Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:27])=[C:6]([C@@:8]2([CH3:26])[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=3[O:23][CH3:24])[C:12](=[O:25])[CH2:11]S[CH2:9]2)[CH:7]=1.O[O:29][S:30]([O-:32])=O.[K+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:27])=[C:6]([C@@:8]2([CH3:26])[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=3[O:23][CH3:24])[C:12](=[O:25])[CH2:11][S:30](=[O:32])(=[O:29])[CH2:9]2)[CH:7]=1
Reactant: COc1ccc(CN2C(=O)CSC[C@@]2(C)c2cc(Br)ccc2F)c(OC)c1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Product: COc1ccc(CN2C(=O)CS(=O)(=O)C[C@@]2(C)c2cc(Br)ccc2F)c(OC)c1
Temperature: 23 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
To a solution of (R)-5-(5-bromo-2-fluorophenyl)-4-(2,4-dimethoxybenzyl)-5-methylthiomorpholin-3-one (2.95 g, 6.49 mmol, Eq: 1.00) in methanol (100 ml) was added at 23° C. Oxone® (7.98 g, 13.0 mmol, Eq: 2.00). The reaction mixture was stirred at 23° C. for 16 hours. The reaction mixture was carefully quenched by addition of water at 0° C., then 10 ml of a diluted NaHSO3-solution, sat. NaHCO3-solution and ethyl acetate were added. Vigorous stirring was continued for 10 min. The organic layer was separated and washed with water, then dried over Na2SO4, filtered and evaporated to give a yellow oil which was chromatographed on 20 g silica gel with 0-50% ethyl acetate in heptane to give (R)-5-(5-bromo-2-fluoro-phenyl)-4-(2,4-dimethoxy-benzyl)-5-methyl-1,1-dioxo-1λ6-thiomorpholin-3-one (3 g, 6.17 mmol, 95.0% yield) as a white foam. MS (ISP): m/z=486.2 [M+H]+ and 488.1 [M+2+H]+.
Reaction SMILES: [CH2:1]([N:5]([CH2:37][CH2:38][CH2:39][CH3:40])[C:6]([C:8]1[CH:12]=[C:11]([CH3:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=2[C:23]([N:25]2[C@H:34]([CH2:35][OH:36])[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)=[O:24])[N:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[Si:41](Cl)([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42].N1C=CN=C1>C(Cl)Cl.O>[CH2:37]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([C:8]1[CH:12]=[C:11]([CH3:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=2[C:23]([N:25]2[C@H:34]([CH2:35][O:36][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)=[O:24])[N:9]=1)=[O:7])[CH2:38][CH2:39][CH3:40]
Reactant: CCCCN(CCCC)C(=O)c1cc(C)n(-c2ccc([N+](=O)[O-])cc2C(=O)N2Cc3ccccc3C[C@H]2CO)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CCCCN(CCCC)C(=O)c1cc(C)n(-c2ccc([N+](=O)[O-])cc2C(=O)N2Cc3ccccc3C[C@H]2CO[Si](C)(C)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 64.5 %

Procedure:
To a solution of (S)—N,N-dibutyl-1-(2-(3-(hydroxymethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-nitrophenyl)-5-methyl-1H-pyrazole-3-carboxamide (9.0 g, 16.4 mmol) in DCM (150 mL) were added TBDMS-chloride (2.98 g, 19.7 mmol), imidazole (2.23 g, 32.9 mmol) followed by stirring at RT for 12 h. The reaction mixture was diluted with water and extracted with EtOAc (300 mL×2), twice. The combined organic layers were washed with water (300 mL), brine (100 mL), dried over sodium sulphate and concentrated invacuo. The residue was purified on silica gel (100-200 mesh) to afford the title compound as a liquid 7 g (64%). Rf=0.74 (25% EtOAc in hexane); 1H NMR (400 MHz, DMSO-d6): δ 8.60-8.20 (m, 2H), 8.05-7.80 (m, 1H), 7.40-6.80 (m, 4H), 6.60-6.30 (m, 1H), 5.10-3.84 (m, 4H), 3.82-2.40 (m, 7H), 2.40-2.20 (m, 3H), 1.60-0.55 (m, 23H), 0.05-−0.40 (m, 6H); LC-MS: m/z 662.4 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[NH2:10])([O-:3])=[O:2].CC([O-])=O.[Na+].[Br:16]Br.C([O-])(O)=O.[Na+]>O.C(O)(=O)C>[Br:16][C:8]1[CH:7]=[N:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[C:9]=1[NH2:10]
Reactant: Nc1ccncc1[N+](=O)[O-]
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1c(Br)cncc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 76.5 %

Procedure:
A mixture of 3-nitropyridin-4-amine (LVII) (10 g, 71.94 mmol) and acetic acid (120 mL) was added to a sealed tube followed by addition of NaOAc (29.50 g, 93.52 mmol) and dropwise addition of bromine (4.7 ml 359.7 mmol) under stirring. The sealed tube was heated at 100° C. for 28 h until TLC showed consumption of starting material. The reaction mixture was concentrated to obtain a solid which was dissolved in water, basified with NaHCO3 and extracted with EtOAc. The combined organic extracts were dried and concentrated to produce 3-bromo-5-nitropyridin-4-amine (LVIII) as a yellow solid (12 g, 55 mmol, 77% yield). 1H NMR (DMSO-d6) δ ppm 9.19 (s, 1H), 8.58 (s, 1H); ESIMS found for C5H4BrN3O2 m/z 217, 219 (M+, M+2).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:7]2=[N:6][C:5]=1[CH3:17].CC(O)C.Cl.[H][H]>[Pd].CO>[ClH:1].[Cl:1][CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH2:11][CH:12]([O:15][CH3:16])[CH2:13][CH2:14][C:7]2=[N:6][C:5]=1[CH3:17]
Reactant: [H][H]
Reactant: COc1ccc2nc(C)c(CCCl)c(=O)n2c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: COC1CCc2nc(C)c(CCCl)c(=O)n2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
A mixture of 10 parts of 3-(2-chloroethyl)-7-methoxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, 40 parts of 2-propanol saturated with hydrogen chloride and 160 parts of methanol was hydrogenated at normal pressure and at room temperature with 2.0 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off over diatomaceous earth and the filtrate was evaporated. The oily residue was taken up in 80 parts of 2-propanol and 2,2′-oxybispropane. After stirring overnight at room temperature, the precipitated product was filtered off, washed with a mixture of 2-propanol and 2,2′-oxybispropane and dried in vacuo at 50° C., yielding 7.5 parts (64.0%) of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-7-methoxy-2-methyl4H-pyrido[1,2-a]pyrimidin-4-one monohydrochloride; mp. 170° C. (intermediate 4)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[Cl:21][CH2:22][C:23](=O)[CH2:24][OH:25]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:23]([CH2:24][OH:25])[CH2:22][Cl:21])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: NNC1=Nc2ccc(Br)cc2C(c2ccccc2)=NC1
Reactant: O=C(CO)CCl
Solvent: C1CCOC1
Product: OCC(CCl)=NNC1=Nc2ccc(Br)cc2C(c2ccccc2)=NC1

Procedure:
In the manner given in Example 1, 7-bromo-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine in tetrahydrofuran can be treated with 1-chloro-3-hydroxypropanone under nitrogen to give 7-bromo-2-[[2-chloro-1-(hydroxymethyl)ethylidene]hydrazino]-5-phenyl-3H-1,4-benzodiazepine.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[O:26][C:27]([C:34]([O:36][CH2:37][CH3:38])=[O:35])([CH2:31][CH2:32][CH3:33])[CH2:28][CH2:29][CH3:30])/[C:9]1=[O:39])=O)(C)(C)C.[F:40][C:41]1[CH:42]=[CH:43][C:44]([CH3:56])=[C:45]([CH:47]=[N:48][C:49]([O:51][Si](C)(C)C)=[CH2:50])[CH:46]=1>C1(C)C=CC=CC=1>[Cl:25][C:23]1[CH:22]=[CH:21][C:20]([O:26][C:27]([C:34]([O:36][CH2:37][CH3:38])=[O:35])([CH2:28][CH2:29][CH3:30])[CH2:31][CH2:32][CH3:33])=[C:19]([CH:18]2[CH2:51][C:49](=[O:50])[NH:48][CH:47]([C:45]3[CH:46]=[C:41]([F:40])[CH:42]=[CH:43][C:44]=3[CH3:56])[C:10]32[C:11]2[C:16](=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[NH:8][C:9]3=[O:39])[CH:24]=1
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Reactant: CCCC(CCC)(Oc1ccc(Cl)cc1/C=C1\C(=O)N(C(=O)OC(C)(C)C)c2cc(Cl)ccc21)C(=O)OCC
Solvent: Cc1ccccc1
Product: CCCC(CCC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)OCC
Yield: 9.9 %

Procedure:
In a manner similar to the method described in Example 10d, E/Z-6-chloro-3-[5-chloro-2-(1-ethoxycarbonyl-1-propyl-butoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (1.3 g, 2.3 mmol) was reacted with 1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (10 mmol) prepared in Example 1d in toluene to give the title compound as a white solid (150 mg).
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH2:19]Cl)[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=O)=O)C=CC=CC=1.[CH3:21][O-:22].[Na+]>CO.C(OCC)(=O)C>[CH3:21][O:22][CH2:19][C:17]1[CH:18]=[C:13]2[CH:12]=[CH:11][NH:10][C:14]2=[N:15][CH:16]=1
Reactant: C[O-]
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(CCl)cnc21
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COCc1cnc2[nH]ccc2c1
Reaction time: 12 h
Yield: 99.7 %

Procedure:
To a mixture of 1-benzenesulfonyl-5-chloromethyl-1H-pyrrolo[2,3-b]pyridine (3.3 g, 10.76 mmol) in methanol (15 mL) was added sodium methoxide (1.74 g, 32.3 mmol) at room temperature and the resulting mixture was stirred for 12 h. The mixture was diluted with ethyl acetate (250 mL), washed with brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 5-methoxymethyl-1H-pyrrolo[2,3-b]pyridine (1.74 g, quant.) as a light yellow solid which was used in the next step without further purification: LC/MS m/e calcd for C9H10N2O [M+H]+ 163.19, observed 162.9.
Reaction SMILES: Cl.C(OC([NH:9][C@H:10]([C:26]([NH:28][C:29]1[CH:59]=[CH:58][CH:57]=[C:56]([F:60])[C:30]=1[O:31][CH2:32][C@H:33]1[O:38][CH2:37][C@@H:36]([CH2:39][O:40][C:41]([NH:43][CH2:44][C:45]([F:48])([F:47])[F:46])=[O:42])[N:35](C(OC(C)(C)C)=O)[CH2:34]1)=[O:27])[CH:11]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=O)(C)(C)C>O1CCOCC1>[F:48][C:45]([F:46])([F:47])[CH2:44][NH:43][C:41](=[O:42])[O:40][CH2:39][C@@H:36]1[CH2:37][O:38][C@H:33]([CH2:32][O:31][C:30]2[C:56]([F:60])=[CH:57][CH:58]=[CH:59][C:29]=2[NH:28][C:26](=[O:27])[C@@H:10]([NH2:9])[CH:11]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH2:34][NH:35]1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)Nc1cccc(F)c1OC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](COC(=O)NCC(F)(F)F)CO1)C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H](C(=O)Nc1cccc(F)c1OC[C@@H]1CN[C@H](COC(=O)NCC(F)(F)F)CO1)C(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 8 h
Yield: 96.2 %

Procedure:
4M HCl (922 μl, 3.69 mmol) in dioxane was added to a solution of tert-butyl (2S,5S)-2-[(2-{[N-(tert-butoxycarbonyl)-4-fluoro-β-(4-fluorophenyl)-L-phenylalanyl]amino}-6-fluorophenoxy)methyl]-5-[({[(2,2,2-trifluoroethyl)amino]carbonyl}oxy)methyl]morpholine-4-carboxylate (310 mg, 0.369 mmol) in Dioxane (3.69 ml) at room temperature and the reaction stirred until complete by LC/MS (8 hrs). The solvent was removed in vacuo and ether was added to the residue. The desired product was filtered off to afford the title compound (253 mg, 0.355 mmol, 96% yield) as a white solid, MS (ESI): m/z=641.4 (M+H); 100% pure by LC/MS.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:11].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)[C:5]([I:11])=[N:6]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Fc1ccc2[nH]nc(I)c2c1
Reactant: BrCc1ccccc1
Product: Fc1ccc2c(c1)c(I)nn2Cc1ccccc1
Yield: 75 %

Procedure:
The title compound was prepared in 75% yield from 5-fluoro-3-iodo-indazole and benzyl bromide according to the general procedure for Preparation 10A. The minor isomer was not isolated or characterized. 1H NMR (400 MHz, CDCl3): δ 5.59 (2H, s), 7.11-7.21 (5H, m), 7.23-7.31 (3H, m).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][C:16]([OH:18])=O)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N+:38]([O-:40])=[O:39])[C:33]=1[OH:41]>ClCCl.O>[OH:41][C:33]1[C:34]([N+:38]([O-:40])=[O:39])=[CH:35][CH:36]=[CH:37][C:32]=1[NH:31][C:16](=[O:18])[CH2:15][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:8]=1
Reactant: COc1ccc(CC(=O)O)cc1OC1CCCC1
Reactant: Nc1cccc([N+](=O)[O-])c1O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CC(=O)Nc2cccc([N+](=O)[O-])c2O)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
A suspension of 3-cyclopentyloxy-4-methoxyphenylacetic acid (1.00 g) and 1,1'-carbonyldiimidazole (821 mg) in dichloromethane (5 ml) was stirred at room temperature, under argon, for 2 hours. The resulting solution was added to a stirred solution of 2-amino-6-nitrophenol (723 mg) in dichloromethane (10 ml) and the mixture stirred at room temperature, under argon, overnight. The reaction mixture was diluted with water (100 ml) and extracted with dichloromethane (3×50 ml). The combined organic extracts were washed with water (100 ml), 1N HCl (50 ml) and brine (50 ml), dried over CaSO4 and evaporated in-vacuo to yield the title compound (1.05 g, 68%) as an orange solid. δH (250 MHz;d6DMSO), 1.58-1.97 (8H,m,4 ×CH2), 3.73 (2H,s,CH2), 3.87 (3H,s,OMe), 4.79 (1H,m,CH), 6.78-6.93 (3H,m,ArH), 6.98 (1H,t,ArH), 7.78 (1H,dd,ArH), 7.95 (1H,bs,CONH), 8.71 (1H,dd,ArH), 10.5 (1H,bs,ArOH).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH:21]=O)=[CH:13]1.[OH-].[Na+].O>CO>[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](/[CH:21]=[C:6]2/[C:7](=[O:11])[C:8]3[C:4]([CH2:5]/2)=[CH:3][C:2]([OH:1])=[CH:10][CH:9]=3)=[CH:13]1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: O=C1CCc2cc(O)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C1/C(=C/c2c[nH]c3ccccc23)Cc2cc(O)ccc21
Temperature: 50 °C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
A solution of 5-hydroxy-2,3-dihydro-1H-inden-1-one (0.30 g, 2.0 mmol) and 1H-indole-3-carboxaldehyde (0.32 g, 2.2 mmol) in methanol (10 mL) was added with 50% sodium hydroxide (0.34 mL), and the mixture was stirred at 50° C. for 2 hours. The reaction mixture was cooled to room temperature, and then added with water, and the precipitated solid was collected by filtration, and washed with methanol to obtain (E)-2-[(1H-indol-3-yl)methylene]-5-hydroxy-2,3-dihydro-1H-inden-1-one (0.45 g, 83%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:14])([CH3:13])[C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1.[H-].[Na+].I[CH3:18]>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:14])([CH3:13])[C:8](=[O:12])[N:9]2[CH3:18])=[CH:5][CH:4]=1
Reactant: CI
Reactant: COc1ccc2c(c1)NC(=O)C2(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)N(C)C(=O)C2(C)C
Reaction time: 0.25 h

Procedure:
To a cooled solution (−5°−0° C.) of 6-methoxy-3,3-dimethyl-1,3-dihydro-indol-2-one (600 mg, 3.14 mmol, example 78) in THF (10.5 mL) is added 60% NaH (132 mg, 3.30 mmol) and is stirred for 15 min. Iodomethane (215 μL, 3.45 mmol) is added to the reaction mixture and stirred for 2 hrs. Quenched reaction with sat NH4Cl soln and diluted with EtOAc. Washed organic layer with sat NH4Cl soln, brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (silica, 30% ethyl acetate in hexanes) to give the title compound as a white crystalline solid. MS (ESI) 206 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](SC)=[N:7][CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1.[NH3:23]>C(OCC)(=O)C>[NH2:23][C:8]1[C:9]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:11][CH:10]=2)[CH:5]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[CH2:6][N:7]=1
Reactant: CSC1=NCC(c2ccc([N+](=O)[O-])cc2)c2cc(Cl)ccc21
Reactant: N
Solvent: CCOC(C)=O
Product: NC1=NCC(c2ccc([N+](=O)[O-])cc2)c2cc(Cl)ccc21
Reaction time: 15 h

Procedure:
A solution of 0.45 g of 6-chloro-1-methylthio-4-(4-nitrophenyl)-3,4-dihydroisoquinoline and 30 ml of ammonia-saturated THF solution was heated in an autoclave at 80° C. for 10 hours and then at 12° C. for a further 15 hours. Subsequent MPLC on an MPRC cartridge and a mixture of 20 parts by volume of ethyl acetate:10 parts by volume of n-heptane:3 parts by volume of glacial acetic acid leads to elution of starting material (6-chloro-1-methylthio-4-(4-nitrophenyl)-3,4-dihydroisoquinoline). Subsequent elution with methanol results in 1-amino-6-chloro-4-(4-nitrophenyl)-3,4-dihydroisoquinoline.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9]O)[CH:5]=[C:6]([F:8])[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:30]N1C(=O)CCC1=O>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([CH2:9][Br:30])[CH:3]=1
Reactant: OCc1cc(F)cc(Br)c1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1cc(Br)cc(CBr)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
(3-Bromo-5-fluorophenyl)methanol (0.78 g, 3.8 mmol) and triphenylphosphine (2.0 g, 7.6 mmol) were combined in tetrahydrofuran (20 mL) and cooled to 0° C. N-Bromosuccinimide (1.4 g, 7.98 mmol) was introduced in portions and the reaction allowed to warm to room temperature. After 16 h, the reaction mixture was diluted with ethyl acetate, washed with concentrated sodium bicarbonate (2×), then brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (5% ethyl acetate/hexanes) gave 0.8 g (79%) as a white powder. 1H-NMR (CDCl3, 300 MHz) 7.30 (s, 1H), 7.14-7.18 (m, 1H), 7.01-7.05 (m, 1H), 4.36 (s, 2H).
Reaction SMILES: [CH2:1]([S:13]([N:16]1[CH2:21][CH2:20][CH2:19][S:18][C:17]1=[CH:22][N+:23]([O-:25])=[O:24])(=[O:15])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Cl:26]N1C(=O)CCC1=O>>[CH2:1]([S:13]([N:16]1[CH2:21][CH2:20][CH2:19][S:18][C:17]1=[C:22]([Cl:26])[N+:23]([O-:25])=[O:24])(=[O:14])=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCCCCCCCCCCS(=O)(=O)N1CCCSC1=C[N+](=O)[O-]
Product: CCCCCCCCCCCCS(=O)(=O)N1CCCSC1=C(Cl)[N+](=O)[O-]

Procedure:
was prepared, as a yellow solid, m.p.: 76°-77° C., by treating (3A) with N-chlorosuccinimide according to the procedure described in Example 2.
Reaction SMILES: C([Mg]Cl)(C)C.[Cl:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([O:15][C:16]2[C:21]([Br:22])=[CH:20][CH:19]=[C:18](Br)[C:17]=2[F:24])[CH:14]=1)[C:10]#[N:11].CN([CH:28]=[O:29])C>C1COCC1.C1(C)C=CC=CC=1>[Br:22][C:21]1[C:16]([O:15][C:13]2[CH:12]=[C:9]([CH:8]=[C:7]([Cl:6])[CH:14]=2)[C:10]#[N:11])=[C:17]([F:24])[C:18]([CH:28]=[O:29])=[CH:19][CH:20]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(Br)c2F)c1
Reactant: CN(C)C=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(C=O)c2F)c1
Reaction time: 1.5 h
Yield: 98 %

Procedure:
A solution of i-PrMgCl (17.3 mL of a 2 M solution in THF, 1.75 equiv) was added slowly to a solution of the 103 (8.0 g, 19.7 mmol) in toluene (160 mL) at −78 C. The solution was aged for 1.5 h then transferred by cannula to a flask containing DMF (2.3 mL, 1.5 equiv) in toluene (30 mL). The solution was quenched with aqueous NH4Cl, and diluted with EtOAc. The organic layer was separated, washed with brine, dried, and evaporated. The crude product was purified by SiO2 by chromatography eluting with 20% EtOAc/hexanes to afford 6.5 g (98%) of 3-(6-bromo-2-fluoro-3-formyl-phenoxy)-5-chloro-benzonitrile (105) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:13])[C:5]2[N:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:6]=2[N:7]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[C:14]([NH:1][C:2]1[NH:3][C:4](=[O:13])[C:5]2[N:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:6]=2[N:7]=1)(=[O:16])[CH3:15]
Reactant: Nc1nc2ccc(Cl)nc2c(=O)[nH]1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1nc2ccc(Cl)nc2c(=O)[nH]1
Yield: 80 %

Procedure:
A suspension of 2-amino-6-chloro-pyrido[3,2-d]pyrimidin-4(3H)-one (1.96 g, 10 mmol) in acetic anhydride (200 ml) was refluxed for 2 hours till a clear solution was obtained. The solvents were evaporated in vacuo till crystallization started. The precipitate was filtered off and dried under vacuum yielding the pure title compound (2 g, 80%) which was characterised as follows:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15](C([O-])=O)[C:16]([O-:18])=[O:17])=[C:11]([N+:22]([O-:24])=[O:23])[CH:10]=2)=[CH:5][CH:4]=1>Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[C:11]([N+:22]([O-:24])=[O:23])[CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccc(C(C(=O)[O-])C(=O)[O-])c([N+](=O)[O-])c2)cc1
Agent: Cl
Product: COc1ccc(-c2ccc(CC(=O)O)c([N+](=O)[O-])c2)cc1

Procedure:
Crude 4′-methoxy-3-nitro-biphenyl-4-malonate was heated at 100° C. in 60 mL of 6N hydrochloric acid for 15 hours and cooled. The precipitate was collected by filtration, washed with water and hexane, and dried to give 7.2 g of crude 4′-methoxy-3-nitrobiphenyl-4-acetic acid as a light tan solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[C@H:19]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:18][CH2:17]3)=[N:7][CH:8]=1)#[N:2].[SH2:29].C(NCC)C>CN(C=O)C>[NH2:2][C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[C@H:19]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:18][CH2:17]3)=[N:7][CH:8]=1)=[S:29]
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(C#N)cn3)ccc21
Reactant: S
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(C(N)=S)cn3)ccc21
Reaction time: 0.33 h
Yield: 86 %

Procedure:
Through a solution of ethyl ((1S)-5-{3-[(5-cyano-2-pyridinyl)oxy]propoxy}2,3-dihydro-1H-inden-1-yl)acetate (Example 258) (600 mg, 1.58 mmol) in DMF (8 mL) was passed H2S, gently at rt for 20 min. Diethylamine (0.24 mL, 2.37 mmol) was added in one portion and the resultant light-green solution was heated at 60° C. for 3 h (TLC in 2:1 hexanes/EtOAc indicated that the reaction was complete). The darkgreen solution was purged with a strong flow of argon, and then concentrated under reduced pressure. The product (0.56 g, 86%) was isolated by column chromatography (1:1 hexanes/EtOAc) as a bright yellow solid. 1H NMR (400 MHz, CD2Cl2) δ 8.65 (dd, 1H), 8.16 (dd, 1H), 7.56 (b, 1H), 7.19 (b, 1H), 7.04 (d, 1H), 6.80-6.72 (m, 2H), 6.69 (dd, 1H), 4.56 (t, 2H), 4.16 (q, 2H), 4.12 (t, 2H), 3.50 (qt, 1H), 2.90-2.78 (m, 2H), 2.70 (dd, 1H), 2.45-2.32 (m, 2H), 2.30-2.22 (m, 2H), 1.80-1.70 (m, 1H), 1.28 (t, 3H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C@@:11]([C:15]([F:18])([F:17])[F:16])([OH:14])[C@@H:10]([OH:19])[CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[F:18][C:15]([F:16])([F:17])[C@@:11]1([OH:14])[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]1[OH:19]
Reactant: O[C@H]1CN(Cc2ccccc2)CC[C@]1(O)C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O[C@H]1CNCC[C@]1(O)C(F)(F)F

Procedure:
A mixture of 1.50 g (5.45 mmol) of (3S,4R)-1-benzyl-4-trifluoromethylpiperidin-3,4-diol and 170 mg of Pd/C (10%) in 17 mL of MeOH was hydrogenated at RT and 3 bar hydrogen pressure for 5 hours. The catalyst was filtered off and the filtrate was evaporated down in vacuo. Yield: 910 mg (90% of theoretical); C6H10F3NO2 (M=185.144); calc.: molpeak (M+H)+: 186; found: molpeak (M+H)+: 186; Rf value: 0.35 (silica gel, EtOAc/MeOH/conc. aqueous ammonia 7:3:0.3).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14]C)=[O:13])[CH:10]=2)[NH:5][N:4]=1.Cl>O1CCOCC1>[CH3:1][NH:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=2)[NH:5][N:4]=1
Reactant: CNc1n[nH]c2ccc(C(=O)OC)cc12
Agent: Cl
Solvent: C1COCCO1
Product: CNc1n[nH]c2ccc(C(=O)O)cc12
Temperature: 100 °C
Reaction time: 8 h
Yield: 113.6 %

Procedure:
Methyl 3-(methylamino)-1H-indazole-5-carboxylate (60.0 mg, 0.29 mmol) was dissolved in 1,4-dioxane (0.5 mL). 3N Aqueous hydrochloric acid (0.3 mL, 0.9 mmol) was added and the reaction was heated to 100° C. for 11.5 hours. The heat was removed and the reaction was left stirring at room temperature overnight. The reaction was concentrated to give the title compound (63 mg, 95%) as a tan solid. +ESI (M+H) 192.1; 1H NMR (400 MHz, CD3OD, δ): 8.61 (d, J=0.78 Hz, 1H), 8.19 (dd, J=8.80, 1.57 Hz, 1H), 7.38 (d, J=8.80 Hz, 1H), 3.02 (s, 3H).