Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:18])[N:8]([CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:19]=O.[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][C:30]=1[NH:31][C:32](=[O:36])[C@@H:33]([OH:35])[CH3:34])[NH:27][C:26](=[O:37])[CH2:25]2>>[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][C:30]=1[NH:31][C:32](=[O:36])[C@@H:33]([OH:35])[CH3:34])[NH:27][C:26](=[O:37])[C:25]2=[CH:19][C:3]1[NH:4][C:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)[C:7](=[O:18])[C:6]=2[C:2]=1[CH3:1]
Reactant: C[C@H](O)C(=O)Nc1cc2c(cc1F)CC(=O)N2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Product: Cc1c(C=C2C(=O)Nc3cc(NC(=O)[C@H](C)O)c(F)cc32)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Yield: 67.9 %

Procedure:
The title compound was prepared under the same conditions as described in Example 13 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and (S)—N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-propionamide as starting materials to give (S)—N-{5-fluoro-3-[3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxy-propionamide (48 mg, 67.9%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1.[F:7][C:8]([F:28])([F:27])[C:9]1[C:18]([C:19](Cl)=[O:20])=[C:17]([OH:22])[C:16]2[C:11](=[C:12]([C:23]([F:26])([F:25])[F:24])[CH:13]=[CH:14][CH:15]=2)[N:10]=1.C(N(CC)CC)C>C(OCC)(=O)C>[F:27][C:8]([F:7])([F:28])[C:9]1[C:18]([C:19]([NH:1][C:2]2[NH:6][N:5]=[N:4][N:3]=2)=[O:20])=[C:17]([OH:22])[C:16]2[C:11](=[C:12]([C:23]([F:26])([F:24])[F:25])[CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: Nc1nnn[nH]1
Reactant: O=C(Cl)c1c(C(F)(F)F)nc2c(C(F)(F)F)cccc2c1O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(Nc1nnn[nH]1)c1c(C(F)(F)F)nc2c(C(F)(F)F)cccc2c1O
Yield: 52.9 %

Procedure:
5.03 g of anhydrous 5-amino-tetrazole were suspended with stirring at 8° C. in 230 ml of ethyl acetate and a solution of 21.9 g of 2,8-bis-(trifluoromethyl)-4-hydroxy-3-quinoline-carboxylic acid chloride in 230 ml of ethyl acetate and a solution of 18 g of triethylamine in 180 ml of ethyl acetate were simultaneously added to the reaction mixture over 15 minutes. The mixture returned to room temperature and was refluxed for one hour and cooled. The mixture was vacuum filtered and the recovered product was dissolved in one liter of water. The filtrate wash waters were added to the solution and the pH was adjusted to 1 by addition of 20% hydrochloric acid. The mixture was vacuum filtered and the recovered product was dissolved in 50 ml of 2 N sodium hydroxide. 150 ml of water were added to the solution and the mixture was heated to reflux and cooled. The mixture was acidified with 100 ml of 20% hydrochloric acid and was vacuum filtered. The product was dried and crystallized from 250 ml of acetic acid to obtain 12.279 g of 2,8-bis-(trifluoromethyl)-4-hydroxy-N-(1H-tetrazol-5-yl)-3-quinolinecarboxamide melting at >260° C.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24].Cl>CN(C)C(=O)C>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([C:26]1[CH:27]=[CH:28][C:29]([NH:32][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])=[CH:30][CH:31]=1)(=[O:24])=[O:25]
Reactant: COc1ccccc1S(=O)(=O)c1ccc(N)cc1
Reactant: CC(O)(C(=O)O)C(F)(F)F
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: COc1ccccc1S(=O)(=O)c1ccc(NC(=O)C(C)(O)C(F)(F)F)cc1
Reaction time: 1 h

Procedure:
To a stirred, cooled (-20° C.) solution of 3,3,3-trifluoro2-hydroxy-2-methylpropanoic acid (1.42 g, 9.0 mmol) in N,N-dimethylacetamide (13 mL) was added thionyl chloride (1.13 g, 9.5 mmol) and the mixture stirred at -15° to -5° C. for 1 hour. 4-(2-Methoxyphenyl)sulfonyl-benzeneamine (1.58 g, 6.0 mmol) was added in one portion and the reaction mixture stirred at room temperature overnight. The mixture was poured into 250 mL of 0.5N HCl. The clear supernatient was decanted from the resulting gum. The gum was crystallized from methylene chloride/hexane to yield the title propanamide which contained about 10 mole % of methylene chloride by NMR analysis. The methylene chloride was not removed by heating at 140°/0.1 mm for 40 hours. The yield of white solid was 1.70 g (69%), mp 209°-211° C. 1H--NMR (300 MHz, d6 --DMSO): 1.55 (s, 3H, CH3) 3.72 (s, 3H, OCH3) 5.73 (s, CH2Cl) 7.11-7.17 (m, 2H, aromatic) 7.53 (s, 1H, OH) 7.60-7.63 (m, 1H, aromatic) 7.80-7.83 (m, 2H, aromatic) 0.92-7.97 (m, 3H, aromatic) 10.36 (s, 1H, NH). MS (CI, CH4): 294 (M+1).
Reaction SMILES: O=P1([O:10][CH:11]([C:25]#[N:26])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:13]=2)OCC(C)(C)CO1.[Na].[Cl:28][C:29]([Cl:39])=[CH:30][CH:31]1[CH:33]([C:34](O)=[O:35])[C:32]1([CH3:38])[CH3:37]>O>[O:18]([C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[CH:11]([O:10][C:34]([CH:33]1[CH:31]([CH:30]=[C:29]([Cl:28])[Cl:39])[C:32]1([CH3:38])[CH3:37])=[O:35])[C:25]#[N:26])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC1(C)C(C=C(Cl)Cl)C1C(=O)O
Reactant: CC1(C)COP(=O)(OC(C#N)c2cccc(Oc3ccccc3)c2)OC1
Agent: [Na]
Solvent: O
Product: CC1(C)C(C=C(Cl)Cl)C1C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1
Yield: 77 %

Procedure:
A slurry of 38 g of 2-oxo-2-(3-phenoxy-α-cyanobenzyloxy)-5,5-dimethyl-1,3,2-dioxa-phosphorinane, 26 g of the sodium salt of 3-(2,2-dichloro-vinyl)-2,2-dimethylcyclopropane-1-carboxylic acid and 260 g of diglycol dimethyl ether was heated to 150° C. for 20 hours, while stirring. After cooling, the mixture was poured into water and the product was extracted with ligroin. The ligroin phase was washed 3 times with water and dried over sodium sulphate. After filtration, the ligroin was distilled off from the filtrate in vacuo and the residue was subjected to incipient distillation under a high vacuum. 32 g (77% of theory) of 3-(2,2-dichlorovinyl)-2,2-dimethyl-cyclopropane-1-carboxylic acid 3-phenoxy-α-cyano-benzyl ester were obtained as the residue.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:30][C:31]([CH3:36])([CH3:35])[CH2:32][CH2:33]O.Cl.[K+].[Br-]>C(Cl)(Cl)Cl>[CH3:30][C:31]([CH3:36])([CH3:35])[CH2:32][CH2:33][O:24][C:23]([C:18]1([C:20]([O:22][CH2:33][CH2:32][C:31]([CH3:36])([CH3:35])[CH3:30])=[O:21])[O:17][C:16]2[CH:26]=[CH:27][C:13]([CH2:12][CH:11]([NH:10][CH2:9][CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[OH:29])[CH3:28])=[CH:14][C:15]=2[O:19]1)=[O:25]
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Reactant: CC(C)(C)CCO
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(Cc1ccc2c(c1)OC(C(=O)OCCC(C)(C)C)(C(=O)OCCC(C)(C)C)O2)NCC(O)c1cccc(Cl)c1

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylarnino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and 3,3-dimethylbutanol according to the procedure of Example 30 as a white foam (HCl salt); 1H NMR (CDCl3) δ 0.90 (s, 18H), 1.33 (bs, 3H), 1.62 (t, J=7.4 Hz, 4H), 2.80 (bs, 1H), 3.18 (bs, 2H), 3.48 (bs, 2H), 4.35 (t, J=7.4 Hz, 4H), 5.45 (bs, 1H), 6.80 (m, 3 H), 7.26 (m, 2H), 7.43 (s, 1H), 8.70 (bs, 1H), 10.10 (bs, 1H); IR (KBr): 1765 cm-1 (C=O); MS (CI) m/z 590 (MH+); [α]D5 -24° (c, 1.0, CHCl3). Anal. Calcd. for C32H44ClNO7 ·HCl: C, 61.34; H, 7.08; N, 2.24; Cl, 11.32. Found: C, 60.79; H, 7.46; N, 2.09; Cl, 11.95.
Reaction SMILES: [CH3:1][N:2]([CH3:35])[C:3]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:8][CH2:7][C:6]([CH2:10][CH2:11][CH2:12][C:13]2[C:17]3[CH:18]=[N:19][CH:20]=[CH:21][C:16]=3[NH:15][C:14]=2[Si](CC)(CC)CC)([OH:9])[CH2:5][CH2:4]1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:35][N:2]([CH3:1])[C:3]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:8][CH2:7][C:6]([CH2:10][CH2:11][CH2:12][C:13]2[C:17]3[CH:18]=[N:19][CH:20]=[CH:21][C:16]=3[NH:15][CH:14]=2)([OH:9])[CH2:5][CH2:4]1
Reactant: CC[Si](CC)(CC)c1[nH]c2ccncc2c1CCCC1(O)CCC(c2ccccc2)(N(C)C)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C1(c2ccccc2)CCC(O)(CCCc2c[nH]c3ccncc23)CC1

Procedure:
A solution of 4-dimethylamino-4-phenyl-1-[3-(2-triethylsilanyl-1H-pyrrolo[3,2-c]pyridin-3-yl)propyl]cyclohexanol (410 mg, 0.83 mmol) in anhydrous tetrahydrofuran (25 mL) was mixed with tetra-n-butyl ammonium fluoride trihydrate (1.05 g, 3.32 mmol) and boiled with reflux for 6 h. The reaction mixture was then concentrated to low volume in a vacuum and the raw product purified by means of flash chromatography (38 g, 20×2.5 cm) with ethyl acetate/methanol (2:1). The product was taken up in dichloromethane (40 mL), the solution dried with sodium sulphate and concentrated to low volume in a vacuum.
Reaction SMILES: C(OC([N:8]1[CH2:13][C@H:12]([CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][C@H:16]2[CH3:21])[N:11]([CH2:22][C:23]([N:25]2[C:33]3[C:28](=[N:29][CH:30]=[C:31]([CH2:34][C:35]4[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=4)[CH:32]=3)[C:27]([CH3:43])([CH3:42])[CH2:26]2)=[O:24])[CH2:10][C@H:9]1[CH3:44])=O)(C)(C)C.Cl>C(OCC)(=O)C.O1CCOCC1>[F:41][C:38]1[CH:39]=[CH:40][C:35]([CH2:34][C:31]2[CH:32]=[C:33]3[N:25]([C:23](=[O:24])[CH2:22][N:11]4[CH2:10][C@@H:9]([CH3:44])[NH:8][CH2:13][C@@H:12]4[CH2:14][N:15]4[CH2:20][CH2:19][O:18][CH2:17][C@H:16]4[CH3:21])[CH2:26][C:27]([CH3:43])([CH3:42])[C:28]3=[N:29][CH:30]=2)=[CH:36][CH:37]=1
Reactant: C[C@@H]1COCCN1C[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1CC(=O)N1CC(C)(C)c2ncc(Cc3ccc(F)cc3)cc21
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@@H]1CN(CC(=O)N2CC(C)(C)c3ncc(Cc4ccc(F)cc4)cc32)[C@@H](CN2CCOC[C@H]2C)CN1
Reaction time: 18 h
Yield: 87.9 %

Procedure:
To a vigorously stirred solution of (2R,5S)-4-{2-[6-(4-fluoro-benzyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl}-2-methyl-5-((R)-3-methyl-morpholin-4-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (11.3 g, 18.5 mmol) in ethyl acetate (100 mL) at 20° C. was added a solution of HCl in dioxan (100 mL) and stirring was continued for 18 h. The resulting fine yellow precipitate was collected by filtration and dried in vacuo. This material was suspended in water (200 mL) and extracted with EtOAc (200 mL). The organic phase was washed with 0.1 M aqueous HCl (50 mL) and the combined aqueous extracts were cooled in an ice bath and basified by the dropwise addition of 5 M aqueous NaOH. Resulting mixture was extracted with DCM (4×60 mL) and the combined extracts were dried (Na2SO4) and evaporated in vacuo to give the title compound (8.29 g) as a colourless foam. 1H NMR and MS data were consistent with those obtained above for Example 262. IR vC═O 1685 cm−1.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[S:9][C:10]([CH2:13][CH2:14][C:15](OC)=[O:16])=[CH:11][N:12]=1.O>O1CCCC1>[CH3:7][C:8]1[S:9][C:10]([CH2:13][CH2:14][CH2:15][OH:16])=[CH:11][N:12]=1
Reactant: COC(=O)CCc1cnc(C)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ncc(CCCO)s1
Temperature: 10 °C
Yield: 69.2 %

Procedure:
A mixture of 125 ml of tetrahydrofuran and 3.42 g of lithium aluminum hydride was cooled to about 10° C. and a mixture of 10.9 g of methyl 2-methyl-5-thiazolepropanoate in 70 ml of tetrahydrofuran was slowly added thereto with stirring while keeping the temperature between 10-15° C. The mixture was then stirred for about 30 minutes and tetrahydrofuran containing 20% of water was slowly added. The mixture was filtered and the filter was washed with ethyl acetate. The filtrate was dried over magnesium sulfate and concentrated to dryness under reduced pressure to obtain 8.4 g of a raw product which was rectified under reduced pressure to obtain 6.4 g of 2-methyl-5-thiazole-propanol with a boiling point of 106° C. at 0.05 mm Hg.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][C:6]2[NH:7][C:8](=[O:25])[CH2:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]4[O:22][N:21]=[C:20]([CH2:23]O)[CH:19]=4)[CH:13]=3)=[N:11][C:5]=2[CH:4]=1.O=S(Cl)Cl.[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1>>[CH3:32][N:2]([CH3:1])[C:3]1[C:27]([C:28]([F:29])([F:30])[F:31])=[CH:26][C:6]2[NH:7][C:8](=[O:25])[CH2:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]4[O:22][N:21]=[C:20]([CH2:23][N:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)[CH:19]=4)[CH:13]=3)=[N:11][C:5]=2[CH:4]=1
Reactant: C1CCNC1
Reactant: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cc(CO)no3)c1)=N2
Solvent: O=S(Cl)Cl
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cc(CN4CCCC4)no3)c1)=N2

Procedure:
The title compound was prepared from 7-dimethylamino-4-[3-(3-hydroxymethyl-isoxazol-5-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 46) (111 mg, 0.25 mmol) by treatment with SOCl2 (3 eq.) and pyrrolidine (10 eq.) as described in Example 45. Obtained as a yellow solid (28 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15](C(N)=O)[CH:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.C[O:23][CH:24]([O:28][CH3:29])N(C)C>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([C:24]([O:28][CH3:29])=[O:23])[CH:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: NC(=O)c1cc(-c2c[nH]nc2-c2ccc(F)cc2)ccn1
Reactant: COC(OC)N(C)C
Solvent: CO
Product: COC(=O)c1cc(-c2c[nH]nc2-c2ccc(F)cc2)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a suspension of 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinecarboxamide prepared as set forth in Example A-223 (2.9 g, 0.01 mol) in 50 mL of methanol was added N,N-dimethylformamide dimethyl acetal (3.67 g, 0.03 mol) dropwise. The reaction mixture was stirred at room temperature overnight and heated at reflux for 4 hours. After cooling, the precipitate was collected by filtration and air-dried to give 2.0 g of methyl 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinecarboxylate as a white solid (69% yield), mp: 239–241° C. Anal. Calc'd for C16H12FN3O2: C, 64.64; H, 4.07; N, 14.13. Found: C, 64.36; H, 4.10; N, 14.27.
Reaction SMILES: [NH2:1][CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4].[Cl:7][C:8]1[C:9]([F:16])=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=O.O>ClCCl>[Cl:7][C:8]1[C:9]([F:16])=[C:10](/[CH:11]=[N:1]/[CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4])[CH:13]=[CH:14][CH:15]=1
Reactant: O=Cc1cccc(Cl)c1F
Reactant: C[Si](C)(C)CN
Solvent: O
Solvent: ClCCl
Product: C[Si](C)(C)C/N=C/c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.4 %

Procedure:
To a solution of (aminomethyl)trimethylsilane (Fluka) (1.03 g, 10 mmol) in dichloromethane (50 mL) was added 3-chloro-2-fluoro-benzaldehyde (Oakwood) (1.6 g, 10 mmol). The reaction mixture was stirred at room temperature for 3 h. Water was added. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated to give [1-(3-chloro-2-fluoro-phenyl)-meth-(E)-ylidene]-trimethylsilanylmethyl-amine as a colorless oil (2.4 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([NH:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[N:13]=[CH:12][N:11]=2.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([NH:17][CH:18]1[CH2:23][CH2:22][N:21]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:20][CH2:19]1)[N:13]=[CH:12][N:11]=2
Reactant: CS(=O)(=O)Cl
Reactant: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(NC4CCNCC4)ncnc32)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CCC(Nc2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Reaction time: 16 h
Yield: 92 %

Procedure:
To a solution of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-N-(piperidin-4-yl)-9H-purin-6-amine (18.4 mg, 0.042 mmol, 1 eq.) in 2 mL of THF was added methanesulfonyl chloride (0.005 mL, 0.063 mmol, 1.5 eq.) and triethylamine (0.02 mL, 0.126 mmol, 3 eq.). The mixture was stirred for 16 h. The reaction was concentrated in vacuo. The crude material was purified by silica gel column chromatography using 0-100% ethyl acetate/hexanes to yield 20 mg (91%) of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-N-(1-methanesulfonylpiperidin-4-yl)-9H-purin-6-amine. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.58-1.76 (m, 2 H) 2.21 (d, J=10.64 Hz, 2 H) 2.76 (s, 3 H) 2.90 (t, J=10.93 Hz, 2 H) 3.77 (d, J=12.15 Hz, 2 H) 4.33 (br. s., 1 H) 5.84 (br. s., 1 H) 7.04-7.51 (m, 8 H) 8.36 (s, 1 H), [M−H]− 515.7.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:14])=O>>[Cl:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: O=C(O)c1ccc(I)cc1Cl
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(I)cc1Cl
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of 2-chloro-4-iodo-benzoic acid (470 mg) in thionyl chloride (6 mL) was stirred at 60° C. for 3 h. The excess thionyl chloride was removed in vacuo. The residue was washed with ether and dried to afford 2-chloro-4-iodo-benzoyl chloride (0.5 g), which was used directly in the next step where it was dissolved in 1,4-dioxane (10 mL). Phosphoryl chloride (5 mL) and IId (246 mg) were added, and the mixture was stirred at 90° C. for 1.5 h. The volatiles were removed in vacuo. The residue was partitioned between water and DCM. The organic layer was washed with sat. aq. NaHCO3, dried over NaSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluent: pentane:EtOAc 10:1 to 5:1) to afford example Id7 (250 mg). LC/MS (method WXE-AB10): RT(PDA)=2.26 min; PDA/ELS purities 99%/99%; mass observed 422.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:4]=1[NH2:5].[Cl:13]N1C(=O)CCC1=O>CC#N>[Cl:13][C:8]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:4]([NH2:5])=[C:3]([O:2][CH3:1])[CH:9]=1
Reactant: COc1cccc([N+](=O)[O-])c1N
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: COc1cc(Cl)cc([N+](=O)[O-])c1N
Reaction time: 16 h

Procedure:
To a solution of the title compound of Example 21, Step A (26.6 mmol, 4.5 g) in MeCN (30 mL) at 60° C. was added N-chlorosuccinimide (29 mmol, 3.9 g). The solution was brought to reflux for 2 h and allowed to stand at ambient temperature for 16 h. The reaction mixture was partitioned between CH2Cl2 and saturated NaHCO3. The organic phase was washed with brine, dried with Na2SO4, and concentrated in vacuo to afford the product as a brown solid. LC-MS (ESI, Method B): 2.14 min, m/z 203.11 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([OH:13])=O)=[C:6]2[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:3]=1.[NH2:24][C:25]1[CH:26]=[C:27]([S:31]([NH2:34])(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1>>[S:31]([C:27]1[CH:26]=[C:25]([NH:24][C:11]([C:10]2[CH:9]=[N:8][N:7]3[C:2]([CH3:1])=[CH:3][C:4]([C:14]4[CH:15]=[CH:16][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:18][CH:19]=4)=[N:5][C:6]=23)=[O:13])[CH:30]=[CH:29][CH:28]=1)(=[O:32])(=[O:33])[NH2:34]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc2c(C(=O)O)cnn12
Reactant: Nc1cccc(S(N)(=O)=O)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc2c(C(=O)Nc3cccc(S(N)(=O)=O)c3)cnn12

Procedure:
The title compound was prepared from 7-methyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.25) and 3-amino-benzenesulfonamide according to general procedure II. Pale-yellow solid. MS (ISP) 476.5 [(M+H)+]; mp 270-272° C.
Reaction SMILES: Cl.[O:2]=[C:3]1[C:11]2([CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]1[CH2:18][C:19]([O:21]C(C)(C)C)=[O:20]>CCOC(C)=O>[O:2]=[C:3]1[C:11]2([CH2:12][CH2:13][C:14](=[O:17])[CH2:15][CH2:16]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]1[CH2:18][C:19]([OH:21])=[O:20]
Reactant: CC(C)(C)OC(=O)CN1C(=O)C2(CCC(=O)CC2)c2ccccc21
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(O)CN1C(=O)C2(CCC(=O)CC2)c2ccccc21
Reaction time: 3 h

Procedure:
HCl (g) was bubbled into a solution of tert-butyl (2′,4-dioxospiro[cyclohexane-1,3′-indol]-1′(2′H)-yl)acetate from Step B (800 mg, 2.43 mmol) in EtOAc (10 mL) for 5 min. After 3 h, the reaction was concentrated in vacuo to give the desired product. MS: m/z=274 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH:10]=[O:11].CO.C1(C)C=CC(S([CH2:23][N+:24]#[C-:25])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CCCCCC>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[O:11][CH:25]=[N:24][CH:23]=1
Reactant: O=Cc1cc2ccccc2[nH]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CO
Product: c1ccc2[nH]c(-c3cnco3)cc2c1
Yield: 79.8 %

Procedure:
To a 100 mL round-bottom flask was added 1H-indole-2-carbaldehyde 18 (1.52 g, 10.48 mmol), methanol (50 mL), p-toluene sulfonylmethyl isocyanide (2.25 g, 11.52 mmol), followed by potassium carbonate (1.86 g, 13.45 mmol). The reaction mixture was stirred at reflux for about 1.5 hour and followed by TLC. The solvent was then evaporated and saturated aq.NaHCO3 was added. The resultant suspension was extracted with CH2Cl2 (3×30 mL). Combined organic layers were washed with brine, dried (anhydrous Na2SO4), and concentrated to leave a yellow solid. Crude product was further purified by silica-column chromatographed (Biotage) using Acetone:Hexane as an eluent to yield 5-(1H-indol-2-yl)oxazole 19 (1.54 g, 79% yield). MS (ES) m/z 185 (M+H+).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]([CH3:14])[C:4](=[O:15])[C:3]=1[C:16]([O:18]C)=O.Cl.[CH3:21][O:22][C:23](=[O:27])[C@H:24]([CH3:26])[NH2:25]>O1CCOCC1>[OH:1][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]([CH3:14])[C:4](=[O:15])[C:3]=1[C:16]([NH:25][C@@H:24]([CH3:26])[C:23]([O:22][CH3:21])=[O:27])=[O:18]
Reactant: COC(=O)c1c(O)c2cccc(OC)c2n(C)c1=O
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@H](C)NC(=O)c1c(O)c2cccc(OC)c2n(C)c1=O
Temperature: 120 °C
Reaction time: 18 h

Procedure:
In a 35 mL sealed vial under N2 was suspended methyl 4-hydroxy-8-methoxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate (0.50 g, 1.9 mmol) in 1,4-dioxane (15 mL). To this solution was added L-alanine methyl ester hydrochloride (0.29 g, 2.1 mmol) and the reaction mixture was stirred at 120° C. overnight (18 h). The solution was removed from the heat and filtered over a fine frit funnel to remove any undissolved starting material. The filtrate was concentrated in vacuo and the remaining precipitate was suspended in Et2O, filtered and washed with Et2O and dried to provide a light yellow solid. Yield=0.40 g, 63%.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13](=[O:15])[CH3:14])=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:22]=[N:21][CH:20]=[C:19](Cl)[N:18]=1>>[Cl:16][C:17]1[N:18]=[C:19]([O:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([NH:12][C:13](=[O:15])[CH3:14])=[CH:4][CH:3]=2)[CH:20]=[N:21][CH:22]=1
Reactant: CC(=O)Nc1ccc(O)c2ccccc12
Reactant: Clc1cncc(Cl)n1
Product: CC(=O)Nc1ccc(Oc2cncc(Cl)n2)c2ccccc12
Yield: 68.2 %

Procedure:
Method DD was followed (in a round-bottomed flask, reaction time: 20 hours) with N-(4-hydroxynaphthalen-1-yl)acetamide (1.22 g, 6.08 mmol) and 2,6-dichloropyrazine (1.09 g, 7.30 mmol). The DMF was evaporated in vacuo. The resulting crude was dissolved in a mixture (hot) of AcOEt (25 mL) and acetone (175 mL) and filtered. The volume of the filtrate was reduced to 100 mL and this filtrate crystallised upon storage at low temperature to yield the title compound (1.30 g). Yield: 68%. 1H NMR (500 MHz, DMSO-d6) δ 2.21 (s, 3H), 7.42 (d, 1H, J=8.2 Hz), 7.57 (t, 1H, J=7.5 Hz), 7.64 (t, 1H, J=7.6 Hz), 7.72 (d, 1H, J=8.1 Hz), 7.90 (d, 1H, J=8.3 Hz), 8.16 (d, 1H, J=8.5 Hz), 8.52 (s, 1H), 8.72 (s, 1H), 10.02 (s, 1H). 13C NMR (125.8 MHz, DMSO-d6) δ 23.42, 117.59, 121.40, 121.65, 123.42, 126.53, 126.71, 126.85, 128.90, 131.85, 133.59, 137.50, 144.40, 145.04, 158.92, 169.04. m/z 314.0 [(M+H)+ calcd for C16H12ClN3O2 313.1].