/[C@H](O)COc1ccc(F)cc1
Agent: Cl
Solvent: CO
Product: COC(=O)COC[C@H](O)[C@H](O)/C=C/C=C/C#C/C=C/[C@H](O)COc1ccc(F)cc1
Reaction time: 48 h
Yield: 145.4 %

Procedure:
A solution of 2-[[(4S,5R)-5-[(1E,3E,7E,9S)-9-hydroxy-10-(4-fluorophenoxy)-1,3,7-decatrien-5-ynyl]-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy]ethanoic acid, methyl ester, (1.1 g, 1.8 mmol) in methanol (25 mL) was treated with 1 mL of 1 N hydrochloric acid and the reaction was stirred for 2 days. The pH of the reaction was adjusted to neutrality. Purification on preparative reverse phase semi-prep column using a gradient of acetonitrile in water yielded 1.1 g of (5S,6R,7E,9E,13E,15S)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-3-oxahexadeca-7,9,13-trien-11-ynoic acid, methyl ester, as an oil; 1H NMR (CDCl3) δ 3.67 (m, 2H), 3.75 (s, 3H), 3.83 (m, 1H), 3.95 (m, 1H), 4.13 (m, 2H), 4.37 (m, 1H), 4.58 (m, 1H), 5.73 (dd, 1H), 5.86 (dd, 1H), 6.04 (dt, 1H), 6.17 (m, 1H), 6.40 (m, 1H), 6.58 (m, 1H), 6.9 (m, 4H) ppm.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:6][CH:7]=1.N([O-])=O.[Na+].[OH-].[Na+].[BrH:20]>O.S.[Cu]>[Br:20][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:6][CH:7]=1
Reactant: Br
Reactant: Cc1cc(N)cnc1CCCCN
Agent: [Cu]
Agent: O=N[O-]
Agent: S
Solvent: O
Product: Cc1cc(Br)cnc1CCCCN

Procedure:
5-Amino-2-(4-aminobutyl)-3-methylpyridine (5.11 g) in hydrobromic acid (48%, 47 ml) was reacted with cuprous bromide (4.98 g) and copper bronze (0.18 g). A solution of sodium nitrite (2.45 g) in water (16 ml) was added at 5° to 8° C. over 45 minutes, the reaction mixture was allowed to stir at 5° to 8° C. for a further hour and then stirred at room temperature for 3.5 hours. The reaction mixture was diluted with water, and hydrogen sulphide gas was passed, while the pH was progressively raised to 11 by the addition of sodium hydroxide solution. The precipitated copper salts were filtered off at intervals during the above procedure. The product was then extracted at pH 11 with chloroform to give 5-bromo-2-(4-aminobutyl)-3-methylpyridine (4.95 g) m.p. 35°-37° C.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([OH:16])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:19]1(C)C(S(O)(=O)=O)=CC=CC=1>CO>[C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([O:16][CH3:19])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: CN1CCC(O)N(c2nnc(C(C)(C)C)s2)C1=O
Solvent: CO
Product: COC1CCN(C)C(=O)N1c1nnc(C(C)(C)C)s1

Procedure:
Tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (7 grams), methyl alcohol (50 ml) and toluenesulfonic acid (0.2 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is then heated at reflux for a period of about 24 hours. After this time the mixture is stripped of unreacted alcohol under reduced pressure to yield a solid product. This product is then recrystallized to yield the desired product tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-methoxy-2(1H)-pyrimidinone.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([CH2:14][C:15]3[CH:16]=[C:17]([CH:37]=[CH:38][CH:39]=3)[C:18]([NH:20][C:21]3[S:22][C:23]4[CH2:29][C@@H:28]([NH:30][CH2:31][CH2:32][C:33]([F:36])([F:35])[F:34])[CH2:27][CH2:26][C:24]=4[N:25]=3)=[O:19])[CH:13]=2)=[CH:5][CH:4]=1)#[N:2].C=O.[C:42]([BH3-])#N.[Na+]>CO.C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([CH2:14][C:15]3[CH:16]=[C:17]([CH:37]=[CH:38][CH:39]=3)[C:18]([NH:20][C:21]3[S:22][C:23]4[CH2:29][C@@H:28]([N:30]([CH3:42])[CH2:31][CH2:32][C:33]([F:36])([F:35])[F:34])[CH2:27][CH2:26][C:24]=4[N:25]=3)=[O:19])[CH:13]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(-c2cnn(Cc3cccc(C(=O)Nc4nc5c(s4)C[C@@H](NCCC(F)(F)F)CC5)c3)c2)cc1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CN(CCC(F)(F)F)[C@H]1CCc2nc(NC(=O)c3cccc(Cn4cc(-c5ccc(C#N)cc5)cn4)c3)sc2C1
Yield: 83.7 %

Procedure:
Stir a solution of 3-[4-(4-cyano-phenyl)-pyrazol-1-ylmethyl]-N—[(S)-6-(3,3,3-trifluoro-propylamino)-4,5,6,7-tetrahydro-benzothiazol-2-yl]-benzamide (0.063 g, 0.11 mmol) and formaldehyde solution (0.08 mL, 1.14 mmol, 37 wt % in H2O) and sodium cyanoborohydride (0.014 g, 0.23 mmol) in 1 mL 20% MeOH/CH2Cl2 overnight at room temperature in a capped flask. Concentrate the mixture, add aq. H2O and extract the product 4×EtOAc, washed 3×H2O. Dry the mixture with a drying agent and concentrate. Purify the product on a prep plate eluting with 5% MeOH/CH2Cl2 which affords 0.052 g, 80% yield of 3-[4-(4-cyano-phenyl)-pyrazol-1-ylmethyl]-N-{(S)-6-[methyl-(3,3,3-trifluoro-propyl)-amino]-4,5,6,7-tetrahydro-benzothiazol-2-yl}-benzamide as a clear resin. MS, electrospray 565.71 (M+H), room temperature 1.60 min. The following compound is prepared analogously (Example 11)
Reaction SMILES: B(O)O.[C:4]([O:8][C:9](=[O:11])[NH2:10])([CH3:7])([CH3:6])[CH3:5].[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][CH2:21][CH:20]1[C:24]1[NH:25][C:26]([C:29]2[CH:34]=[CH:33][C:32](Br)=[CH:31][CH:30]=2)=[CH:27][N:28]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C([O-])([O-])=O.[K+].[K+]>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.COCCOC.O>[C:4]([O:8][C:9]([N:10]1[CH2:23][CH2:22][CH2:21][CH:20]1[C:24]1[NH:25][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:32]3[CH:31]=[CH:30][C:29]([C:26]4[NH:25][C:24]([C:20]5([NH:19][C:17]([O:16][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:18])[CH2:21][CH2:22][CH2:23]5)=[N:28][CH:27]=4)=[CH:34][CH:33]=3)=[CH:31][CH:30]=2)=[CH:27][N:28]=1)=[O:11])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(N)=O
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(Br)cc2)[nH]1
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: OBO
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2ncc(-c3ccc(-c4ccc(-c5cnc(C6CCCN6C(=O)OC(C)(C)C)[nH]5)cc4)cc3)[nH]2)CCC1
Temperature: 80 °C
Reaction time: 18 h
Yield: 9.4 %

Procedure:
1-[1H-Imidazol-2-yl]-cyclobutyl}-carbamic acid tert-butyl ester boronic acid (60 mg, 0.17 mmol) and 2-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (65 mg, 17 mmol) in 3:1 DME/H2O (1.5 mL) were treated with Pd(PPh3)4 (10 mg, 0.0084 mmol) and K2CO3 (2 M solution, 0.25 mL, 0.50 mmol). The mixture was stirred in a sealed tube at 80° C. for 18 hours. The mixture was filtered through a fitted glass funnel and concentrated. The mixture was subjected to a reverse phase HPLC column (5-95% MeCN—H2O; 0.1% TFA modifier) to afford 2-(5-{4′-[2-(1-tert-butoxycarbonylamino-cyclobutyl)-3H-imidazol-4-yl]-biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (10 mg, 9%): MS (ESI) m/z 625 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.Cl.[CH3:20][S:21]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][C@@H:25]1[CH3:30])(=[O:23])=[O:22]>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:27]3[CH2:28][CH2:29][N:24]([S:21]([CH3:20])(=[O:22])=[O:23])[C@@H:25]([CH3:30])[CH2:26]3)=[CH:8][C:6]=2[N:7]=1
Reactant: C[C@H]1CNCCN1S(C)(=O)=O
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: Cl
Product: C[C@H]1CN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CCN1S(C)(=O)=O

Procedure:
Reaction between 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde and (S)-1-methanesulfonyl-2-methyl-piperazine hydrochloride salt using procedure C yielded 2-chloro-6-((S)-4-methanesulfonyl-3-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine. This compound was subjected to procedure A to yield the desired final compound which was purified using flash chromatography.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[NH:7][C:6]([C:12]([N:14]1[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16][CH2:15]1)=[O:13])=[CH:5]2.C(N(CC)CC)C.[C:29]([O:32][CH2:33]C)(=[O:31])C>C(O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:33][O:32][C:29]([C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[NH:7][C:6]([C:12]([N:14]1[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16][CH2:15]1)=[O:13])=[CH:5]2)=[O:31]
Reactant: CCOC(C)=O
Reactant: O=C(c1cc2cc(Br)cc(Cl)c2[nH]1)N1CCC(F)(F)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(Cl)c2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1
Temperature: 25 °C
Yield: 69 %

Procedure:
The mixture consistent of 100 mg (0.265 mmol) (5-bromo-7-chloro-1H-indol-2-yl)-(4,4-difluoro-piperidin-1-yl)-methanone, 15 mg (0.0184 mmol) 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride and 55.6 μL (0.398 mmol) triethylamine in 1 mL ethanol and 1 mL ethyl acetate was stirred overnight at 100° C. under an atmosphere of carbon monoxide (120 bar). After cooling to room temperature the reaction mixture is filtered, evaporated and chromatographed on silica gel with ethyl acetate:n-heptane (1:2 v/v) as eluant to give the desired compound as a colorless solid (69%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[CH:7]=[C:8]1[C:20]2[N:19]3[CH:21]=[CH:22][N:23]=[C:18]3[C:17](=[O:24])[NH:16][C:15]=2[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2)([OH:3])=[O:2].CO>[Pd].CN(C)C=O>[C:1]([C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[CH2:7][CH:8]1[C:20]2[N:19]3[CH:21]=[CH:22][N:23]=[C:18]3[C:17](=[O:24])[NH:16][C:15]=2[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2)([OH:3])=[O:2]
Reactant: O=C(O)c1cccc(C=c2c3ccccc3c3[nH]c(=O)c4nccn4c23)c1
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(O)c1cccc(CC2c3ccccc3-c3[nH]c(=O)c4nccn4c32)c1
Yield: 73.5 %

Procedure:
The process is performed as in Example 3 but starting with 6.9 g of 10-(3-carboxybenzylidene)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one, 50 ml of methanol, 250 ml of dimethylformamide and 0.7 g of 10% palladium-on-charcoal. After evaporation of the solvents and trituration of the solid obtained with 100 ml of methanol, 5.1 g of 10-(3-carboxybenzyl)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one are obtained in the form of an off-white solid melting above 260° C., which product is converted into the sodium salt of formula C21 H14N3O3Na (Analysis, % calculated C 66.49, H: 3.72, N: 11.08, O: 12.65, Na : 6.06, % found C: 66.6, H: 3.7, N: 10.9).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].N1C=CC=CC=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]2[O:27][C:26]([CH3:28])=[N:25][C:24]=2[CH:29]=1.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([NH:19][C:20]1[CH:21]=[CH:22][C:23]2[O:27][C:26]([CH3:28])=[N:25][C:24]=2[CH:29]=1)(=[O:11])=[O:10]
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Reactant: Cc1nc2cc(N)ccc2o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1nc2cc(NS(=O)(=O)c3cc(Cl)ccc3Cl)ccc2o1
Reaction time: 0.08 h
Yield: 63 %

Procedure:
To a solution of 2,5-dichlorobenzenesulphonyl chloride (52 mg, 0.21 mmol) in dichloromethane (1.5 mL) was added pyridine (40 μL, 0.5 mmol) and the mixture was stirred under N2 for 5 min, after which time 5-amino-2-methylbenzoxazole (30 mg, 0.20 mmol) was added. The resulting mixture was stirred for 1 h at room temperature, then saturated NaHCO3 solution was added (8 mL) and the mixture was extracted into ethyl acetate (15 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford a pale pink solid (45 mg, 63%), single spot at Rf 0.53 (1:1 hexane:ethyl acetate). mp 193.5-193.9° C., HPLC purity 98% (tR 2.27 min in 10% water-acetonitrile). 1H NMR (CDCl3): δ 7.86 (1H, d, J=2.2 Hz), 7.39 (4H, m), 7.12 (1H, dd, J=8.4, 1.8 Hz), 2.58 (3H, s). LCMS: 355.07 (M−). FAB-MS (MH+, C14H10Cl2N2O3S): calcd 356.9867, found 356.9878.
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([N:19]=[CH:20][CH:21](C)[CH3:22])[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1.[CH3:29]O.[BH4-].[Li+].Cl>O1CCCC1.O>[CH:20]1([NH:19][N:16]2[C:17](=[O:18])[C:12]([C:4]3[NH:5][C:6]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[S:2](=[O:1])(=[O:28])[N:3]=3)=[C:13]([OH:27])[C:14]3[S:26][CH:25]=[CH:24][C:15]2=3)[CH2:29][CH2:22][CH2:21]1
Reactant: CO
Reactant: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc2n1NC1CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 269A (0.077 g, 0.21 mmol) in tetrahydrofuran (4 mL) and methanol (0.030 mL, 0.8 mmol) at 0° C. was treated dropwise with a 2.0M solution of lithium borohydride in tetrahydrofuran (0.200 mL, 0.4 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1M hydrochloric acid to pH of approximately 2-4, diluted with water (15 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 1% methanol in chloroform to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.81 (m, 6 H) 3.85 (m, 1 H) 6.84 (s, 1 H) 7.49 (d, J=5.15 Hz, 1 H) 7.55 (t, J=7.91 Hz, 1 H) 7.62 (d, J=8.09 Hz, 1 H) 7.78 (t, J=7.91 Hz, 1 H) 7.93 (d, J=8.09 Hz, 1 H) 8.33 (d, J=5.15 Hz, 1 H) 14.21 (s, 1 H) 14.82 (s, 1 H). MS (ESI−) m/z 415 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[N:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:22])C=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:5]=[N+:6]([O-:22])[CH:7]=1
Reactant: Cc1cnnc(-c2ccccc2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1cc(-c2ccccc2)n[n+]([O-])c1
Yield: 73.1 %

Procedure:
To a solution of 5-methyl-3-phenylpyridazine (2.0 g) in 40 mL of CHCl3 is added m-chloroperbenzoic acid (2.9 g, 80% pure). The solution is permitted to stand at room temperature until the reaction is complete. The precipitate which forms during the reaction period is removed by filtration, and the filtrate diluted with ether. The ether solution is then washed sequentially with 10% aqueous sodium sulfite, saturated sodium bicarbonate, and saturated brine. The washed liquid is dried over MgSO4 and then concentrated in vacuo to give 1.6 g (73%) of a pale yellow crystalline solid having a melting point of 112°-114° C.
Reaction SMILES: [O:1]=[C:2]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2)[CH2:3][CH2:4][CH2:5][Cl:6].[I-].[Na+].[CH2:20]1[O:28][C:27]2[CH:26]=[CH:25][C:24]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[CH:23][C:22]=2[O:21]1.C1CCN2C(=NCCC2)CC1.C(=O)([O-])O.[Na+].Cl>CS(C)=O.CO>[ClH:6].[O:1]=[C:2]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2)[CH2:3][CH2:4][CH2:5][N:32]1[CH2:33][CH2:34][N:29]([C:24]2[CH:25]=[CH:26][C:27]3[O:28][CH2:20][O:21][C:22]=3[CH:23]=2)[CH2:30][CH2:31]1
Reactant: O=C1CCc2cc(C(=O)CCCCl)ccc2N1
Reactant: c1cc2c(cc1N1CCNCC1)OCO2
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Solvent: CS(C)=O
Product: O=C1CCc2cc(C(=O)CCCN3CCN(c4ccc5c(c4)OCO5)CC3)ccc2N1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
2.7 Grams of 6-(1-oxo-4-chlorobutyl)-3,4-dihydrocarbostyril and 1.5 g of sodium iodide were mixed in 30 ml of dimethyl sulfoxide and the mixture was stirred at 50° C. for 2 hours. Then to the reaction mixture were added 2.0 g of 4-(3,4-methylenedioxyphenyl)piperazine and 3 g of DBU and the reaction mixture was stirred at 70°-80° C. for 5 hours. After the reaction was completed, the reaction mixture was poured into 10 ml of 2%-sodium hydrogencarbonate and the organic layer was extracted with chloroform. The chloroform layer was washed with water, dried and chloroform was removed by distillation. To the residue thus obtained were added 50 ml of methanol and 5 ml of concentrated hydrochloric acid and the mixture was concentrated under a reduced pressure to dryness. The residue thus obtained was crystallized by adding ethanol-acetone to obtain crude crystals, and the crude crystals were recrystallized from ethanol-water. 2.1 Grams of 6-{1-oxo-4-[4-(3,4-methylenedioxy-phenyl)-1-piperazinyl]butyl}-3,4-dihydrocarbostyril monohydrochloride in colorless powdery crystals were obtained.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].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.Br[C:50]1[CH:51]=[C:52]([N:56]2[C:60]3[CH:61]=[C:62]([F:65])[CH:63]=[CH:64][C:59]=3[N:58]=[C:57]2[CH:66]([NH:68][C:69](=[O:71])[CH3:70])[CH3:67])[CH:53]=[N:54][CH:55]=1.[CH3:72][S:73]([NH2:76])(=[O:75])=[O:74]>O1CCOCC1.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:65][C:62]1[CH:63]=[CH:64][C:59]2[N:58]=[C:57]([CH:66]([NH:68][C:69](=[O:71])[CH3:70])[CH3:67])[N:56]([C:52]3[CH:53]=[N:54][CH:55]=[C:50]([NH:76][S:73]([CH3:72])(=[O:75])=[O:74])[CH:51]=3)[C:60]=2[CH:61]=1
Reactant: CS(N)(=O)=O
Reactant: CC(=O)NC(C)c1nc2ccc(F)cc2n1-c1cncc(Br)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(=O)NC(C)c1nc2ccc(F)cc2n1-c1cncc(NS(C)(=O)=O)c1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
To a microwave vial was added cesium carbonate (1.30 g, 3.98 mmol), Pd2(dba)3 (0.146 g, 0.159 mmol), Xantphos (0.230 g, 0.398 mmol), N-(1-(1-(5-bromopyridin-3-yl)-6-fluoro-1H-benzo[d]imidazol-2-yl)ethyl)acetamide (0.600 g, 1.59 mmol), and methanesulfonamide (0.166 g, 1.75 mmol) in dioxane (7.95 mL). The suspension was purged with nitrogen for 5 min then was stirred at 120° C. for 3 h under microwave irradiation. The solution was loaded directly onto silica gel then purified by MPLC (eluted with a gradient of 0-10% MeOH in DCM) to afford N-(1-(6-fluoro-1-(5-(methylsulfonamido)pyridin-3-yl)-1H-benzo[d]imidazol-2-yl)ethyl)acetamide as an off-white solid. LC-MS (ESI) m/z 392.1 [M+H]+.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[CH:10]=[O:11].C([O-])([O-])=O.[Cs+].[Cs+].I[CH2:19][CH3:20]>CN(C)C=O>[CH2:19]([N:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[CH:10]=[O:11])[CH3:20]
Reactant: O=Cc1cc2cccnc2[nH]1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCn1c(C=O)cc2cccnc21
Temperature: 20 °C

Procedure:
In a separate reaction: To a suspension of 1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde (600 mg, 4.11 mmol) and Cs2CO3 (2675 mg, 8.21 mmol) in N,N-Dimethylformamide (DMF) (20 mL) stirred under nitrogen at 20° C. was added iodoethane (0.498 mL, 6.16 mmol) dropwise during 0.5 min. The reaction mixture was stirred at r.t. for 1 h, TLC showed complete conversion.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1>CO.Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]=[C:5]([NH2:8])[C:4]([NH2:9])=[N:9]2
Reactant: Nc1ccc(Cl)cc1N
Agent: Cl
Solvent: CO
Product: Nc1nc2ccc(Cl)cc2nc1N

Procedure:
A solution of dimethyl oxaldiimidate (48 parts) in methanol (80 parts) was added to a slurry of 4-chloro-o-phenylenediamine (56 parts) in 0.3% aqueous hydrochloric acid (60 parts). The temperature rose to 54°. The reaction mixture was cooled and filtered to give a brown solid. After washing with THF, 61.4 parts of tan solid remained (80%). Recrystallization from THF or dioxane gave light-yellow crystals of 6-chloro-2,3-diaminoquinoxaline, m.p. 300°-303°.
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].CI.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:11]=1[C:17]#[C:18][C@H:19]1[CH2:23][CH2:22][CH2:21][N:20]1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>>[Br:16][C:13]1[CH:12]=[C:11]2[C:10](=[CH:15][CH:14]=1)[N:9]([CH3:1])[C:18]([C@H:19]1[CH2:23][CH2:22][CH2:21][N:20]1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:17]2
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C#Cc1cc(Br)ccc1N
Agent: [K+]
Solvent: CI
Product: Cn1c([C@H]2CCCN2C(=O)OC(C)(C)C)cc2cc(Br)ccc21
Yield: 78 %

Procedure:
(R)-tert-Butyl 2-(5-bromo-1-methyl-1H-indol-2-yl)pyrrolidine-1-carboxylate (3.245 g) was prepared via t-BuOK cyclization/MeI alkylation sequence described in Example 156, Step 2, from (R)-tert-butyl 2-((2-amino-5-bromophenyl)ethynyl)pyrrolidine-1-carboxylate (3.989 g, 10.92 mmol) in 78% yield.