Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.Cl.[NH2:24][C:25]1[C:29]([NH2:30])=[CH:28][S:27][CH:26]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CC#N>[NH2:30][C:29]1[C:25]([NH:24][C:17](=[O:19])[C:16]2[CH:15]=[CH:14][C:13]([CH2:12][NH:11][C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:21][CH:20]=2)=[CH:26][S:27][CH:28]=1
Reactant: Nc1cscc1N
Reactant: COc1ccc(NCc2ccc(C(=O)O)cc2)cc1OC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(NCc2ccc(C(=O)Nc3cscc3N)cc2)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 38 %

Procedure:
Acid 424a (1040 mg; 3.62 mmol); 3,4-diaminothiophene dihydrochloride (1017 mg; 5.44 mmol; 1.50 eq.) and BOP (1770 mg; 4.0 mmol; 1.1 eq.) were suspended in MeCN, treated with triethylamine (4 mL; 29 mmol) and stirred for 18 h at room temperature; concentrated and purified by chromatographic column on silica gel (elution 50% EtOAc in DCM) to render 527 mg (1.37 mmol; 38% yield) of compound 424c which was 90% pure. 1H-NMR (300.07 MHz; DMSO-d6) δ (ppm): 8.56 (s, 1H), 7.78 (d, J=7.9 Hz, 2H), 7.43 (d, J=3.5 Hz, 1H), 7.38 (d, J=7.9 Hz, 2H), 6.73 (d, J=8.8 Hz, 1H), 6.33 (d, J=3.5 Hz, 1H), 6.58 (d, J=2.6 Hz, 1H), 6.13 (dd, J=2.6, 8.3 Hz, 1H), 4.33 (s, 2H), 3.80 (s, 3H), 3.78 (s, 3H). LRMS: calc: 383.4642. found: 384.2 (M+H); 406.2 (M+Na) and 192.6 (M+2H)/2.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[CH:16]=[CH:15][N:14]=3)[N:10]=[CH:9]2)C=CC=CC=1.N1C=C(C2C=C(C#N)C=CN=2)N=C1>>[NH:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1
Reactant: COC(=O)c1ccnc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1
Agent: N#Cc1ccnc(-c2c[nH]cn2)c1
Product: COC(=O)c1ccnc(-c2c[nH]cn2)c1
Yield: 44 %

Procedure:
The title compound was prepared in 44% yield (two steps) from methyl 2-[1-(triphenylmethyl)-1H-imidazol-4-yl]pyridine-4-carboxylate according to the procedure for 2-(1H-imidazol-4-yl)pyridine-4-carbonitrile in Example 35. [M+H] Calc'd for C10H9N3O2, 204. Found, 204.
Reaction SMILES: O=[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[N:4][NH:3]1.P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:2]1[N:3]=[N:4][CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]=1[C:8]#[N:9]
Reactant: N#Cc1c(-c2ccccc2)cn[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: N#Cc1c(-c2ccccc2)cnnc1Cl
Temperature: 100 °C

Procedure:
3-Oxo-5-phenyl-2,3-dihydro-pyridazine-4-carbonitrile (70 mg) was suspended in 1 mL phosphorous oxychloride and heated to 100° C. for 6 hours. The mixture was then cooled and poured onto ice. The resulting brown solid product was filtered and air dried and used in the next step without further purification.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH:14]2[CH2:16][CH:11]1[CH2:12][CH:13]2[OH:17])=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl[C:19]1[N:20]=[C:21]([N:34]2[CH:39]3[CH2:40][CH2:41][CH:35]2[CH2:36][O:37][CH2:38]3)[C:22]2[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:26][S:25][C:23]=2[N:24]=1.CO>C1COCC1>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH:14]2[CH2:16][CH:11]1[CH2:12][CH:13]2[O:17][C:19]1[N:20]=[C:21]([N:34]2[CH:35]3[CH2:41][CH2:40][CH:39]2[CH2:38][O:37][CH2:36]3)[C:22]2[C:27]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:26][S:25][C:23]=2[N:24]=1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: Clc1nc(N2C3CCC2COC3)c2c(-c3ccccc3)csc2n1
Reactant: CC(C)(C)OC(=O)N1CC2CC1CC2O
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC2CC1CC2Oc1nc(N2C3CCC2COC3)c2c(-c3ccccc3)csc2n1
Reaction time: 0.17 h
Yield: 162.2 %

Procedure:
Sodium hydride (0.02481 g, 0.6203 mmol, 60 mass %) was added to a solution of 5-hydroxy-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (0.1023 g, 0.4652 mmol) in dry THF (2 mL). The mixture was stirred for 10 min and then a solution of 8-(2-chloro-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-3-oxa-8-azabicyclo[3.2.1]octane (0.111 g, 0.3101 mmol) in dry THF (3 mL) was added. The mixture was stirred overnight at room temperature. A second batch of sodium hydride (0.02481 g, 0.6203 mmol, 60 mass %) was added and the mixture was stirred overnight. Further batches of 5-hydroxy-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (0.1023 g, 0.4652 mmol) and sodium hydride (0.02481 g, 0.6203 mmol, 60 mass %) were added and the mixture was stirred for 3 nights. It was poured into methanol to quench the reaction, and then the solvent was evaporated. The residue was dissolved in EtOAc (10 mL) and water (10 mL). The layers were separated and the aqueous was extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine (1×10 mL), filtered through a hydrophobic frit and evaporated to give tert-butyl-5-[4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5-phenyl-thieno[2,3-d]pyrimidin-2-yl]oxy-2-azabicyclo[2.2.1]heptane-2-carboxylate as a brown solid (269 mg) which was used in the next step without further purification. LCMS RT=4.23 min. M+1=535.
Reaction SMILES: C[O:2][C:3]1[C:4]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[F:16])=[CH:5][CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br>ClCCl>[F:15][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]([F:16])[C:9]=1[C:4]1[C:3]([OH:2])=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COc1ccccc1-c1c(F)cccc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccccc1-c1c(F)cccc1F
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
Treatment of 2,6-difluorobromobenzene (8.9 g, 46.1 mmol) with 2-methoxybenzeneboronic acid (10.51 g, 69.2 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (1.81 g, 2.3 mmol), and potassium carbonate (15.9 g, 115.3 mmol) generally according to the procedure described for Intermediate 37 provided 4.6 g (45%) of 2′,6′-difluoro-1,1′-biphenyl-2-yl methyl ether. To a solution of 2′,6′-difluoro-1,1′-biphenyl-2-yl methyl ether (4.5 g, 20.4 mmol) in dichloromethane (100 mL) cooled to −78° C. was added boron tribromide (5.11 g, 1.0 M in dichloromethane) and the reaction mixture was allowed to stir for 30 min. The reaction mixture was allowed to warn to room temperature and was quenched by the addition of ice (150 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (500 mL). The combined organic layers were washed with water (400 mL), saturated aqueous sodium chloride (100 mL), dried (magnesium sulfate), and the solvent removed in vacuo to provide a crude oil. Purification by flash column chromatography (silica, hexanes:ethyl acetate 95:5) provided 3.95 g (94%) of 2′,6′-difluoro-1,1′-biphenyl-2-ol as a colorless oil. Anal. calcd. for C12H8F2O: C, 69.9; H, 3.91. Found: C, 68.51; H, 4.06.
Reaction SMILES: [Br-].[C:2]([C:4]1[C:5]([S:30][C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=2)=[N:6][CH:7]=[C:8]([CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:9]=1)#[N:3].C(N(CC)CC)C.C(Cl)(Cl)Cl.[CH2:51]([O:53][C:54]([C:56]1[CH:63]=[CH:62][C:59]([CH:60]=O)=[CH:58][CH:57]=1)=[O:55])[CH3:52]>O>[C:2]([C:4]1[C:5]([S:30][C:31]2[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=2)=[N:6][CH:7]=[C:8]([CH:10]=[CH:60][C:59]2[CH:58]=[CH:57][C:56]([C:54]([O:53][CH2:51][CH3:52])=[O:55])=[CH:63][CH:62]=2)[CH:9]=1)#[N:3]
Reactant: N#Cc1cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cnc1Sc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)c1ccc(C=O)cc1
Agent: [Br-]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)c1ccc(C=Cc2cnc(Sc3ccc([N+](=O)[O-])cc3)c(C#N)c2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.1 %

Procedure:
A mixture of 4.544 g (7.42 mmol) of [3-cyano-2-(4-nitrophenylthio)-5-pyridinylmethyl]triphenylphosphonium bromide, 0.751 g (7.42 mmol) of triethylamine and 50 mL of chloroform was stirred at room temperature for 15 minutes and 1.322 g (7.42 mmol) of 4-ethoxycarbonylbenzaldehyde then were added. After stirring at room temperature for 96 hours, 100 mL of water were added, the mixture was filtered, and the organic layer was separated and washed twice with 100 mL portions of water, dried and filtered. Evaporation of the filtrate under reduced pressure gave a residue which was chromatographed on silica gel. Unreacted aldehyde was eluted with 2:1 petroleum ether:benzene, while the title compound was eluted with benzene. Evaporation of the benzene eluate gave 2.82 g (88%) of 3-cyano-2-(4-nitrophenylthio)-5-[2-(4-ethoxycarbonylphenyl)ethenyl]-pyridine as a light yellow solid. The product turns from a solid to a gum below 100° C. and then to a clear liquid between 180° and 220° C.; NMR (Me2SO-d6) delta 1.34 (t, 3H, J=6.3 Hz), 4.32 (q, 2H, J=6.3 Hz), 6.73 (d, 1H, J=13 Hz), 6.99 (d, 1H, J=13 Hz), 7.27 (d, 2H, J=9 Hz), 7.74, 7.85, 7.94 (dd, 2H, 2H), 8.26, 8.31 (dd, 2H, 1H), 8.38 (d, 1H, J=1.8 Hz); IR (KBr) 2220, 1707, 1605, 1597, 1575, 1512, 1344, 1295-1277, 1174 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9](I)[O:10][C:3]=12.[CH3:12][O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:16]3[CH:17]=[C:18]([O:22][CH3:23])[C:19]([O:20][CH3:21])=[C:14]([O:13][CH3:12])[CH:15]=3)[O:10][C:3]=12
Reactant: Clc1ccnc2cc(I)oc12
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(-c2cc3nccc(Cl)c3o2)cc(OC)c1OC
Temperature: 150 °C
Yield: 57 %

Procedure:
7-Chloro-2-iodo-furo[3,2-b]pyridine (1.467 mmol), 3,4,5-trimethoxybenzene boronic acid (1.539 mmol), palladium(II)-acetate (0.076 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.146 mmol) and K2CO3 (4.399 mmol) are suspended in 1,4-dioxane (11 ml) and water (1.00 ml) is added. The suspension is heated over 45 min at 150° C. in the microwave. The solvent is removed in vacuo. The product is purified over column chromatography (SiO2, heptane, ethyl acetate). The product is isolated as yellow powder (yield 57%); LCMS (method E): 2.43 min (purity 100%), M+H+ 320.0; 1H NMR (500 MHz, DMSO-d6) δ [ppm] 8.45 (d, J=5.3, 1H), 7.79 (s, 1H), 7.49 (d, J=5.2, 1H), 7.29 (s, 2H), 3.91 (s, 6H), 3.75 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[CH2:4][O:5][CH3:6].C(N(C(C)C)C(C)C)C.[CH3:17][C:18]1[O:22][C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:20][C:19]=1[CH2:29][CH2:30][O:31][C:32]1[C:40]2[CH:39]=[CH:38][S:37][C:36]=2[C:35]([CH:41]=[O:42])=[CH:34][CH:33]=1>C1COCC1.ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:7])[CH:4]([O:5][CH3:6])[CH:41]([OH:42])[C:35]1[C:36]2[S:37][CH:38]=[CH:39][C:40]=2[C:32]([O:31][CH2:30][CH2:29][C:19]2[N:20]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:22][C:18]=2[CH3:17])=[CH:33][CH:34]=1
Reactant: COCC(=O)OC
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=O)c2sccc12
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)C(OC)C(O)c1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 127.6 %

Procedure:
To a solution of 3.17 ml methoxyacetic acid methyl ester (31.4 mmol) in 30 ml of THF, 3.5 ml of titanium tetrachloride (31.4 mmol) was added dropwise within 15 min at 0° C. After stirring the yellow solution for additional 15 min at the same temperature, 6.0 ml of N-ethyldiisopropylamine (34.1 mmol) were added within 5 min and the yellow/orange solution stirred for additional 15 min. A solution of 5.00 g of 4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-carbaldehyde (13.66 mmol) in 70 ml of dichloromethane was added dropwise within 20 min and the the reaction mixture was stirred for additional 60 min. The reaction solution was allowed to warm up to r.t. and stirred the same temperature for 90 min, cooled to 0° C. and treated with 50 ml of ice water. The organic layer was separated, washed with 25 ml water, dried over sodium sulfate and evaporated to dryness to yield 8.15 g of crude 3-Hydroxy-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid methyl ester ((syn/anti=6:4) as an orange oil. After this intermediate was dissolved at r.t. in 50 ml of DMF, 1.20 ml of conc. sulfuric acid (10.5 mmol) were added and the resulting dark brown solution was stirred at 100° C. for 17 h. The reaction solution was cooled to r.t., whereas the product crystallized. 50 ml of ethanol were added and the suspension stirred for 1 h at 0° C. The white crystals were filtered off, washed with 75 ml of cold (−15° C.) methanol in two portions and dried to constant weight (20° C./5 mbar/16 h) to afford 3.82 g (61%) of the title compound with a purity of 98.6% (GC area).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:18]3[CH:19]=[N:20][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:22]=3)[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:4]=2[CH:3]=1.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[NH2:38]>>[C:26]([O:25][C:23]([N:21]1[CH:22]=[C:18]([C:9]2[N:10]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[C:4]3[CH:3]=[C:2]([NH:38][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[O:31][CH3:30])[N:7]=[CH:6][C:5]=3[CH:8]=2)[CH:19]=[N:20]1)=[O:24])([CH3:28])([CH3:27])[CH3:29]
Reactant: COc1ccccc1N
Reactant: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Br)cc3n2C(=O)OC(C)(C)C)cn1
Product: COc1ccccc1Nc1cc2c(cn1)cc(-c1cnn(C(=O)OC(C)(C)C)c1)n2C(=O)OC(C)(C)C
Yield: 48 %

Procedure:
The title compound was prepared in 48% yield from compound 10 and 2-methoxyphenyl amine using the method described for Preparation 35. 1H-NMR (CDCl3, 500 MHz): δ 1.53 (s, 9H), 1.69 (s, 9H), 3.92 (s, 3H), 6.58 (d, J=0.95 Hz, 1H), 6.91-6.99 (m, 3H), 7.08 (br s, 1H), 7.66 (m, 1H), 7.83 (d, J=0.95 Hz, 1H), 7.92-7.95 (m, 1H), 8.33 (d, J=0.63 Hz, 1H), 8.49 (d, J=0.95 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:22][C:23]([F:26])([F:25])[F:24])(=O)=O.O>CN(C=O)C>[CH3:1][C:2]1[C:7]([O:8][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: Cc1ccc(O)c(C)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(OCC(F)(F)F)c(C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
To a suspension of 2,6-dimethylpyridin-3-ol (5.0 g, 41 mmol) and cesium carbonate (15 g, 47 mmol) in DMF (50 mL) was added 2,2,2-trifluoroethyl trifluoromethane-sulfonate (11 mL, 47 mmol) dropwise. The reaction mixture was stirred at room temperature for 1 hour. After being stirred at room temperature for 18 hours, the mixture was poured into H2O, and the aqueous phase was extracted with ethyl acetate (twice). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to give 8.3 g (quantitative yield) of the title compound as a brown oil:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:13](=O)[C:14]([O:16]C)=O)=[CH:8][N:9]2[CH3:12])=[CH:5][CH:4]=1.[CH3:19][N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[CH:27]=2)[C:22]([CH2:34][C:35]([NH2:37])=[O:36])=[CH:21]1>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:13]3[C:14](=[O:16])[NH:37][C:35](=[O:36])[C:34]=3[C:22]3[C:23]4[C:28](=[CH:27][C:26]([N:29]5[CH2:30][CH2:31][CH2:32][CH2:33]5)=[CH:25][CH:24]=4)[N:20]([CH3:19])[CH:21]=3)=[CH:8][N:9]2[CH3:12])=[CH:5][CH:4]=1
Reactant: COC(=O)C(=O)c1cn(C)c2cc(OC)ccc12
Reactant: Cn1cc(CC(N)=O)c2ccc(N3CCCC3)cc21
Product: COc1ccc2c(C3=C(c4cn(C)c5cc(N6CCCC6)ccc45)C(=O)NC3=O)cn(C)c2c1
Yield: 57.6 %

Procedure:
3-(6-Methoxy-1-methyl-1H-indol-3-yl)-4-(1-methyl-6-pyrrolidin-1-yl-1H-indol-3-yl)pyrrole-2,5-dione (55 mg, 58%) was prepared from methyl (6-methoxy-1methyl -1H-indol-3-yl)-glyoxylate (57mg, 0.23 mmol) and (1-methyl-6-pyrrolidin-1-yl-1H-indol-3-yl)-acetamide (54 mg, 0.21 mmol).
Reaction SMILES: [CH:1]1([C:4]2[C:24]([C:25]([O:27]C)=[O:26])=[C:7]3[CH:8]=[C:9]([CH3:23])[CH:10]=[C:11]([O:12][CH2:13][C:14]4[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=4[F:22])[N:6]3[N:5]=2)[CH2:3][CH2:2]1.[OH-].[Na+].Cl>O1CCOCC1.CS(C)=O>[CH:1]1([C:4]2[C:24]([C:25]([OH:27])=[O:26])=[C:7]3[CH:8]=[C:9]([CH3:23])[CH:10]=[C:11]([O:12][CH2:13][C:14]4[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=4[F:22])[N:6]3[N:5]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1c(C2CC2)nn2c(OCc3c(F)ccc(F)c3F)cc(C)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: Cc1cc(OCc2c(F)ccc(F)c2F)n2nc(C3CC3)c(C(=O)O)c2c1
Temperature: 100 °C
Reaction time: 6.5 h
Yield: 78.9 %

Procedure:
A solution of 462 mg (1.01 mmol; purity 85%) of methyl 2-cyclopropyl-5-methyl-7-[(2,3,6-trifluorobenzyl)oxy]pyrazolo[1,5-a]pyridine-3-carboxylate from Example 156A in 10.5 ml of dioxane and 3 ml of DMSO was admixed with 5.55 ml (11.10 mmol) of 2 N sodium hydroxide solution, and the mixture was stirred at 100° C. for 6.5 h. Another 1 ml (2 mmol) of 2 N sodium hydroxide solution was added and the mixture was stirred at 100° C. for a further 2.5 h. The reaction solution was cooled down to 0° C. and adjusted to pH 2 with 1 N hydrochloric acid. The solids that precipitated out were stirred for 30 min, filtered off and dried under high vacuum. 300 mg of the title compound were obtained (74% of theory, 93% purity) and were converted without further purification.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([CH3:11])[C:8]2[N:7]([CH3:12])[C:6]3[CH2:13][CH:14]4[NH:18][CH:17]([C:5]=3[C:4]=2[C:3]=1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][CH2:15]4.[C:26]1([S:32]([O-:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[Na+].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>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[C:26]1([S:32]([C:2]2[CH:10]=[C:9]([CH3:11])[C:8]3[N:7]([CH3:12])[C:6]4[CH2:13][CH:14]5[NH:18][CH:17]([C:5]=4[C:4]=3[C:3]=2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][CH2:15]5)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1cc(Br)c(C(=O)OC(C)(C)C)c2c3c(n(C)c12)CC1CCC3N1
Reactant: O=S([O-])c1ccccc1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1cc(S(=O)(=O)c2ccccc2)c(C(=O)OC(C)(C)C)c2c3c(n(C)c12)CC1CCC3N1
Temperature: 25 °C
Yield: 41.4 %

Procedure:
A mixture of the product of step C (230 mg, 0.57 mmol), sodium benzenesulfinate (112 mg, 0.68 mmol), di-palladium-tris(dibenzylideneacetone) (52 mg, 0.057 mmol), cesium carbonate (277 mg, 0.85 mmol), xantphos (66 mg, 0.11 mmol) and tetrabutyl ammonium chloride (189 mg, 0.68 mmol) was taken up in toluene (3.2 mL). The reaction flask was purged with nitrogen and heated at reflux for 4 h under a nitrogen atmosphere. After cooling to ambient temperature the reaction mixture was filtered through a celite pad and the resulting filtrate concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 7.5:2.5 hexanes/ethyl acetate) to give tert-butyl 2-phenylsulfonyl-4,5-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (110 mg, 41%) as an off-white solid: 1H NMR (CDCl3, 300 MHz): δ 8.02 (br s, 1H), 7.93-7.96 (m, 2H), 7.40-7.52 (m, 3H), 7.34 (br s, 1H), 5.13-5.33 (m, 1H), 4.53-4.80 (m, 1H), 3.83 (s, 3H), 3.14-3.47 (m, 1H), 2.74 (s, 3H), 2.45 (d, J=15.9 Hz, 1H), 2.10-2.38 (m, 2H), 1.86-1.98 (m, 1H), 1.58-1.67 (m, 1H), 1.37 (br s, 9H).
Reaction SMILES: Cl[C:2]([S:4]Cl)=[O:3].[NH2:6]/[C:7](/[CH3:14])=[CH:8]\[C:9]([O:11][CH2:12][CH3:13])=[O:10]>C1(C)C=CC=CC=1>[CH3:14][C:7]1[NH:6][C:2](=[O:3])[S:4][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: O=C(Cl)SCl
Reactant: CCOC(=O)/C=C(/C)N
Solvent: Cc1ccccc1
Product: CCOC(=O)c1sc(=O)[nH]c1C
Yield: 62.4 %

Procedure:
25 g of chlorocarbonylsulphenyl chloride was added dropwise to 25 g of ethyl 3-aminocrotonate in 300 ml of toluene while being cooled with ice. The solution was heat-refluxed for 2 hours, and then cooled. The crystals precipitated were collected through filtration, and then washed twice with toluene to obtain 22.3 g of 4-methyl-5-ethoxycarbonyl-2-thiazolone as purple crystals.
Reaction SMILES: [OH:1][CH:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][N:4]1[C:8]2[N:9]=[CH:10][NH:11][C:12](=O)[C:7]=2[CH:6]=[N:5]1.C1C(=O)N([Br:27])C(=O)C1.CN(C)P(N(C)C)N(C)C.[Li+].[Br-]>C(#N)C>[Br:27][C:12]1[N:11]=[CH:10][N:9]=[C:8]2[N:4]([CH2:3][CH:2]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[OH:1])[N:5]=[CH:6][C:7]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1[nH]cnc2c1cnn2CC(O)c1ccccc1
Agent: CN(C)P(N(C)C)N(C)C
Agent: [Br-]
Agent: [Li+]
Solvent: CC#N
Product: OC(Cn1ncc2c(Br)ncnc21)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.9 %

Procedure:
To a cold (−20° C.) suspension of 10 (2.56 g, 10 mmol) and NBS (7.12 g, 40 mmol) in dry acetonitrile (20 mL), hexamethylphosphorous triamide (HT) (6.53 g, 40 mmol) was added dropwise. After addition, the cold bath was removed and the reaction mixture stirred at room temperature for 0.5 h. LiBr (3.44 g, 40 mmol) was added and the mixture was heated at 70° C. for 5 h. The mixture was evaporated under reduced pressure. The dark oil was purified by column chromatography (Silica Gel, 100 Mesh) using CHCl3 as the eluant, to afford the pure product 11 (1.40 g, 44%) as a white solid: mp 146-147° C. 1H NMR: δ 3.46-3.53 (br s, 1H, OH, disappears with D2O), 4.57-4.79 (m, 2H, CH2N), 5.18-5.29 (m, 1H, CHO), 7.30-7.52 (m, 5H Ar), 8.01 (s, 1H, H-3), 8.48 (s, 1H, H-6). IR cm−1: 3240-2500 (OH). Anal. (C13H11N4OBr) C, H, N.
Reaction SMILES: OC(C1C=CC=CC=1)C(NC(CC)CCC[C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=O.[CH2:24]([C@H:26]([NH2:36])[CH2:27][CH2:28][CH2:29]C1C=NC=CC=1)[CH3:25].CO>Cl>[CH2:24]([C@H:26]([NH2:36])[CH2:27][CH2:28][CH2:29][C:11]1[CH:10]=[CH:15][CH:14]=[CH:13][N:12]=1)[CH3:25]
Reactant: CCC(CCCc1cccnc1)NC(=O)C(O)c1ccccc1
Reactant: CC[C@H](N)CCCc1cccnc1
Agent: Cl
Solvent: CO
Product: CC[C@H](N)CCCc1ccccn1

Procedure:
As in Example 16, a solution of 31.2 g of [S-(R*,R*)]-alpha-hydroxy-N-[1-ethyl-4-(3-pyridinyl)butyl]benzeneacetamide in 175 ml of 6N HCl was treated with 16 mL of conc. HCl and then was heated at reflux for 42 hours. The normal work up furnished 16.4 g of (S)-alpha-ethyl-3-pyridinebutanamine, (bp 95°-98° C./0.1 mm); [α]D25 +11.75° (c, 1.0, MeOH).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.[S:14](N)([NH2:17])(=[O:16])=[O:15]>O1CCOCC1>[NH2:17][S:14]([N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]1)(=[O:16])=[O:15]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(S(N)(=O)=O)C1
Temperature: 110 °C

Procedure:
To a solution of tert-butyl (3R)-pyrrolidin-3-ylcarbamate (1.3 g) in dioxane (50 ml) was added sulfamide (1.55 g) and the reaction was heated at 110° C. for 18 h. The reaction mixture was then partitioned between DCM (100 ml) and H2O (100 ml). The organics were separated and the aqueous layer was re-extracted with DCM (2×100 ml). Organics were combined, dried (MgSO4) and reduced in vacuo to give the subtitle compound as a pale yellow solid. Yield: 1.69 g