Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[CH:7]1(Br)[CH2:9][CH2:8]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:9][CH2:8]2)[CH:6]=1
Reactant: BrC1CC1
Reactant: Brc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Brc1cnn(C2CC2)c1
Temperature: 160 °C

Procedure:
4-Bromo-1H-pyrazole (1.76 g, 12 mmol) is dissolved in anhydrous dimethylformamide (15 mL). Cyclopropyl bromide (2.9 mL, 36 mmol) and caesium carbonate (7.8 g, 24 mmol) are successively added thereto. The reaction mixture is heated for 15 hours at 160° C. in a sealed flask. At the end of the reaction, the solvent is evaporated off in vacuo and the residue is purified by chromatography over silica gel using heptane and dichloromethane as eluants to yield the expected compound.
Reaction SMILES: [C:1]([S:11]C1C=CC(Cl)=CC=1)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl-:19].[Al+3].[Cl-].[Cl-]>>[Cl:19][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[O:10][C:1](=[S:11])[CH:2]=[CH:3]2
Reactant: O=C(C=Cc1ccccc1)Sc1ccc(Cl)cc1
Reactant: [Cl-]
Agent: [Al+3]
Product: S=c1ccc2cc(Cl)ccc2o1
Temperature: 125 °C
Yield: 14.4 %

Procedure:
A powdered mixture of S-(4-chlorophenyl) thiocinnamate (19.4 g) and aluminum chloride (52 g) was stirred and heated at 125° C. for 3 hours. The hot reaction mixture was poured carefully over ice/water, then was extracted with ethyl acetate (3×300 mL), washed with brine (200 mL), dried (MgSO4) and was concentrated. The residue was triturated with hexane/ethyl acetate to afford 2.0 g (14%) of the desired product as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.CC(=CC)C.Cl([O-])=[O:19].[Na+].O.P([O-])(O)(O)=O.[Na+]>O.C(OCC)(=O)C.O1CCOCC1>[Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([OH:19])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1c(Cl)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 47.2 %

Procedure:
A mechanically stirred suspension of 15 g (83.5 mmol) of 2-chloroindole-3-carboxaldehyde [XXVI: R1 =R3 =H, X=Cl] (Schule, et al., Arch. Pharm. [Weinheim] 1972;305:523-533), 84 mL of 2-methyl-2-butene, and 200 mL of p-dioxane in an ice bath was treated with a solution of 40 g each of sodium chlorite and sodium dihydrogen phosphate monohydrate in 200 mL of water. The biphasic mixture was then stirred vigorously at 25° C. for 3.5 hours. An additional 16 g each of solid sodium chlorite and sodium dihydrogen phosphate monohydrate was added and the mixture was stirred for another 3.5 hours. The mixture was diluted with 350 mL of ethyl acetate and 200 mL of water. The layers were separated and the aqueous phase was extracted with 300 mL of ethyl acetate. The combined organic extracts were extracted with cold 2% aqueous NaOH (3×200 mL). The basic extracts were combined and acidified to pH 4 with 6N aqueous HCl. The precipitated solids were collected by filtration, washed well with water, and air dried overnight. The solids were dissolved in 150 mL of hot acetone and the solution was treated with 65 mL of hexane. After storage at 3° C. for 20 hours, the solids were collected by filtration, washed with cold acetone, and dried to leave 7.71 g of pure 2-chloroindole-3-carboxylic acid [XXVII: R1 =R3 =H, X=Cl] as an off-white solid; mp 181.5° C. (dec). Further processing of the filtrate as above afforded 2.41 g of a second crop; mp 179.5° C. (dec). Total yield 10.12 g (62%).
Reaction SMILES: [Cl-].[CH3:2][C:3]1[N:8]2[N:9]=[C:10]([CH2:12][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:11]=[C:7]2[C:6]([CH3:32])=[N:5][CH:4]=1.[CH:33]1([N:36]([CH3:45])[C:37]2[N:41]=[C:40]([CH:42]=O)[N:39]([CH3:44])[N:38]=2)[CH2:35][CH2:34]1>>[CH:33]1([N:36]([C:37]2[N:41]=[C:40]([CH:42]=[CH:12][C:10]3[N:11]=[C:7]4[C:6]([CH3:32])=[N:5][CH:4]=[C:3]([CH3:2])[N:8]4[N:9]=3)[N:39]([CH3:44])[N:38]=2)[CH3:45])[CH2:34][CH2:35]1
Reactant: Cc1ncc(C)n2nc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc12
Reactant: CN(c1nc(C=O)n(C)n1)C1CC1
Agent: [Cl-]
Product: Cc1ncc(C)n2nc(C=Cc3nc(N(C)C4CC4)nn3C)nc12
Yield: 33.4 %

Procedure:
Was prepared in the same manner as described in General Procedure Example 1g) using ((5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methyl)triphenylphosphonium chloride (127 mg, 277 μmol, Eq: 1.00) and 3-(cyclopropyl(methyl)amino)-1-methyl-1H-1,2,4-triazole-5-carbaldehyde (50 mg, 277 μmol, Eq: 1.00) as starting materials. Chromatography afforded Cyclopropyl-{5-[2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-vinyl]-1-methyl-1H-[1,2,4]triazol-3-yl}-methyl-amine (30 mg, 33.3%) as light yellow waxy solid. MS: m/z=325.5 (M+H+)
Reaction SMILES: Cl[CH2:2][C:3](=[O:33])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([C:19](=[O:23])[CH2:20]2)[C@:16]2([CH3:17])[C@H:11]([CH2:12][C@H:13]([OH:32])[C@@H:14]([N:24]4[CH2:29][CH2:28][O:27][C:26]([CH3:31])([CH3:30])[CH2:25]4)[CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.CS(O)(=O)=O.[S-:39][C:40]#[N:41].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[OH:32][C@@H:13]1[C@@H:14]([N:24]2[CH2:29][CH2:28][O:27][C:26]([CH3:31])([CH3:30])[CH2:25]2)[CH2:15][C@@:16]2([CH3:17])[C@@H:11]([CH2:10][CH2:9][C@@H:8]3[C@@H:18]2[C:19](=[O:23])[CH2:20][C@@:21]2([CH3:22])[C@H:7]3[CH2:6][CH2:5][C@@H:4]2[C:3](=[O:33])[CH2:2][S:39][C:40]#[N:41])[CH2:12]1
Reactant: CC1(C)CN([C@H]2C[C@@]3(C)[C@@H](CC[C@H]4[C@@H]5CC[C@H](C(=O)CCl)[C@@]5(C)CC(=O)[C@@H]43)C[C@@H]2O)CCO1
Reactant: N#C[S-]
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC1(C)CN([C@H]2C[C@@]3(C)[C@@H](CC[C@H]4[C@@H]5CC[C@H](C(=O)CSC#N)[C@@]5(C)CC(=O)[C@@H]43)C[C@@H]2O)CCO1
Temperature: 25 °C
Reaction time: 24 h
Yield: 17.6 %

Procedure:
To (2β,3α,5α)-21-chloro-3-hydroxy-2-(2,2-dimethyl-4-morpholinyl)pregnane-11,20-dione (3.1 g) was added a solution of methanesulfonic acid (615 mg) in methanol (63 ml) and then a solution of potassium thiocyanate (12.4 g) in water (32 ml). The resulting solution was stirred at room temperature for 24 h, poured into water and sodium carbonate was then added until the pH exceeded 9. The precipitated solid was filtered off, washed with water and dissolved in dichloromethane. This solution was dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel and the purified product was crystallised from diethyl ether and then from methanol to give (2β,3α,5α)-3-hydroxy-2-(2,2-dimethyl-4-morpholinyl)-21-thiocyanatopregnane-11,20-dione (572 mg). m.p. 197°-198° C.; [α]D +99.3° (c 0.8).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH:23][C:24](=[O:40])[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]2[CH:38]=[C:37]([CH3:39])[N:36]=[CH:35]2)[CH:29]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]#[C:14][C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([N:34]5[CH:38]=[C:37]([CH3:39])[N:36]=[CH:35]5)[CH:29]=4)[CH2:25][C:24](=[O:40])[NH:23][C:9]=3[CH:10]=2)=[CH:21][CH:20]=1
Reactant: Cc1cn(-c2cccc(C(=O)CC(=O)Nc3cc(C#Cc4ccc(F)cc4)ccc3NC(=O)OC(C)(C)C)c2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cn(-c2cccc(C3=Nc4ccc(C#Cc5ccc(F)cc5)cc4NC(=O)C3)c2)cn1

Procedure:
Prepared from (4-(4-fluoro-phenylethynyl)-2-{3-[3-(4-methyl-imidazol-1-yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert.-butyl ester (Example K49) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (122 mg).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([F:19])[CH:13]=1)O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:20]1(=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](=[O:29])[NH:21]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1(C)C=CC=CC=1.C1COCC1>[Si:1]([O:8][CH2:9][C@@H:10]([N:21]1[C:22](=[O:29])[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20]1=[O:30])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([F:19])[CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](O)c1ccc(Cl)c(F)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC[C@H](c1ccc(Cl)c(F)c1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 74.7 %

Procedure:
To a solution of 64 (13.50 g, 44.28 mmol) and THF (150 mL) cooled to 0° C. was added isoindoline-1,3-dione (7.167 g, 48.71 mmol) and PPh3 (17.42 g, 66.42 mmol) followed by the dropwise addition of a 40% solution DEAD (26.15 mL, 66.42 mmol) in toluene. The reaction was warmed to RT and stirred for 20 h. The reaction was concentrated and dissolved in Et2O (might require sonication). The solids were filtered and the filtrate was concentrated. The crude residue was purified by SiO2 chromatography (Biotage 65) eluting with 10% EtOAc/hexane to afford 14.35 g of (74.67%) (S)-2-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)isoindoline-1,3-dione (66).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]([N:11]2[C:19]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[CH:13]=[CH:12]2)=[O:10])=[C:4]([Cl:20])[CH:3]=1.[C:21]([O:25][CH2:26][CH3:27])(=[O:24])[CH:22]=[CH2:23].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:20][C:4]1[CH:3]=[C:2](/[CH:23]=[CH:22]/[C:21]([O:25][CH2:26][CH3:27])=[O:24])[CH:7]=[C:6]([Cl:8])[C:5]=1[C:9]([N:11]1[C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[CH:13]=[CH:12]1)=[O:10]
Reactant: O=C(c1c(Cl)cc(Br)cc1Cl)n1ccc2cnccc21
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1cc(Cl)c(C(=O)n2ccc3cnccc32)c(Cl)c1
Temperature: 25 °C
Yield: 61.7 %

Procedure:
A solution of (4-bromo-2,6-dichlorophenyl)(1H-pyrrolo[3,2-c]pyridin-1-yl)methanone (100 mg, 0.27 mmol) and ethyl acrylate (3.06 mL, 30.58 mmol) in dimethylformamide (3 mL) was stirred at room temperature. Triethylamine (0.15 mL, 1.08 mmol) was added followed by triphenylphosphine (42.6 mg, 0.16 mmol) and palladium acetate (18.16 mg, 0.008 mmol). The reaction mixture was purged with argon and heated under reflux for about 20 hours. The reaction mixture was cooled to room temperature and the residue was poured into water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered and the solvent was removed under rotary evaporator. Ethyl(2E)-3-[3,5-dichloro-4-(1H-pyrrolo[3,2-c]pyridin-1-ylcarbonyl)phenyl]prop-2-enoate (64.8 mg, 61.59%) was isolated by silica gel column chromatography using ethyl acetate in hexane (15-17%) as eluant.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[NH:14][N:15]=[CH:16][C:11]3=[C:10]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)[C:9]=2[C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.Br[CH2:29][CH2:30][CH2:31][O:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:22]3[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=3)=[C:10]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)[C:11]3[C:12](=[N:14][N:15]([CH2:29][CH2:30][CH2:31][O:32][CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][O:34]4)[CH:16]=3)[N:13]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2nc3[nH]ncc3c(-c3ccco3)c2-c2ccncc2)cc1
Reactant: BrCCCOC1CCCCO1
Product: Fc1ccc(-c2nc3nn(CCCOC4CCCCO4)cc3c(-c3ccco3)c2-c2ccncc2)cc1

Procedure:
Following a similar procedure to that described in examples 6 and 7, but starting from 6-(4-fluorophenyl)-4-(2-furyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine (obtained in example 171) and 2-(3-bromopropoxy)tetrahydropyran, the desired compound was obtained.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[C:9]([O:12][CH3:13])(=[O:11])[CH3:10].[Br:14][C:15]1[CH:16]=[C:17]([C:21](=[N:23][S@@:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])[CH3:22])[CH:18]=[CH:19][CH:20]=1.[NH4+].[Cl-]>C1COCC1.O>[Br:14][C:15]1[CH:16]=[C:17]([C@:21]([NH:23][S@@:24]([C:26]([CH3:27])([CH3:29])[CH3:28])=[O:25])([CH3:22])[CH2:10][C:9]([O:12][CH3:13])=[O:11])[CH:18]=[CH:19][CH:20]=1
Reactant: COC(C)=O
Reactant: CC(=N[S@](=O)C(C)(C)C)c1cccc(Br)c1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C[C@](C)(N[S@](=O)C(C)(C)C)c1cccc(Br)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Add LDA (2M in heptane/THF, 3.4 mL, 6.9 mmol) to a solution of methyl acetate (0.6 mL, 6.9 mmol) in THF (5 mL) dropwise via a syringe at −78° C. After stirring at −78° C. for 30 min, add a solution of CITi(Oi-Pr)3 (1.8 mL, 7.6 mmol) in THF (5 mL) dropwise. After stirring for another 30 min, add (R)—N-(1-(3-bromophenyl)ethylidene)-2-methylpropane-2-sulfinamide (1.03 g, 3.4 mmol) in THF (2 mL) dropwise via a syringe. After 3 h add a saturated aqueous solution of NH4Cl (10 eq) and allow the mixture to warm to room temperature. Dilute the mixture with H2O (50 mL) and stir for 10 min, then partition the mixture between H2O (50 mL) and EtOAc (50 mL). Collect the organic layer and extract the aqueous layer with EtOAc (3×50 mL). Wash the combined organic extracts with brine, then dry (MgSO4), filter and concentrate to give a crude product. Chromatograph the crude product on a silica gel column and elute with EtOAc/hexanes to afford (S)-methyl 3-(3-bromophenyl)-3-((R)-1,1-dimethylethylsulfinamido)butanoate.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[C@@H:19]3[C@@H:14]([C:15]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24]C)[C:16]=4[CH2:17][CH2:18]3)[CH2:13][CH2:12]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>Br>[CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[C@@H:19]3[C@@H:14]([C:15]4[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[C:16]=4[CH2:17][CH2:18]3)[CH2:13][CH2:12]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cccc2c1CC[C@H]1[C@@H]2CCN1CCCCC1CCCCC1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Product: Oc1cccc2c1CC[C@H]1[C@@H]2CCN1CCCCC1CCCCC1
Temperature: 0 °C
Yield: 89.9 %

Procedure:
5.0 g (0.0146 mol) of rac-cis-3-(4-cyclohexyl-butyl)-2,3,3a,4,5,9b-hexahydro-6-methoxy-1H-benzo[e]indole were dissolved in 0.17 l of 48% aqueous HBr and boiled under reflux for 5 hours. The mixture was poured on to ~200 g of ice and treated with 200 ml of 28% aqueous NaOH solution. The mixture was extracted three times with ethyl acetate, whereupon the organic phase was washed with saturated sodium chloride solution, dried with MgSO4, filtered and concentrated. By chromatography of the residue over silica gel with n-hexane/ethyl acetate 1:1 there were obtained 4.3 g (90%) of oily rac-cis-3-(4-cyclohexyl-butyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-6-ol.
Reaction SMILES: [C:1]([CH2:4][N:5]([C:10](=[O:44])[C:11]1[CH:16]=[C:15]([O:17]CC2C=CC=CC=2)[CH:14]=[C:13]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH:12]=1)[CH2:6][C:7]([OH:9])=[O:8])([OH:3])=[O:2].[H][H]>[Pd].C1COCC1>[C:7]([CH2:6][N:5]([C:10](=[O:44])[C:11]1[CH:12]=[C:13]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH:14]=[C:15]([OH:17])[CH:16]=1)[CH2:4][C:1]([OH:3])=[O:2])([OH:9])=[O:8]
Reactant: [H][H]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(OCc2ccccc2)cc(C(=O)N(CC(=O)O)CC(=O)O)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOc1cc(O)cc(C(=O)N(CC(=O)O)CC(=O)O)c1

Procedure:
A mixture of 0.30 g of N-(carboxymethyl)-N-[3-(octadecyloxy)-5-(phenylmethoxy)benzoyl]glycine and 0.1 g of 10% palladium on carbon in 25 ml of THF was stirred in a hydrogen atmosphere for 2 hours. The usual workup followed by recrystallization from ether-hexane gave N-(carboxymethyl)-N-[3-hydroxy-5-(octadecyloxy)benzoyl]glycine, mp 160°-164°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][C:12]([F:20])=[CH:13][C:14]=3F)[N:9]=2)[CH:5]=[C:4]([CH3:21])[N:3]=1.[CH3:22][O-:23].[Na+].CO.O>CN(C=O)C.C(O)(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][C:12]([F:20])=[CH:13][C:14]=3[O:23][CH3:22])[N:9]=2)[CH:5]=[C:4]([CH3:21])[N:3]=1
Reactant: C[O-]
Reactant: Cc1cc(-c2nc3cc(F)cc(F)c3c(=O)[nH]2)cc(C)n1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc(F)cc2nc(-c3cc(C)nc(C)c3)[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of 2-(2,6-dimethyl-pyridin-4-yl)-5,7-difluoro-3H-quinazolin-4-one (2.70 g, 9.4 mmol) in DMF (15 mL), a solution of sodium methoxide in methanol (25 wt %, 6.0 g, 28.2 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. Water was added, acidified to pH approximately 4-5 with acetic acid and the precipitated solid was filtered and dried under vacuum to give crude 2-(2,6-dimethyl-pyridin-4-yl)-7-fluoro-5-methoxy-3H-quinazolin-4-one (2.40 g), which was further purified by column chromatography (silica gel 230-400 mesh; eluting with 2% methanol solution in dichloromethane) to yield pure compound as a light yellow solid. Yield: 0.35 g (12.4%).
Reaction SMILES: [ClH:1].[I:2][C:3]1[CH:4]=[CH:5][C:6](N)=[N:7][C:8]=1[CH3:9].N([O-])=O.[Na+]>O>[Cl:1][C:6]1[N:7]=[C:8]([CH3:9])[C:3]([I:2])=[CH:4][CH:5]=1
Reactant: Cc1nc(N)ccc1I
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1nc(Cl)ccc1I
Temperature: 25 °C
Reaction time: 16 h
Yield: 30 %

Procedure:
To a stirred solution of concentrated hydrochloride acid (233 mL) at 0° C. was added 5-iodo-6-methyl-pyridin-2-ylamine (25 g, 107 mmol, 1 eq) followed by addition of pre-dissolved sodium nitrite (29.5 g, 427 mmol, 4 eq) in water (150 mL) in drop wise manner over period of 30 minutes. Resulting reaction mixture was stirred at room temperature for 16 hours. After complete consumption of starting material, reaction mixture was cooled to 0° C., and pH was adjusted to 12 by saturated aqueous sodium hydroxide solution, extracted with DCM (3×200 mL). Combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to get brown oil (20 g, crude). Crude was purified by column chromatography using silica gel (100-200 mesh). Desired compound was eluted at 4% ethyl acetate in hexane to get title compound as brown oil (8 g, 30%). 1H NMR (400 MHz, CDCl3) δ: 2.69 (s, 3H), 6.88 (d, J=8.04 Hz, 1H), 7.95 (d, J=8.24 Hz, 1H). LC-MS (m/z): 254.0 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>CN(C=O)C.CN(C)C1C=CN=CC=1>[CH3:15][S:16]([NH:1][C:2]1[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2)(=[O:18])=[O:17]
Reactant: COC(=O)c1cc(N)c2cc[nH]c2c1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(NS(C)(=O)=O)c2cc[nH]c2c1
Temperature: 60 °C
Yield: 50.5 %

Procedure:
To a mixture of methyl 4-amino-1H-indole-6-carboxylate (1.0 g) in DMF (10 mL) was added 4-dimethylaminopyridine (1.46 g) and methanesulfonyl chloride (0.6 g). The mixture was heated to 60° C. for 3 h, cooled to room temperature, and partitioned between water and ethyl acetate. The layers were separated and the organic layer washed three times with brine, dried over anhydrous sodium sulfate and concentrated to give 0.71 g of the title compound: 1H NMR (CDCl3) δ 3.02, 3.94, 6.69, 7.42, 7.81, 8.04.
Reaction SMILES: [N:1]1([C:5]2[CH:6]=[CH:7][C:8]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=[C:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:13]=3)=[N:9][CH:10]=2)[CH2:4][CH2:3][CH2:2]1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][C:32](=O)[O:33]C2C=CC=CC=2)[N:26]=1.C(N(CC)CC)C>CS(C)=O.O>[N:1]1([C:5]2[CH:6]=[CH:7][C:8]([O:11][C:12]3[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=3)[CH:18]=[C:19]3[CH2:20][CH2:21][N:22]([C:32]([NH:31][C:27]4[N:26]=[N:25][CH:30]=[CH:29][CH:28]=4)=[O:33])[CH2:23][CH2:24]3)=[N:9][CH:10]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(Nc1cccnn1)Oc1ccccc1
Reactant: C(=C1CCNCC1)c1cccc(Oc2ccc(N3CCC3)cn2)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: O=C(Nc1cccnn1)N1CCC(=Cc2cccc(Oc3ccc(N4CCC4)cn3)c2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 65 %

Procedure:
To a solution of 5-(azetidin-1-yl)-2-(3-(piperidin-4-ylidenemethyl)phenoxy)pyridine (0.045 g, 0.139 mmol) in DMSO (2 mL) was added phenyl pyridazin-3-ylcarbamate (0.03 g, 0.139 mmol) followed by triethylamine (0.048 mL, 0.352 mmol). The resulting mixture was stirred at RT for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (28% acetone/hexane) to give the title compound (0.04 g, 64.5% yield). 1H NMR (500 MHz, CDCl3): δ 8.76 (s, 1H), 8.52 (s, 1H), 7.52 (s, 1H), 7.47 (d, J=2 Hz, 1H), 7.27 (m, 2H), 6.93 (d, J=7.5 Hz, 1H), 6.90 (d, J=8.5 Hz, 1H), 6.86 (m, 2H), 6.80 (m, 1H), 6.39 (s, 1H), 3.88 (t, J=7 Hz, 4H), 3.72 (m, 2H), 3.61 (m, 2H), 2.60 (d, J=6 Hz, 2H), 2.47 (m, 2H), 2.38 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 156.44, 156.01, 155.45, 145.21, 138.58, 137.18, 130.97, 129.35, 125.16, 123.98, 123.06, 119.87, 117.73, 112.55, 53.11, 45.73, 44.73, 35.76, 29.70, 29.12, 17.53; m/z (443.2, MH+); HPLC: 95.0%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][C:10]([O:12]CC)=O)=[C:4]([OH:16])[CH:3]=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([C:8]([OH:15])=[CH:9][C:10](=[O:12])[O:16]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)c1ccc(Br)cc1O
Solvent: Cc1ccccc1
Product: O=c1cc(O)c2ccc(Br)cc2o1
Yield: 78.6 %

Procedure:
A solution of ethyl 3-(4-bromo-2-hydroxyphenyl)-3-oxopropanoate (Intermediate 30) (2.0 g) in dry toluene (20 ml) was stirred at reflux under nitrogen for 24 h. On cooling the resulting precipitate was collected by filtration, washed with ether and dried to give the title compound as a white solid (1.32 g).
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:11][S:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)(=[O:14])=[O:13])[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].O.[OH-].[Li+].CO.O>O1CCCC1>[N:29]1[CH:30]=[CH:31][CH:32]=[C:27]([C:24]2[CH:23]=[CH:22][C:21]([N:18]3[CH2:19][CH2:20][N:15]([S:12]([CH2:11][C:5]4([C:3]([OH:4])=[O:2])[CH2:6][CH2:7][O:8][CH2:9][CH2:10]4)(=[O:14])=[O:13])[CH2:16][CH2:17]3)=[CH:26][CH:25]=2)[CH:28]=1
Reactant: COC(=O)C1(CS(=O)(=O)N2CCN(c3ccc(-c4cccnc4)cc3)CC2)CCOCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1(CS(=O)(=O)N2CCN(c3ccc(-c4cccnc4)cc3)CC2)CCOCC1
Yield: 70.6 %

Procedure:
4-[4-(4-Pyridin-3-yl-phenyl)piperazine-1-sulfonylmethyl]-tetrahydropyran-4-carboxylic acid methyl ester (0.19 g) and lithium hydroxide monohydrate (0.087 g) were combined in tetrahydrofuran (10 ml), methanol (5 ml) and water (5 ml) and heated to reflux for 2 h. The solvents were then removed in vacuo and the residue diluted with 1 M sodium hydroxide (50 ml) and washed with ethyl acetate (3×20 ml). The aqueous phase was then acidified pH 5 and the suspension formed extracted with 10% methanol/dichloromethane (5×40 ml). The combined extracts were then washed with water (2×20 ml), saturated brine (20 ml), dried (Na2SO4) and reduced in vacuo to provide the title compound as a white solid (0.13 g, 72%).