Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[O:9][CH:5]([CH2:6][NH:7][CH2:8]1)[CH2:4][N:3]([CH2:10][CH2:11][CH2:12][NH:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1)[CH2:2]2.C([O-])([O-])=O.[K+].[K+].Cl[CH2:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32].C(Cl)Cl>CC#N>[CH3:32][C:31]([CH3:34])([CH3:33])[C:30](=[O:35])[CH2:29][N:7]1[CH2:8][CH:1]2[O:9][CH:5]([CH2:4][N:3]([CH2:10][CH2:11][CH2:12][NH:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[CH2:2]2)[CH2:6]1
Reactant: CC(C)(C)C(=O)CCl
Reactant: N#Cc1ccc(NCCCN2CC3CNCC(C2)O3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)C(=O)CN1CC2CN(CCCNc3ccc(C#N)cc3)CC(C1)O2
Yield: 75.4 %

Procedure:
A mixture of 4-{[3-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)propyl]amino}-benzonitrile (Preparation C; 5.73 g, 0.02 mol), K2CO3 (11.05 g, 0.08 mol) in MeCN (300 mL) was treated with 1-chloropinacolone (4.44 g, 0.032 mol). The mixture was stirred at 50° C. overnight before DCM was added and the mixture filtered. The filter cake was then washed with a mixture of DCM and MeCN before the solvent was evaporated from the filtrate. The resulting residue was purified by chromatography on silica, eluting with a gradient of ethyl acetate methanol:ammoniacal methanol (95:5:0 to 95:0:5), to give the title compound (5.8 g, 73.9%).
Reaction SMILES: [N:1]([CH:4]([CH2:8][CH2:9][CH3:10])[C:5](O)=[O:6])=[N+:2]=[N-:3].C(Cl)(=O)C([Cl:14])=O.CN(C)C=O>ClCCl>[N:1]([CH:4]([CH2:8][CH2:9][CH3:10])[C:5]([Cl:14])=[O:6])=[N+:2]=[N-:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCC(N=[N+]=[N-])C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCC(N=[N+]=[N-])C(=O)Cl
Yield: 89 %

Procedure:
A solution of (2R and 2S) 2-azidopentanoic acid (2.213 g, 15.46 mmol) in dry dichloromethane (20 ml) was treated with oxalyl chloride (1.57 ml, 18.55 mmol) and a drop of N,N-dimethyl formamide. After the evolution of gas had ceased (2 h), the solvent was evaporated under reduced pressure and the residual liquid was distilled off (bulb to bulb) under vacuum to give 2.224 g (89%) of a clear oil: bp 50°-55° C./5 torr (air bath temperature); ir (film) νmax : 2105 (N3), 1785 cm-1 (C=O), 1Hmr (CDCl3) δ: 4.1 (1H, dd, J=7, J=6, H-2), 2.2-1.2 (4H, m, H-3 and H-4) and 0.98 ppm (3H, distorted t, J=6, H-5).
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([C:14](OCC)=[O:15])=[N:11][C:10]=2[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])=[CH:5][CH:4]=1.[Na]>CO>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([C:14]([NH2:1])=[O:15])=[N:11][C:10]=2[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])=[CH:5][CH:4]=1
Reactant: N
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)s1
Agent: [Na]
Solvent: CO
Product: NC(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)s1
Reaction time: 3 h
Yield: 76 %

Procedure:
Part A: Gaseous NH3 is led through a stirred solution of ethyl 5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)thiazole-2-carboxylate (1.65 gram, 4.0 mmol) in methanol (25 mL) at room temperature. A small piece of sodium metal is added. After stirring the resulting mixture for three hours the precipitate is collected by filtration, washed with a small portion of methanol and dried to give 5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)thiazole-2-carboxamide (1.16 gram, 76% yield), melting point 195-198° C. 1H-NMR (200 MHz, CDCl3): δ 7.48 (br s, 1H), 7.22-7.35 (m, 4H), 7.05-7.20 (m, 3H) 5.55-5.65 (M, 1H).
Reaction SMILES: C([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[CH:16][C:11]=2[N:10]=[CH:9]1)(OC(C)(C)C)=O.C([O-])([O-])=O.[K+].[K+].[CH:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][C:34]=1[CH2:43]Br>CN(C=O)C.O>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][N:17]([CH2:43][C:34]2[CH:35]=[CH:36][C:37]3[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:33]=2)[C:15]2[CH:14]=[CH:13][C:12]3[N:8]=[CH:9][NH:10][C:11]=3[CH:16]=2)=[CH:24][CH:23]=1
Reactant: BrCc1ccc2ccccc2c1
Reactant: COc1ccc(CNc2ccc3c(c2)ncn3C(=O)OC(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN(Cc2ccc3ccccc3c2)c2ccc3nc[nH]c3c2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
N1-Boc-N-(4-methoxybenzyl)benzimidazol-5-amine (353 mg; 1 mmol; 1 eq.) was dissolved in DMF (5 ml), treated with K2CO3 (166 mg; 1.2 mmol; 1.2 eq.) and naphthalen-2-yl-methyl-bromide (265 mg; 1.2 mmol; 1.2 eq.) and stirred at room temperature for 24 h. The mixture was diluted with water and extracted with ethyl acetate (3×25 ml). The combined organic layers were dried over Na2SO4 and evaporated. The remains were taken up with THF (5 ml), treated with 5 N NaOCH3 and stirred for 2 h at room temperature. The mixture was diluted with water and extracted with ethyl acetate (3×25 ml). The combined organic layers were dried over Na2SO4 and evaporated. The residue was purified by flash chromatography on silica using a CHCl3/MeOH gradient. Yield: 0.058 mg (14.8%); MS m/z: 394.2 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 3.70 (s, 3H); 4.68 (s, 2H); 4.80 (s, 2H); 6.76 (d, 1H, 4J=2.1 Hz); 6.82 (dd, 1H, 4J=2.3 Hz, 3J=8.9 Hz); 6.87-6.89 (m, 2H); 7.22-7.24 (m, 2H); 7.34 (d, 1H, 3J=8.9 Hz); 7.43-7.47 (m, 5H); 7.75 (br s, 1H); 7.79-7.81 (m, 1H); 7.85-7.87 (m 2H); 7.94 (s, 1H); HPLC (METHOD [A]): rt 18.12 min (95.6%)
Reaction SMILES: [NH:1]1[C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[NH:4][C:2]1=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:13].[OH-].[Na+]>N1C=CC=CC=1>[NH:1]1[C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[NH:4][C:2]1=[S:13]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=c1[nH]c(=O)c2[nH]cnc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: O=c1[nH]c(=S)[nH]c2nc[nH]c12
Yield: 322.7 %

Procedure:
2.77 g (8.0 mM) of xanthine and 2.13 g (9.6 mM) of phosphorus pentasulfide were heated under reflux in 50 ml of pyridine for 7 days. At 0° C., 10.6 ml of 2N NaOH were added within 15 min. The solvents were evaporated in vacuo and the residue suspended (slow crystallization) in water. The solid was collected and washed, redissolved in 50 ml of 1N NaOH and 50 ml of isopropanol, treated twice with 0.3 g of charcoal, filtered neutralized with 5N HCl to pH 7. The isopropanol was distilled off with addition of water and the solid collected, washed and dried to give 2.60 g (89.7%) of crude thioxanthine, which was dissolved in 40 ml of dichloromethane and filtered through 30 g of silica gel: 1.91 g (65.9%) of 6-thioxanthine were recovered, mp 153-4° C.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[Cl:19][C:20]1[CH:21]=[C:22]([CH2:26][C:27](O)=[O:28])[CH:23]=[CH:24][CH:25]=1>>[Cl:19][C:20]1[CH:21]=[C:22]([CH2:26][C:27]([NH:1][N:2]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:18])=[O:28])[CH:23]=[CH:24][CH:25]=1
Reactant: O=C(O)Cc1cccc(Cl)c1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Product: O=C(Cc1cccc(Cl)c1)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-(3-chlorophenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.31 (dd, J=7.9, 1.3 Hz, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.97-8.01 (m, 1H), 7.89-7.93 (m, 1H), 7.47-7.45 (m, 1H), 7.39-7.42 (m, 1H), 7.33-7.37 (m, 2H), 3.78-3.87 (m, 4H), 3.70 (s, 2H), 3.08-3.14 (m, 4H); MS (ESI−) M/Z 397 (M−H)−.
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[CH3:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[CH3:29])[NH2:25]>ClCCl.N1C=CC=CC=1>[CH3:21][C:22]1[CH:23]=[C:24]([NH:25][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:25][C:24]2[CH:26]=[CH:27][C:28]([CH3:29])=[C:22]([CH3:21])[CH:23]=2)=[O:13])[CH:26]=[CH:27][C:28]=1[CH3:29]
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Reactant: Cc1ccc(N)cc1C
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)c2ccccc2SSc2ccccc2C(=O)Nc2ccc(C)c(C)c2)cc1C
Yield: 16.8 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (1.12 g, 3.26 mmol) in 25 mL of dichloromethane and 3,4-dimethylaniline (0.79 g, 6.52 mmol) in 8 mL of pyridine. The crude product was triturated with ethyl ether and filtered to yield 0.28 g of the title compound, mp 224°-227° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10](=O)[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][CH:7]=[CH:6][N:5]=2.[OH-].[Na+].O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:10]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([CH3:1])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(C)[nH]c2ncccc2c1=O
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)c1c(C)nc2ncccc2c1Cl
Temperature: 100 °C
Yield: 95 %

Procedure:
Ethyl 2-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (5.18 mg, 2.23 mmol) was dissolved in POCl3. The mixture was heated to 100° C. for 1.0 h. The mixture was allowed to cool and then it was carefully poured into ice-water (250 ml). The mixture was neutralized with solid NaOH. The product was extracted with EtOAc. The combined organic extracts were dried (MgSO4), filtered and concentrated. Purification was done by flash chromatography (CH2Cl2/MeOH 97:3→96:4) giving 531 mg (95%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[N:26]=[C:25]([O:27][CH3:28])[N:24]=[C:23]([O:29][CH3:30])[N:22]=2)[C:3]=1[C:4](OC1C=CC([N+]([O-])=O)=CC=1)=[O:5].[CH3:31][S:32]([NH2:35])(=[O:34])=[O:33].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[C:3]([C:4]([NH:35][S:32]([CH3:31])(=[O:34])=[O:33])=[O:5])=[C:16]([CH:17]=[CH:18][CH:19]=1)[O:20][C:21]1[N:26]=[C:25]([O:27][CH3:28])[N:24]=[C:23]([O:29][CH3:30])[N:22]=1
Reactant: CS(N)(=O)=O
Reactant: COc1nc(OC)nc(Oc2cccc(Cl)c2C(=O)Oc2ccc([N+](=O)[O-])cc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1nc(OC)nc(Oc2cccc(Cl)c2C(=O)NS(C)(=O)=O)n1

Procedure:
This compound is prepared in a manner analogous to that of Example 1, Step I, using equimolar amounts of 4-nitrophenyl 2-chloro-6-(4,6-dimethoxy-1,3,5-triazin-2-yloxy)benzoate, methanesulfonamide, and potassium carbonate in acetonitrile to yield 2-[3-chloro-2-(methylsulfonylaminocarbonyl)phenoxy]-4,6-dimethoxy-1,3,5-triazine, Compound 38 of Table 1.
Reaction SMILES: [CH:1]1[C:6](=[O:7])[NH:5][C:4]([NH2:8])=[N:3][CH:2]=1.[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]=[O:17])=[CH:12][N:11]=1.Cl>>[NH2:8][C:4]1[NH:3][CH:2]=[C:1]([CH:16]([C:13]2[CH:12]=[N:11][C:10]([CH3:9])=[CH:15][CH:14]=2)[OH:17])[C:6](=[O:7])[N:5]=1
Reactant: Nc1nccc(=O)[nH]1
Reactant: Cc1ccc(C=O)cn1
Agent: Cl
Product: Cc1ccc(C(O)c2c[nH]c(N)nc2=O)cn1

Procedure:
Isocytosine is reacted with 2-methyl-5-formyl pyridine in refluxing concentrated hydrochloric acid for 24 hours to give 2-amino-5-((6-methyl-3-pyridyl)hydroxymethyl)-4(1H)-pyrimidinone.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][CH:18]=[C:17]3[S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])(=O)=O)=CC=1.[CH2:32]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[CH2:32]([N:39]1[CH2:44][CH2:43][N:42]([CH2:12][CH2:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][CH:18]=[C:17]3[S:23]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)(=[O:24])=[O:25])[CH2:41][CH2:40]1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc3[nH]cc(S(=O)(=O)c4ccccc4)c3c2)cc1
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)c1c[nH]c2ccc(CCN3CCN(Cc4ccccc4)CC3)cc12
Temperature: 71 °C
Yield: 95.7 %

Procedure:
A solution of 2-[3-(phenylsulfonyl)-1H-indol-5-yl]ethyl 4-methylbenzenesulfonate (0.16 g, 0.25 mmol) in anhydrous THF (2.5 mL) was added an excess of benzyl piperazine (0.18 mL, 1.02 mmol) and heated to 71° C. for 24 hours. The mixture was partitioned between ethyl acetate and H2O, and the aqueous layer was extracted with ethyl acetate (10 mL). The combined organic layers were washed with 2 M NaOH, (2×15 mL), brine, dried (MgSO4), filtered and concentrated under reduced pressure. Silica gel chromatography (10% EtOH/2N ammonia/dichloromethane) gave the title compound as a light yellow solid (0.11 g, 94%). Mp: 150-153° C. MS (ES+): 460 (M+H).
Reaction SMILES: O.O.[OH-].[Li+].[F:5][CH:6]([F:25])[O:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=2)[N:10](C(OCC)=O)[N:9]=1>C1COCC1>[F:25][CH:6]([F:5])[O:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=2)[NH:10][N:9]=1
Reactant: CCOC(=O)n1nc(OC(F)F)c2cc([N+](=O)[O-])ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc2[nH]nc(OC(F)F)c2c1
Temperature: 80 °C
Yield: 106.2 %

Procedure:
Water (6 ml) and lithium hydroxide monohydrate (640 mg) were added to a THF (19 ml) solution containing ethyl 3-(difluoromethoxy)-5-nitro-1H-indazol-1-carboxylate (1.14 g) obtained in the 1st step, followed by reflux at 80° C. for 3 hours. THF was distilled away under reduced pressure and a saturated ammonium chloride aqueous solution was added. An insoluble precipitate was removed by filtration. The obtained residue was washed with water, dissolved in ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure. A yellow solid of 3-(difluoromethoxy)-5-nitro-1H-indazole (921 mg) was thus obtained.
Reaction SMILES: C[C:2]1[C:3]([C:29]([OH:31])=[O:30])=[N:4][N:5]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])[C:6]=1[C:7]1[O:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[N:10][N:11]=1.[OH-].[Li+]>C1COCC1.O>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[N:5]1[C:6]([C:7]2[O:8][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=3)=[N:10][N:11]=2)=[CH:2][C:3]([C:29]([OH:31])=[O:30])=[N:4]1
Reactant: Cc1c(C(=O)O)nn(-c2ccccc2Cl)c1-c1nnc(-c2cccc(S(C)(=O)=O)c2)o1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cccc(-c2nnc(-c3cc(C(=O)O)nn3-c3ccccc3Cl)o2)c1
Reaction time: 2 h
Yield: 32.1 %

Procedure:
To a stirred solution of compound 11 (100 mg, 0.21 mmol) in THF (4.0 mL) at room temperature, a solution of lithium hydroxide (44 mg, 1.05 mmol) in water (4.0 mL) was added and stirring continued for 2 h. On completion, solvent was removed, diluted with water (20 mL) and washed with ether (30 mL×3). The aqueous layer was acidified with 1N HCl and extracted with 10% methanol in dichloromethane (50 mL×3). Combined organic layer was washed brine, dried over sodium sulphate and concentrated. The crude product after ether and pentane washing furnished the title compound 12 (30 mg, 31%). LCMS: 445.10 (M+1)+; HPLC: 96.20% (@210 nm-370 nm) (Rf; 5.847; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30 OC; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (CDCl3, 400 MHz) δ 8.29 (s, 1H), 8.27 (d, 1H), 8.12 (d, 1H, J=7.6 Hz), 7.79 (s, 1H), 7.74 (t, 1H, J=7.6&7.2 Hz), 7.64-7.50 (m, 4H), 3.10 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[S:8][CH2:7][CH2:6][C:5]2([CH3:13])[CH3:12].[Li]CCCC.CN([CH:22]=[O:23])C>C1COCC1>[CH3:12][C:5]1([CH3:13])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH:22]=[O:23])[CH:3]=2)[S:8][CH2:7][CH2:6]1
Reactant: CN(C)C=O
Reactant: CC1(C)CCSc2ccc(Br)cc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)CCSc2ccc(C=O)cc21
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
1-Bromo-4-[(3-methylbut-3-en-1-yl)sulfanyl]benzene (1.05 g, 4.08 mmol) dissolved in dichloromethane (24.0 mL) was cooled to 0° C., and aluminum chloride (0.60 g, 4.49 mmol) was added portionwise. The reaction mixture was stirred at 0° C. for 1 hour and warmed to room temperature for another hour. It was then poured into an Erlenmeyer flask containing a 10% aqueous NaOH solution and ice. The mixture was extracted with dichloromethane (2×, 40.0 mL), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by silica gel chromatography eluting with 0-10% EtOAc/Hexanes to give 6-bromo-4,4-dimethyl-3,4-dihydro-2H-thiochromene as a pale-yellow oil. 6-Bromo-4,4-dimethyl-3,4-dihydro-2H-thiochromene (798 mg, 3.10 mmol) in THF (21.0 mL) was cooled to −78° C. and n-BuLi (1.50 mL, 3.72 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for 10 minutes and then DMF (961 μl, 12.4 mmol) was added dropwise via a syringe. The resulting mixture was allowed to warm to room temperature and wet silica gel (5.0 g/0.5 mL of water) was added. The mixture was allowed to stir at room temperature for 10 minutes before it was filtered. The silica gel was rinsed with EtOAc and the filtrate was concentrated under vacuum. The crude residue was purified by silica gel chromatography eluting with 0-20% EtOAc/hexanes to obtain the desired product as a pale-yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:12](Cl)(=[O:14])=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[CH3:16][C:17]1[CH:21]=[C:20]([NH2:22])[N:19]([C:23]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=2[CH:25]=[CH:26][CH:27]=[N:28]3)[N:18]=1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([S:12]([NH:22][C:20]2[N:19]([C:23]3[CH:32]=[CH:31][CH:30]=[C:29]4[C:24]=3[CH:25]=[CH:26][CH:27]=[N:28]4)[N:18]=[C:17]([CH3:16])[CH:21]=2)(=[O:14])=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: Cc1cc(N)n(-c2cccc3ncccc23)n1
Reactant: CC(C)Oc1ccc(S(=O)(=O)Cl)cc1F
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: Cc1cc(NS(=O)(=O)c2ccc(OC(C)C)c(F)c2)n(-c2cccc3ncccc23)n1
Temperature: 85 °C
Yield: 30.9 %

Procedure:
A mixture of 3-fluoro-4-isopropoxybenzene-1-sulfonyl chloride (0.050 g, 0.19 mmol), 3-methyl-1-(quinolin-5-yl)-1H-pyrazol-5-amine (prepared from Example 4 step b, 0.025 g, 0.11 mmol), and DMAP (0.020 g, 0.16 mmol) in pyridine (2 mL) was heated at 85° C. for 2 h with stirring. After cooling to room temperature, the reaction mixture was concentrated in vacuo and the crude residue was purified by reverse phase HPLC(C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.015 g, 0.034 mmol, 31%). 1H NMR (400 MHz, CD3OD) δ 8.85 (d, J=4.4 Hz, 1H), 8.11 (d, J=8.4 Hz, 1H), 7.80 (t, J=8.0 Hz, 1H), 7.62 (d, J=8.8 Hz, 1H), 7.45-7.40 (m, 2H), 7.25 (d, J=8.8 Hz, 1H), 7.12 (dd, J=2.4, 10.4 Hz, 1H), 6.92 (t, J=8.4 Hz, 1H), 6.10 (s, 1H), 4.63 (hept, J=6.4 Hz, 1H), 2.27 (s, 3H), 1.37 (d, J=6.4 Hz, 6H); MS: (ES) m/z calculated for C22H22FN4O3S [M+H]+ 441.2. found 441.2.
Reaction SMILES: [C:1]1([CH:7]([C:9]2[C:17]3[C:12](=[CH:13][N:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(Cl)Cl.CO>[C:1]1([C:7]([C:9]2[C:17]3[C:12](=[CH:13][N:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC(c1ccccc1)c1c[nH]c2cnccc12
Solvent: CO
Solvent: ClCCl
Product: O=C(c1ccccc1)c1c[nH]c2cnccc12
Yield: 78 %

Procedure:
Phenyl(1H-pyrrolo[2,3-c]pyridin-3-yl)methanone (379 mg, 78%) was prepared using phenyl(1H-pyrrolo[2,3-c]pyridin-3-yl)methanol (Example 97) as a yellow solid following the procedure described for Reference Example 13: Rf 0.48 (90:10 methylene chloride/methanol); mp 218-220° C.; 1H NMR (300 MHz, DMSO-d6) δ7.55-7.58 (2H, m), 7.62-7.65 (1H, m), 7.81-7.83 (2H, m), 8.09-8.10 (1H, d, J=5.4 Hz), 8.19 (1H, s), 8.33-8.34 (1H, d, J=5.4 Hz), 8.88 (1H, s), 12.50 (1H, br s); ESI MS m/z 223 [C14H10N2O+H]+; HPLC (Method A) 96.6% (AUC), tR=13.2 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([OH:8])=[N:6][CH:7]=1.[H-].[Na+].[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](=[O:8])[N:6]([CH2:20][C:19]2[CH:22]=[CH:23][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)[CH:7]=1
Reactant: O=[N+]([O-])c1cc(Cl)cnc1O
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc(Cl)cc([N+](=O)[O-])c2=O)cc1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 58.4 %

Procedure:
To a stirred solution of 5-chloro-3-nitropyridin-2-ol (12 g, 68.8 mmol) in DMF (80 ml) was added in several portions NaH (3.30 g, 83 mmol) at 0° C. The reaction mixture was stirred in the ice-bath for 2 hours. Then 4-methoxybenzyl chloride (11.19 ml, 83 mmol) was added and the reaction mixture was heated at 80° C. for 1 hour. The reaction mixture was quenched with aqueous saturated NaHCO3 solution and extracted twice with EtOAc. The organic layers were washed with brine, combined, dried over sodium sulphate, filtered and evaporated. The crude material was taken up in n-heptane/AcOEt 10:1 and the suspension was kept in the sonic bath for 10 minutes. After filtration the filtrate was washed with n-heptane and dried in vacuum to obtain 11.84 g (40.2 mmol, 58.4% yield) of the title compound as a greenish solid. LCMS: (M+H)=295; tR=0.94 min (LC-MS 4). 1H-NMR (d6-DMSO, 400 MHz) 8.72 (d, 1H) 8.56 (d, 1H) 7.36 (d, 2H) 6.94 (d, 2H) 5.13 (s, 2H) 3.74 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([CH3:32])[CH:28]=3)[NH:23][C:22]2=[O:33])[CH2:17][CH2:16]1.[CH2:34](Br)[CH:35]=[CH2:36]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:16][CH2:17][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([CH3:32])[CH:28]=3)[N:23]([CH2:36][CH:35]=[CH2:34])[C:22]2=[O:33])[CH2:19][CH2:20]1
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)[nH]c5ccc(C)cc5c4=O)CC3)c2cc1OC
Reactant: C=CCBr
Product: C=CCn1c(=O)n(C2CCN(c3ncnc4cc(OC)c(OC)cc34)CC2)c(=O)c2cc(C)ccc21
Yield: 58 %

Procedure:
The procedure similar to that described in Example 1 was repeated, except that 300 mg (0.67 mmol) of Compound 22 was used in place of Compound 24 and allyl bromide was used in place of methyl iodide. As a result, 187.8 mg (yield: 58%) of Compound 53 was obtained as white crystals.
Reaction SMILES: [C:1]1([C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:18][N:17]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=4)=[O:20])[CH2:16]3)[CH2:11][CH2:10]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:28]([N:35]1[CH2:42][CH2:41][CH:40](O)[C@@H:36]1C(O)=O)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]1([C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:18][N:17]([C:19]([C:21]4[CH:22]=[CH:23][C:24]([O:27][C@H:41]5[CH2:40][CH2:36][N:35]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:42]5)=[CH:25][CH:26]=4)=[O:20])[CH2:16]3)[CH2:11][CH2:10]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(c1ccccc1)N1CCN(C2CN(C(=O)c3ccc(O)cc3)C2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(O)[C@@H]1C(=O)O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc(C(=O)N3CC(N4CCN(C(=O)c5ccccc5)CC4)C3)cc2)C1
Reaction time: 18 h

Procedure:
To a solution of compound 26d (100 mg, 0.273 mmol) and (R)—N-Boc-3-hydroxyproline in THF was added DIAD at 0° C. The resulting reaction mixture was stirred for 18 h. After dilution with water and extraction with EtOAc (3×), the combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resultant residue was purified by flash column chromatography on silica gel using 5% MeOH/CH2Cl2 to give compound 434 (95 mg). 1H NMR (CDCl3): δ 7.52 (d, J=8.6 Hz, 2H), 7.37-7.44 (m, 5H), 7.24-7.29 (m, 3H), 7.18-7.24 (m, 3H), 4.18-4.33 (m, 2H), 4.09-4.17 (m, 3H), 4.01-4.08 (m, 1H), 3.92 (br. S, 1H), 3.74 (br. s., 1H), 3.35-3.63 (m, 2H), 3.17-3.29 (m, 1H), 2.20-2.50 (m, 4H); MS m/z (M+H+) 506.0.