Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1.[N+:17]([CH3:20])([O-:19])=[O:18].C([O-])(=O)C.[NH4+].[BH4-].[Na+]>O.C(O)(=O)C.CS(C)=O.C(OCC)(=O)C>[F:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][CH2:20][N+:17]([O-:19])=[O:18])=[CH:7][CH:6]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(Oc2ccccc2F)cc1
Agent: CC(=O)[O-]
Agent: [BH4-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])CCc1ccc(Oc2ccccc2F)cc1
Temperature: 110 °C
Reaction time: 3 h
Yield: 49.6 %

Procedure:
To an acetic acid (30.0 mL) solution of 4-(2-fluoro-phenoxy)-benzaldehyde (3.00 g, 13.9 mmol) described in Manufacturing Example 83-1-1 were added nitromethane (4.24 g, 69.5 mmol) and ammonium acetate (2.14 g, 27.8 mmol) under nitrogen atmosphere, which was stirred for 3 hours at 110° C. Water and ethyl acetate were added to the reaction mixture, and the organic layer was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain a crude product (3.60 g). To a dimethyl sulfoxide (50.0 mL) solution of this crude product (3.60 g) and acetic acid (3.00 mL) was added sodium borohydride (789 mg, 20.9 mmol) at room temperature while cooling appropriately, which was stirred for 20 minutes at room temperature. Water was then added dropwise at room temperature while cooling appropriately. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:10→1:5) to obtain the title compound (1.80 g, 49.6%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N+:14]([O-])=O)=[C:4]([CH3:17])[CH:3]=1>C(O)(=O)C.[Zn]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH2:14])=[C:4]([CH3:17])[CH:3]=1
Reactant: Cc1cc(F)ccc1-c1ccncc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1cc(F)ccc1-c1ccncc1N
Temperature: 70 °C
Yield: 33.1 %

Procedure:
Zinc dust (4.37 g, 66.7 mmol) was added in three portions over 15 min to 4-(4-fluoro-2-methylphenyl)-3-nitropyridine (3.1 g, 13.3 mmol) in acetic acid (30 mL). The reaction mixture was then heated to 70° C. for two hours. After cooling to room temperature, the reaction mixture was filtered through Celite and all volatiles were removed under reduced pressure. The resulting oil was suspended in EtOAc and washed with saturated aqueous NaHCO3 solution and brine. The organic phase was dried over MgSO4 and filtered. Evaporation of volatiles under reduced pressure gave the crude product which was purified by flash chromatography (EtOAc) to yield the desired compound (890 mg, 33%). The material was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.[CH3:20][O:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[C:23]=1[C:24](Cl)=[O:25].[Al+3].[Cl-].[Cl-].[Cl-].O>C(Cl)Cl.CCOC(C)=O>[CH3:32][O:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:22]([O:21][CH3:20])[C:23]=1[C:24]([C:10]1[C:11]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:12]=2[S:13][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:25]
Reactant: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Reactant: COc1cccc(OC)c1C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2c(OC)cccc2OC)cc1
Reaction time: 6 h
Yield: 60 %

Procedure:
To a well-stirred solution of 2-(4'-methoxyphenyl) - 6-methoxybenzo[b]thiophene (0.500 g, 1.85 mmol) and 2,6-dimethoxybenzoyl chloride (1.11 g, 5.56 mmol) in CH2Cl2 (40 mL) was added AlCl3 (0.986 g, 7.40 mmol) portion-wise over a 15 minute period. After 6 hours, water was added, and the product was isolated initially by extraction with CH2Cl2 and subsequently by extraction with EtOAc. The organic layers were separately washed with brine and then combined and dried over MgSO4. Purification by flash chromatography (silica gel, 60:40 EtOAc/hexane) afforded the title compound (0.484 g, 1.11 mmol, 60%) as an off-white solid. Recrystallization (hexane/ethanol) afforded a highly pure, crystalline sample with mp 146°-152° C.: 1H-NMR (CDCl3, 360 Mhz): δ=8.54 (dd,J=9.1,0.3 Hz, 1H, ArH), 7.25 (d,J=2.1 Hz, 1H, ArH), 7.12 (d,J=8.8 Hz, 2H, ArH), 7.10 (dd,J=9.0,2.5 Hz, 1H, ArH), 6.98 (t,J=8.4 Hz, 1H, ArH), 6.58 (d,J=8.8 Hz, 2H, ArH), 6.20 (d,J=8.4 Hz, 2H, ArH), 3.88 (s,3H, --OCH3), 3.73 (s,3H, --OCH3), 3.60 (s,6H, --OCH3); 13C-NMR (CDCl3, 90 Mhz): δ=190.3, 159.5, 157.5, 157.3, 151.3, 139.3, 132.9, 131.9, 130.8, 130.5, 126.4, 125.7, 120.3 115.0, 112.6, 103.9, 103.6, 55.6, 55.5, 55.3. HRMS (EI) M30 calcd for C25H22O5S 434.1188, found 434.1188.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].I[CH2:22][CH3:23].O>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][N:11]([CH2:22][CH3:23])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCI
Reactant: OC1(c2cc(F)cc(F)c2)CCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCN1CCC(O)(c2cc(F)cc(F)c2)C1
Yield: 21.1 %

Procedure:
To a mixture of 3-(3,5-difluorophenyl)pyrrolidin-3-ol (0.50 g, 2.5 mmol) in acetonitrile (25 mL) was added sodium carbonate (0.34 g, 6.25 mmol) and iodoethane (0.39 g, 2.5 mmol) and the mixture was refluxed for 1 h. Water (50 mL) was added and the aqueous phase was extracted with ethyl acetate (2×50 mL), the combined organic phase was dried (MgSO4) and evaporated. Purification by flash chromatography on silica gel (ethyl acetate/methanol, 1:1) gave the title compound (0.12 g). The amine was converted to the fumaric acid salt and lyophilized from water. MS m/z (relative intensity, 70 eV) 227 (M+, 19), 212 (15), 141 (15), 127 (15), 71 (bp).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:16]=1[NH:15][CH:14]=[C:13]2[CH2:17][C:18]([NH2:20])=[O:19].C[O:22][C:23](=O)[C:24]([C:26]1[C:27]([CH3:54])=[N:28][N:29]2[CH:34]=[CH:33][C:32]([C:35]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[O:36][SiH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:31][C:30]=12)=O.[NH4+].[Cl-].C1CCN2C(=NCCC2)CC1>O1CCCC1.CCOC(C)=O.O>[C:38]([SiH2:37][O:36][C:35]([C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:32]1[CH:33]=[CH:34][N:29]2[N:28]=[C:27]([CH3:54])[C:26]([C:24]3[C:23](=[O:22])[NH:20][C:18](=[O:19])[C:17]=3[C:13]3[C:12]4[C:16](=[C:8]([CH3:7])[CH:9]=[CH:10][CH:11]=4)[NH:15][CH:14]=3)=[C:30]2[CH:31]=1)([CH3:41])([CH3:39])[CH3:40]
Reactant: COC(=O)C(=O)c1c(C)nn2ccc(C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)cc12
Reactant: Cc1cccc2c(CC(N)=O)c[nH]c12
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: Cc1nn2ccc(C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)cc2c1C1=C(c2c[nH]c3c(C)cccc23)C(=O)NC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56.4 %

Procedure:
Potassium tert-butoxide (1.0 M in THF, 6.4 ml, 6.4 mmol, 3.0 equiv) is added dropwise at room temperature under an atmosphere of argon to a solution of 2-(7-methyl-1H-indol-3-yl)-acetamide (400 mg, 2.13 mmol, 1.0 equiv) and of [5-(tert-butyl-diphenyl-silanyloxymethyl)-2-methyl-pyrazolo[1,5-a]pyridin-3-yl]-oxo-acetic acid methyl ester (1.04 g, 2.13 mmol, 1.0 equiv) in anhydrous tetrahydrofuran (10 ml, dried over molecular sieves). The reaction mixture is stirred for 15 minutes at room temperature. It is then diluted with EtOAc and poured into a saturated aqueous NH4Cl solution. After three extractions with EtOAc, the combined organic layers are dried over Na2SO4, filtered and concentrated in vacuo. The residue is dissolved in N,N-dimethylformamide (20 ml), treated with DBU (3.2 ml, 21.3 mmol, 10 equiv) and stirred under an atmosphere of argon for 10 minutes at 100° C. After cooling, the reaction mixture is diluted with water and extracted three times with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification of the residue via flash chromatography (gradient of hexane/EtOAc 100:0 to 50:50) affords the title compound (750 mg, 56%). 1H NMR (400 MHz, d6-DMSO): δ=11.83 (br s, 1H), 11.02 (br s, 1H), 8.54 (d, J=7.8 Hz, 1H), 7.93 (d, J=3.0 Hz, 1H), 7.61-7.59 (m, 4H), 7.48-7.39 (m, 6H), 7.34 (s, 1H), 6.82 (d, J=7.1 Hz, 1H), 6.74 (dd, J=7.1/1.7 Hz, 1H), 6.52 (t, J=7.1 Hz, 1H), 6.20 (d, J=8.1 Hz, 1H), 4.69 (s, 2H), 2.44 (s, 3H), 1.91 (s, 3H), 1.01 (s, 9H). MS (ES+): 625 (M+H)+.
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]([C:9]1[CH:27]=[CH:26][C:12]2[CH2:13][C@@H:14]3[C@H:19]([CH3:20])[C@:18]([CH3:21])([C:11]=2[CH:10]=1)[CH2:17][CH2:16][N:15]3[CH2:22][CH2:23][O:24][CH3:25])=[O:8]>FC(F)(F)C(O)=O>[CH3:25][O:24][CH2:23][CH2:22][N:15]1[CH2:16][CH2:17][C@:18]2([CH3:21])[C@@H:19]([CH3:20])[C@H:14]1[CH2:13][C:12]1[CH:26]=[CH:27][C:9]([C:7]([NH2:6])=[O:8])=[CH:10][C:11]=12
Reactant: COCCN1CC[C@@]2(C)c3cc(C(=O)NCc4ccc(OC)cc4OC)ccc3C[C@@H]1[C@@H]2C
Solvent: O=C(O)C(F)(F)F
Product: COCCN1CC[C@@]2(C)c3cc(C(N)=O)ccc3C[C@@H]1[C@@H]2C
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.7 %

Procedure:
A mixture of (2R,6R,11R)—N-(2,4-dimethoxybenzyl)-3-(2-methoxyethyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocine-8-carboxamide (360 mg, 0.80 mmol) in trifluoroacetic acid (5 mL) was stirred at ambient temperature for 2 hours. The mixture was concentrated under reduced pressure before quenching with ice/ammonium hydroxide (28%) (25 mL). The crude product was extracted twice using dichloromethane (100 mL) and the combined organic layers dried (MgSO4). Filtration and removal of the solvent under reduced pressure gave the crude product that was purified by prep-HPLC giving (2R,6R,11R)-3-(2-methoxyethyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocine-8-carboxamide (130 mg, 54% yield); LC/MS (M+H)+=303.2.
Reaction SMILES: [C:1]([O-])(=[O:3])[CH3:2].[Na+].CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.[NH2:30][C:31]1[S:32][CH:33]=[C:34]([O:38][CH2:39][CH3:40])[C:35]=1[C:36]#[N:37]>O>[C:1]([NH:30][C:31]1[S:32][CH:33]=[C:34]([O:38][CH2:39][CH3:40])[C:35]=1[C:36]#[N:37])(=[O:3])[CH3:2]
Reactant: CCOc1csc(N)c1C#N
Reactant: CC(=O)[O-]
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: [Na+]
Solvent: O
Product: CCOc1csc(NC(C)=O)c1C#N

Procedure:
100 parts of anhydrous sodium acetate are introduced into 400 parts by volume of acetic anhydrice, 168 parts of 2-amino-3-cyano-4-ethoxythiophene are added and the mixture is refluxed for 4 hours. Thereafter, 800 parts of water are added dropwise to the hot mixture, the mixture is left to cool and the product is filtered off under suction, washed with water and dried to give 194 parts of 2-acetylamino-3-cyano-4-ethoxythiophene of melting point 242°-243° C. (from acetic acid).
Reaction SMILES: [C:1]([CH:3]([C:9]([C:11]1[C:12]2[CH2:25][O:24][C:23]3[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=3[C:13]=2[N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:15]=1)=[O:10])[C:4](OCC)=[O:5])#[N:2].[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1(C)C(C)=CC=CC=1>[C:1]([CH:3]([C:9]([C:11]1[C:12]2[CH2:25][O:24][C:23]3[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=3[C:13]=2[N:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:15]=1)=[O:10])[C:4]([NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:5])#[N:2]
Reactant: CCOC(=O)C(C#N)C(=O)c1nn(-c2ccccc2)c2c1COc1ccccc1-2
Reactant: Nc1ccccc1
Solvent: Cc1ccccc1C
Product: N#CC(C(=O)Nc1ccccc1)C(=O)c1nn(-c2ccccc2)c2c1COc1ccccc1-2
Yield: 52 %

Procedure:
2-Cyano-3-(1,4-dihydro-1-phenyl-[1]-benzopyrano[4,3-c]pyrazol-3-yl)-3-oxo-propanoic acid, ethyl ester (1.2 g) is reacted with aniline (1.1 g) in xylene (100 ml) at the reflux temperature for 48 hours. After cooling the precipitate is filtered and washed with xylene, then crystallized from dichloromethane/methanol to give 0.7 g of 2-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzopyrano[4,3-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide, m.p. 280°-282° C.
Reaction SMILES: [CH2:1]([C:4]1[C:21]2[CH2:20][C:19]3[C:10](=[C:11]([CH2:25][CH2:26][CH3:27])[C:12]4[C:17]([C:18]=3[CH2:22][CH2:23][CH3:24])=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:9][C:8]=2[C:7]([CH2:28][CH2:29][CH3:30])=[C:6]([CH2:31][CH2:32][CH3:33])[C:5]=1[CH2:34][CH2:35][CH3:36])[CH2:2][CH3:3].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[CH2:28]([C:7]1[C:8]2[C:21](=[CH:20][C:19]3[C:10]([CH:9]=2)=[C:11]([CH2:25][CH2:26][CH3:27])[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]=3[CH2:22][CH2:23][CH3:24])[C:4]([CH2:1][CH2:2][CH3:3])=[C:5]([CH2:34][CH2:35][CH3:36])[C:6]=1[CH2:31][CH2:32][CH3:33])[CH2:29][CH3:30]
Reactant: CCCc1c(CCC)c(CCC)c2c(c1CCC)Cc1c(c(CCC)c3ccccc3c1CCC)C2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: CCCc1c(CCC)c(CCC)c2cc3c(CCC)c4ccccc4c(CCC)c3cc2c1CCC
Yield: 22.4 %

Procedure:
5,12-Dihydro-1,2,3,4,6,11-hexapropylnaphthacene (0.503 g, 1.04 mmol), 2,3-dichloro-5,6-dicyanobenzoquinone (0.260 g, 1.14 mmol) and 1,4-dioxane (3 ml) were charged in a reactor. The mixture was refluxed for 24 hours. After cooling, the precipitates were removed by filtration. The solvent in the mixture was removed in vacuum followed by recrystallization from chloroform/methanol. The orange red title compound (0.112 g) was obtained. The NMR yield was 36% and the isolation yield was 22%.
Reaction SMILES: ClC1C=CC(COC2C=NNC(=O)C=2)=NC=1.[Br:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][O:25][C:26]2[CH:31]=[N:30][N:29](C3CCCCO3)[C:28](=[O:38])[CH:27]=2)=[N:22][CH:23]=1>>[Br:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][O:25][C:26]2[CH:31]=[N:30][NH:29][C:28](=[O:38])[CH:27]=2)=[N:22][CH:23]=1
Reactant: O=c1cc(OCc2ccc(Br)cn2)cnn1C1CCCCO1
Agent: O=c1cc(OCc2ccc(Cl)cn2)cn[nH]1
Product: O=c1cc(OCc2ccc(Br)cn2)cn[nH]1

Procedure:
5-(5-Bromo-pyridin-2-ylmethoxy)-2H-pyridazin-3-one is prepared following preparation 18b from 5.30 g (14.5 mmol) 5-(5-bromo-pyridin-2-ylmethoxy)-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one (preparation 25a).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13](=[O:17])[NH:14][CH2:15][CH2:16][C:11]=3[NH:10][C:9]=2[CH:18]=O)=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:22]=[C:23]([NH:28][C:29]2[C:30]3[CH2:37][C:36](=[O:38])[NH:35][C:31]=3[N:32]=[CH:33][N:34]=2)[CH:24]=[CH:25][C:26]=1[F:27]>>[Cl:20][C:21]1[CH:22]=[C:23]([NH:28][C:29]2[C:30]3[C:37](=[CH:18][C:9]4[NH:10][C:11]5[CH2:16][CH2:15][NH:14][C:13](=[O:17])[C:12]=5[C:8]=4[C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C:36](=[O:38])[NH:35][C:31]=3[N:32]=[CH:33][N:34]=2)[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Reactant: O=Cc1[nH]c2c(c1-c1ccc(F)cc1)C(=O)NCC2
Product: O=C1Nc2ncnc(Nc3ccc(F)c(Cl)c3)c2C1=Cc1[nH]c2c(c1-c1ccc(F)cc1)C(=O)NCC2
Yield: 77.4 %

Procedure:
The title compound was prepared under the same conditions as described in Example 46 with 3-(4-fluoro-phenyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one as starting materials to give 4-(3-chloro-4-fluoro-phenylamino)-5-[3-(4-fluoro-phenyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-ylmethylene]-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (80 mg, 77.4%) as a red solid.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+].O>C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[OH:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)s1
Reactant: Oc1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2ccccc2O)s1
Reaction time: 0.08 h
Yield: 84.3 %

Procedure:
Tetrakis(triphenylphosphine)palladium(O) (133 mg, 0.12 mmol) is added to a solution of 5-bromothiophene-2-carboxylic acid (850 mg, 4.1 mmol) in degassed THF (10 mL). The resulting solution is stirred for 5 minutes and then 2,4,4,5,5-tetramethyl)-1,3,2-dioxaborolan-2-yl) phenol (1 g, 4.6 mmol) is added followed by aqueous Na2CO3 (2M, 6.9 mL). The mixture is heated at reflux overnight. The reaction mixture is allowed to cool, poured into water (50 mL), and washed with ether (3×50 mL). The aqueous layer is acidified with concentrated HCl to pH<2. The resulting precipitate is collected by filtration, washed with water and dried in vacuo to yield the desired product (761 mg, 83%). MS for C11H7O3S (ESI) (M−H)+ m/z 219.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[NH:9][CH2:8][CH2:7][CH2:6]2.[CH3:16][N:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19](O)=[O:20].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[N:9]([C:19](=[O:20])[C@@H:18]1[CH2:22][CH2:23][CH2:24][N:17]1[CH3:16])[CH2:8][CH2:7][CH2:6]2
Reactant: CN1CCC[C@H]1C(=O)O
Reactant: COc1cc2c(cc1[N+](=O)[O-])NCCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)[C@@H]1CCCN1C)CCC2
Yield: 45.4 %

Procedure:
A solution of 6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroquinoline (3.0 g, 14.41 mmol), 1-methyl-L-proline (2.140 g, 16.57 mmol), HATU (7.12 g, 18.73 mmol), and DIPEA (6.29 mL, 36.0 mmol) in N,N-Dimethylformamide (DMF) (25 mL) was stirred for 2.5 days at room temperature. Reaction was poured into ethyl acetate and washed successively with 5% lithium chloride (aq) and saturated sodium chloride (aq). The organic layer was dried over sodium sulfate, filtered, and purified by column chromatography (10% MeOH/CH2Cl2) to afford 6-(methyloxy)-1-(1-methyl-L-prolyl)-7-nitro-1,2,3,4-tetrahydroquinoline (2.09 g, 6.54 mmol, 45.4% yield). The residue was suspended in ethanol (300 mL) and N,N-dimethylacetamide (50 mL) was added followed by tin(II)chloride dihydrate (6.78 g, 30.1 mmol) and 1.0M HCl (2.505 mL, 2.505 mmol). After overnight stirring the reaction was quenched with excess saturated NaHCO3 (300 mL) and allowed to stir at rt for 30 min. The solids were removed through a celite pad, rinsed with Me0H, and evaporated. The aqueous layer was extracted with DCM (2×100 mL). The combined organic layers were filtered through a cotton plug, and concentrated by rotary evaporation to provide 6-(methyloxy)-1-(1-methyl-L-prolyl)-1,2,3,4-tetrahydro-7-quinolinamine (1.1 g, 26% over two steps). ESIMS (M+H)+=290.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Cl>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[C:26]([F:25])[CH:27]=3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: Fc1cccc(CCl)c1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Product: Fc1cccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)c1

Procedure:
The title compound (0.01 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C, 0.1 g) using 3-fluorobenzyl chloride (0.5 mL) in place of benzyl chloride. MS (ESI): exact mass calculated for C20H19ClFN3, 355.13; found, m/z 356.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.42-7.37 (m, 2H), 7.35-7.32 (m, 2H), 7.28-7.21 (m, 1H), 6.93-6.88 (m, 1H), 6.84 (d, J=7.7 Hz, 1H), 6.75-6.71 (m, 1H), 5.29 (s, 2H), 2.89-2.85 (m, 4H), 2.79-2.76 (m, 2H), 2.74-2.70 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1[OH:18].[C:19]([C:21]1[CH:22]=[C:23]([S:28]([NH:31][C:32]2[S:36][N:35]=[CH:34][N:33]=2)(=[O:30])=[O:29])[CH:24]=[CH:25][C:26]=1F)#[N:20].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:19]([C:21]1[CH:22]=[C:23]([S:28]([NH:31][C:32]2[S:36][N:35]=[CH:34][N:33]=2)(=[O:30])=[O:29])[CH:24]=[CH:25][C:26]=1[O:18][C:9]1[CH:10]=[CH:11][C:12]([C:14]([F:15])([F:17])[F:16])=[CH:13][C:8]=1[C:7]1[CH:6]=[CH:5][N:4]=[N:3][C:2]=1[CH3:1])#[N:20]
Reactant: N#Cc1cc(S(=O)(=O)Nc2ncns2)ccc1F
Reactant: Cc1nnccc1-c1cc(C(F)(F)F)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1nnccc1-c1cc(C(F)(F)F)ccc1Oc1ccc(S(=O)(=O)Nc2ncns2)cc1C#N
Temperature: 90 °C
Yield: 66 %

Procedure:
2-(3-Methylpyridazin-4-yl)-4-(trifluoromethyl)phenol (Preparation 44, 100 mg, 0.38 mmol) and 3-cyano-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (Preparation 39, 108 mg, 0.38 mmol) were dissolved in dimethylsulfoxide (2 mL). Potassium carbonate (157 mg, 1.14 mmol) was added and the reaction mixture was heated to 90° C. for 4 hours. The reaction mixture was cooled and the crude material purified by reverse phase column chromatography (ISCO™ Companion, C18 silica, 5% to 60% acetonitrile in water gradient elution) to afford the title compound as an off-white solid (130 mg).
Reaction SMILES: [Cl-].[C:2]([O:6][C:7](=[O:10])[CH2:8][Zn+])([CH3:5])([CH3:4])[CH3:3].[CH2:11]([O:18][C:19]1[CH:24]=[C:23](Br)[CH:22]=[CH:21][C:20]=1[CH:26]=[CH:27][CH3:28])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:2]([O:6][C:7](=[O:10])[CH2:8][C:23]1[CH:22]=[CH:21][C:20]([CH:26]=[CH:27][CH3:28])=[C:19]([O:18][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:24]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)C[Zn+]
Reactant: CC=Cc1ccc(Br)cc1OCc1ccccc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Solvent: C1COCCO1
Product: CC=Cc1ccc(CC(=O)OC(C)(C)C)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2-tert-butoxy-2-oxoethylzinc chloride (12.2 mL, 6.13 mmol, 1.8 eq.) was added to a solution of 2-benzyloxy-4-bromo-1-(propenyl)-benzene (mixture of E- and Z-isomers ca. 9:1) (1.17 g, 3.40 mmol, 1.00 eq.) and bis(tri-tert-butylphosphine)palladium(0) (266 mg, 0.51 mmol, 0.15 eq.) in dioxane (27 mL). The resulting mixture was stirred at r.t. for 18 hours. The mixture was filtered through Celite and the filter cake was rinsed with dioxane. The filtrate was concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 30 fractions of 45 mL, Heptane 100% to Heptane+12% AcOEt) to yield [3-benzyloxy-4-(propenyl)-phenyl]-acetic acid tert-butyl ester as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[N:16][C:5]2[NH:6][C:7]3[CH:12]=[N:11][C:10]([C:13]([NH2:15])=O)=[CH:9][C:8]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C1COCC1>[Br:1][C:2]1[CH:17]=[N:16][C:5]2[NH:6][C:7]3[CH:12]=[N:11][C:10]([C:13]#[N:15])=[CH:9][C:8]=3[C:4]=2[CH:3]=1
Reactant: NC(=O)c1cc2c(cn1)[nH]c1ncc(Br)cc12
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#Cc1cc2c(cn1)[nH]c1ncc(Br)cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 49 %

Procedure:
To a cooled solution (0° C.) of a mixture of 3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylic acid amide (5.0 g, 17.2 mmol) and triethylamine (24.0 mL, 172 mmol) in THF (200 mL) was slowly added trifluoroacetic anhydride (12.0 mL, 86 mmol). Upon complete addition, the reaction mixture was allowed to warm to ambient temperature and the stirring was continued for an additional 4 h. After this time, the solvent was removed in vacuo and the resultant residue was loaded onto H-MN. The residue was then purified by flash chromatography (silica, 330 g column, ISCO, 0-100% ethyl acetate in hexane) to afford the title compound as a pale brown solid (2.30 g, 49%). 1H NMR (DMSO-D6, 300 MHz): 13.05 (s, 1H), 9.08-9.04 (m, 2H), 8.91 (d, J=1.1 Hz, 1H), 8.79 (d, J=2.3 Hz, 1H). LCMS (Method B): RT=2.98 min, M+H+=271, 273.