Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22](=[O:34])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[O:30][CH:31]=[CH:32][N:33]=3)=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:35]([F:38])([F:37])[F:36].O>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([C:22](=[O:34])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[O:30][CH:31]=[CH:32][N:33]=3)=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:35]([F:37])([F:38])[F:36]
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1ccccc1-c1ncco1)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: O=C(c1ccccc1-c1ncco1)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 57.7 %

Procedure:
A mixture of 4-Chloro-N-[5-chloro-2-(2-oxazol-2-yl-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(15 mg) in 2 mL of 4M HCl in dioxane and 1 mL of water was refluxed for 2 hours. After cooling to rt the mixture was concentrated, diluted with water and then sodium bicarbonate was added until pH was 6. The mixture was extracted with ethyl acetate, dried and concentrated. The residue was purified via flash column (35% ethyl acetate in hexane) to afford 8.0 mg of title compound as an off white solid. MS: (M+H)/z=542.3.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([NH:17][CH2:18][CH3:19])[N:14]=[C:15]([CH3:16])[C:10]=3[CH:9]=[C:8]([CH2:20][CH2:21][C:22]([O:24]CC)=[O:23])[C:7]2=[O:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Li+].Cl>C1COCC1.O>[CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([NH:17][CH2:18][CH3:19])[N:14]=[C:15]([CH3:16])[C:10]=3[CH:9]=[C:8]([CH2:20][CH2:21][C:22]([OH:24])=[O:23])[C:7]2=[O:27])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCNc1nc(C)c2cc(CCC(=O)OCC)c(=O)n(C3CCCC3)c2n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCNc1nc(C)c2cc(CCC(=O)O)c(=O)n(C3CCCC3)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.7 %

Procedure:
Ethyl 3-(8-cyclopentyl-2-(ethylamino)-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)propanoate (167 mg, 0.45 mmole) was dissolved in THF (5 ml) in a reaction vial equipped with a stir bar. Lithium hydroxide (35 mg, 1.46 mmole) was dissolved in water (5 ml) and then added to the reaction vial. The reaction mixture was stirred at ambient temperature for 3 h. The volatiles were removed under reduced pressure to a white solid residue. Aqueous hydrochloric acid (3.26 mmole, 3.26 ml of 1.0 M solution) was added. The white solid was collected by filtration as the title compound (125 mg, 81% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:21]=[CH:20][N:19]=[CH:18][C:7]=3[CH2:8][NH:9][CH:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.N1C=CC=CC=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:21]=[CH:20][N:19]=[CH:18][C:7]=3[CH2:8][N:9]([S:30]([C:27]3[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=3)(=[O:32])=[O:31])[CH:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Clc1ccc2c(c1)C(c1ccccc1Cl)NCc1cncnc1-2
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2Cc3cncnc3-c3ccc(Cl)cc3C2c2ccccc2Cl)cc1

Procedure:
A solution of 14.5 g (42 mmole) of 9-chloro-7-(2-chlorophenyl)-6,7-dihydro-5H-pyrimido[5,4-d][2]benzazepine, 14.5 g (76 mmols) of p-toluene-sulfonyl chloride, 30 ml of pyridine and 0.3 g of 4-dimethylaminopyridine in 300 ml of methylene chloride was stirred at room temperature for 24 hr. The mixture was washed with an excess of dilute ice cold hydrochloric acid and dilute aqueous sodium hydroxide. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. The residue crystallized from a mixture of methylene chloride and ether to give the product as a white solid, mp 200°-201° C. Recrystallization from a mixture of ether and methylene chloride gave the pure product as colorless prisms, mp 200°-201° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][N:15]([CH3:29])[C:16]([C:18]1[C:19]2[CH2:20][CH2:21][NH:22][CH:23]([CH3:28])[C:24]=2[CH:25]=[CH:26][CH:27]=1)=[O:17]>>[CH3:14][N:15]([CH3:29])[C:16]([C:18]1[C:19]2[CH2:20][CH2:21][N:22]([C:11]([C:9]3[CH:10]=[C:5]4[N:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]4[N:8]=3)=[O:13])[CH:23]([CH3:28])[C:24]=2[CH:25]=[CH:26][CH:27]=1)=[O:17]
Reactant: CC1NCCc2c(C(=O)N(C)C)cccc21
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: CC1c2cccc(C(=O)N(C)C)c2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-1,2,3,4-tetrahydro-isoquinoline-5-carboxylic acid dimethylamide to provide the title compound in moderate yield.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28]#[N:29])[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>CN(C)C=O.C(OCC)(=O)C>[CH2:3]([O:10][C:11]([N:13]1[CH2:14][CH2:15][CH:16]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28]#[N:29])[CH:26]=3)[N:21]([S:31]([CH3:30])(=[O:33])=[O:32])[CH:20]=2)[CH2:17][CH2:18]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1ccc2[nH]cc(C3CCN(C(=O)OCc4ccccc4)CC3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)n1cc(C2CCN(C(=O)OCc3ccccc3)CC2)c2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
Sodium hydride (115 mg, 4.8 mmol) was added to a solution of 1-benzyloxycarbonyl-4-(5-cyanoindol-3-yl)piperidine (1.5 g, 4.17 mmol) [prepared as described in Step 1 above] in dimethylformamide (12 ml) at 0° C. After 30 min., methanesulfonyl chloride (0.81 ml, 10.43 mmol) was added and after stirring for 2.5 h the reaction mixture was allowed to warm to RT over 1 h. The reaction mixture was diluted with ethyl acetate (100 ml) and washed with water, brine and dried over MgSO4. The organics were evaporated in vacuo and the residue was chromatographed (PTLC, SiO2, 40% ethyl acetate/hexanes) to give 1-benzyloxycarbonyl-4-(5-cyano-1-methanesulfonylindol-3-yl)piperidine (54%) as a pale yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[CH2:15][C:16]1[O:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:15][C:16]3[O:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: ClCc1nc2ccccc2o1
Reactant: Oc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Oc1ccc(N2CCN(Cc3nc4ccccc4o3)CC2)cc1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 71.7 %

Procedure:
A mixture of 6.06 g (34 mmol) of 1-(4-hydroxyphenyl)piperazine and 5.36 g (32 mmol) of 2-chloromethylbenzoxazole in 100 ml of absolute DMF was warmed to 80° C., and 737 mg of powdered K2CO3 were added with stirring (under a nitrogen atmosphere) in each case after 10 minutes, after a further 25 minutes and after a further 60 minutes (total addition of 2.21 g (16 mmol) of K2CO3). The mixture was stirred for a further 3 hours at 80° C., the DMF was substantially removed by distillation in vacuo, and the residue was taken up in 200 ml of ether and 100 ml of water. After separating the phases, the aqueous phase was extracted a further twice with ether. The combined ether extracts were dried, filtered and evaporated in vacuo. The residue was taken up in diisopropyl ether, whereafter crystallization occurred. The crystalline substance was filtered off under suction. 7.10 g (71.7% of theory) of 1-(4-hydroxyphenyl)-4-(benzoxazol-2-ylmethyl)piperazine, melting point 155°-56° C., were obtained,
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH2:14])[CH:12]=2)[N:7](C(OCC)=O)[C:6]=1[C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:3])[CH3:2].N1C=CC=CC=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH:14][S:35]([CH3:34])(=[O:37])=[O:36])[CH:12]=2)[NH:7][C:6]=1[C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)n1c(C(=O)c2ccccc2)c(NC(C)=O)c2cc(N)ccc21
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1c(C(=O)c2ccccc2)[nH]c2ccc(NS(C)(=O)=O)cc12
Reaction time: 1 h
Yield: 65.8 %

Procedure:
To a solution of 3-acetylamino-5-amino-2-benzoyl-1-ethoxycarbonylindole (Example 99, step 1: 100 mg, 0.27 mmol) in dichloromethane (5 ml) and pyridine (33 μl, 0.41 mmol) was added methanesulfonyl chloride (25 μl, 0.32 mmol) and the mixture was stirred for 1 h. The mixture was partitioned between 2N aqueous HCl (30 ml) and ethyl acetate (30 ml), the organic layer separated and washed cocnsecutively with brine (10 ml), saturated aqueous sodium bicarbonate (10 ml), brine (10 ml) and dried (MgSO4). After removal of solvent the residue was diluted with ethanol (10 ml) and water (5 ml), and potassium hydroxide (0.5 g) added. The mixture was stirred for 4 h, poured into a saturated aqueous ammonium chloride (30 ml) and extracted with ethyl acetate (50 ml×2). The organic layer was washed with brine (50 ml), dried (MgSO4), and solvent removed by evaporation. The residue was recrystallized from methanol/dichloromethane/hexane to give 66 mg of the title compound as a yellow solid. m.p.: 260-261° C. 1H-NMR (DMSO-d6) δ: 11.7 (1H, br s), 9.63 (1H, s), 7.81-8.22 (2H, m), 7.40-7.64 (7H, m), 2.90 (3H, s), 164 (3H, s).
Reaction SMILES: [CH3:1][S:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][S:15]([NH2:18])(=[O:17])=[O:16])=[N:5][N:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25]([N:29]=[C:30]=[O:31])[CH2:26][CH2:27][CH3:28]>CC(=O)CC>[CH2:25]([NH:29][C:30]([NH:18][S:15]([CH2:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[O:7][C:3]([S:2][CH3:1])=[N:4][N:5]=1)(=[O:17])=[O:16])=[O:31])[CH2:26][CH2:27][CH3:28]
Reactant: CCCCN=C=O
Reactant: CSc1nnc(-c2ccccc2CS(N)(=O)=O)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCNC(=O)NS(=O)(=O)Cc1ccccc1-c1nnc(SC)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
A suspension containing 16 g of the sulfonamide of Example 3, 7.7 g of potassium carbonate and 6.7 g of n-butylisocyanate in 130 of 2-butanone was refluxed for 4 hours, then stirred overnight at room temperature. After concentrating the mixture in vacuo, the residue was diluted with about 150 ml of water and the solution was washed 1×100 ml of ethyl ether. The aqueous layer was acidified with concentrated hydrochloric acid (red to litmus paper) and the resulting suspension was filtered, the suction-dried overnight to give 20 g of the subject compound; m.p. 156°-159° C. IR (nujol): 1680 cm-1 (C=O).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[H-].[Na+].Br[CH:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O.C(OCC)(=O)C>[C:17]1([CH:16]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:7]2[C:8]3[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)[C:5](=[O:12])[C:6]2=[O:11])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: O=C1Nc2ccc(F)cc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccc(F)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 52.4 %

Procedure:
To a stirred solution of 5-fluoroisatin (6.00 g, 36.3 mmol) in N,N-dimethylformamide (50 mL) was added sodium hydride (1.60 g, 40.0 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h followed by the addition of bromodiphenylmethane (10.0 g, 38.0 mmol). The mixture was stirred at 60° C. for 7 h, diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness, the residue was recrystallized from ethyl acetate and hexanes to give 1-(diphenylmethyl)-5-fluoro-1H-indole-2,3-dione (6.30 g, 52%): 1H NMR (300 MHz, CDCl3) 7.39-7.27 (m, 11H), 7.04-6.97 (m, 2H), 6.46-6.42 (m, 1H); MS (ES+) m/z 354.2 (M+23).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]([NH:11][C:12]1[NH:18][C:17]2[N:19](C(C)=O)[CH:20]=[N:21][C:16]=2[C:14](=O)[N:13]=1)=[O:10].P(Cl)(Cl)([Cl:27])=O>[Cl-].C([N+](CC)(CC)CC)C.C(#N)C>[C:9]([NH:11][C:12]1[N:18]=[C:17]2[C:16]([NH:21][CH:20]=[N:19]2)=[C:14]([Cl:27])[N:13]=1)(=[O:10])[CH3:8]
Reactant: CC(=O)Nc1nc(=O)c2ncn(C(C)=O)c2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(Cl)c2[nH]cnc2n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 81.1 %

Procedure:
60.0 g (0.36 mol) of tetraethylammonium chloride and 20.3 g (0.2 mol) of triethylamine are added to a suspension of 42.6 g (0.18 mol) of 2,9-diacetylguanine in 450 ml of acetonitrile. 165.3 g (1.08 mol) of phosphorus oxychloride are then added at a temperature of the reaction mixture of 0° C. to 5° C. The mixture is stirred at 25° C. for 20 hours and then worked up as in Example 1. 30.9 g of 2-acetamido-6-chloropurine are obtained.
Reaction SMILES: [CH3:1][C:2]1([C:18]([O:20]C)=[O:19])[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[S:10][C:5]=2[C:4](=[O:17])[NH:3]1.[OH-].[Na+].C(#N)C.CO>CO>[CH3:1][C:2]1([C:18]([OH:20])=[O:19])[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=3)[S:10][C:5]=2[C:4](=[O:17])[NH:3]1
Reactant: COC(=O)C1(C)NC(=O)c2sc(-c3ccncc3)cc2N1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CO
Product: CC1(C(=O)O)NC(=O)c2sc(-c3ccncc3)cc2N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 21.4 %

Procedure:
A mixture of methyl 2-methyl-4-oxo-6-(pyridin-4-yl)-1,2,3,4-tetrahydrothieno[3,2-d]pyrimidine-2-carboxylate (0.152 g, 0.500 mmol) and 2 M sodium hydroxide (0.75 mL, 1.5 mmol) in methanol (10 mL) was stirred at room temperature for 3 h, and the resulting suspension was stored at −20° C. for 65 h. Then, the reaction mixture was warmed to room temperature, and the precipitate was collected by filtration and washed with methanol (1 mL) to give a yellow solid. This yellow solid was partitioned between ethyl acetate (25 mL) and water (10 mL), and the ethyl acetate layer was extracted with water (2×5 mL). The combined aqueous layers were acidified with acetic acid to a pH of 5 to 6, and the resulting orange precipitate was collected by filtration and washed with water to give an orange solid. Trituration with acetonitrile/methanol gave the title compound (0.031 g, 21%) as an orange solid:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1.Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C([O-])(=O)C.[Na+].O>C(O)C>[CH3:8][C:4]1[CH:3]=[C:2]([NH:1][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1cccc(N)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CNc1cccc(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of m-toluidine (10 g), ethyl bromoacetate (10.3 ml), sodium acetate (7.6 g) and water (5 ml in ethanol (50 ml) was stirred at room temperature overnight. The product was filtered off as the hydrobromide salt. Yield 11.6 g.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C@H:9]([NH:16][C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:10][C@H:11]([CH3:15])[NH:12]2)=[CH:7][C:6]=1[O:27][CH3:28])=[O:4].N1C=CC=CC=1.Cl[C:36]([O:38][CH2:39][CH3:40])=[O:37].ClC(OC)=O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C@H:9]([NH:16][C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:10][C@H:11]([CH3:15])[N:12]2[C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:7][C:6]=1[O:27][CH3:28])=[O:4]
Reactant: CCOC(=O)Cl
Reactant: COC(=O)c1cc2c(cc1OC)[C@H](NC(=O)OCc1ccccc1)C[C@H](C)N2
Agent: COC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)N1c2cc(C(=O)OC)c(OC)cc2[C@H](NC(=O)OCc2ccccc2)C[C@@H]1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
To a solution of cis-4-benzyloxycarbonylamino-6-methoxy-2-methyl-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid methyl ester (0.99 g, 2.6 mmol) in anhydrous dichloromethane (30 mL) was added pyridine (0.27 mL, 3.35 mmol). The mixture was cooled to 0° C., and ethyl chloroformate (0.29 mL, 3.1 mmol) was slowly added. The reaction was stirred at 0° C. for 30 min, then at room temperature for 2.5 h. Additional aliquots of pyridine and methyl chloroformate were added to drive the reaction to completion. The reaction mixture was evaporated to dryness, and the residue was partitioned between ethyl acetate (75 ml) and water (25 ml). The organic layer was washed with water (25 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to give the crude product. Purification by silica gel chromatography using 25% ethyl acetate/hexanes as eluent afforded the title product (1.06 g). MS m/z 457 (M+ +1); 1H NMR (DMSO-d6) δ 1.45 (d, 3H), 6.68 (s, 1H).
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:25][CH:26]([CH3:29])[CH2:27][OH:28]>>[CH:18]1([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:25][CH:26]([CH3:29])[CH2:27][OH:28])=[O:24])=[CH:5][N:6]=3)=[C:16]([CH3:17])[O:15][N:14]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CC(N)CO
Reactant: COC(=O)c1ccc(OCc2c(C3CCCCC3)noc2C)nc1
Product: Cc1onc(C2CCCCC2)c1COc1ccc(C(=O)NC(C)CO)cn1
Temperature: 50 °C
Yield: 70.6 %

Procedure:
A mixture of 6-(3-cyclohexyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (500 mg, 1.1 mmol), rac-2-amino-1-propanol (95 mg, 1.3 mmol) and TBD (44 mg, 0.31 mmol) was heated at 50° C. for 15 h under argon. The reaction mixture was concentrated onto silica then purified by chromatography (silica, 0 to 5% methanol in dichloromethane) to give the title compound (290 mg, 73%) as a white solid. MS: m/e=374.4 [M+H]+.
Reaction SMILES: ClC(Cl)(Cl)COC(=O)[NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:32])[NH:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=3)=[CH:16][C:15]=2[NH:33][C:34]2[C:35]3[CH:43]=[CH:42][C:41]([CH:44]([CH3:46])[CH3:45])=[N:40][C:36]=3[N:37]=[CH:38][N:39]=2)=[CH:9][CH:8]=1.[OH-].[Na+].Cl>O1CCCC1.O>[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][N:23]=3)=[O:32])=[CH:16][C:15]=2[NH:33][C:34]2[C:35]3[CH:43]=[CH:42][C:41]([CH:44]([CH3:46])[CH3:45])=[N:40][C:36]=3[N:37]=[CH:38][N:39]=2)=[CH:9][CH:8]=1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(C(F)(F)F)cn4)ccc3Sc3ccc(NC(=O)OCC(Cl)(Cl)Cl)cc3)ncnc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(C(F)(F)F)cn4)ccc3Sc3ccc(N)cc3)ncnc2n1
Temperature: 60 °C

Procedure:
To a solution of the product of Example 175B in tetrahydrofuran and water (1:1) was added 1 M NaOH (5 equiv). The solution was heated at 60° C. for 40 minutes, cooled, adjusted to pH 6 with 1N aqueous hydrochloric acid and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated under vacuum. The crude product was purified by silica gel chromatography eluting with 2% methanol in dichloromethane to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.34 (d, J=6.62 Hz, 6 H) 3.15-3.29 (m, 1 H) 5.63 (s, 2 H) 6.65 (d, J=8.46 Hz, 2 H) 6.84 (d, J=8.46 Hz, 1 H) 7.16 (d, J=8.46 Hz, 2 H) 7.64 (d, J=8.46 Hz, 1 H) 7.90 (d, J=6.99 Hz, 1 H) 8.06 (s, 1 H) 8.23 (dd, J=8.82, 1.47 Hz, 1 H) 8.39 (d, J=8.82 Hz, 1 H) 8.59 (s, 1 H) 8.76 (s, 1 H) 8.89 (d, J=8.46 Hz, 1 H) 10.14 (s, 1 H) 11.20 (s, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][CH:31]=2)[CH2:25][CH2:24]1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>CC#N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:33]3[CH:32]=[CH:31][C:30]([CH2:29][N:26]4[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]4)=[CH:35][CH:34]=3)=[CH:9][N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: CN1CCN(Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccc(CN4CCN(C)CC4)cc3)c3cc(Br)cnc32)cc1

Procedure:
5-Bromo-3-iodo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (200 mg, 0.419 mmol), 1-methyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-piperazine (160 mg, 0.503 mmol) and dichlorobis(triphenylphosphine)palladium (II) (30 mg, 0.042 mmol) were combined in CH3CN (5 ml) and 1 M Na2CO3 (5 ml) and stirred at 60° C. for 2 hrs. EtOAc was added and the organic phase was washed with water, dried and evaporated.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[SH2:17]>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][N:5]=[CH:6][C:7]=1[C:8](=[S:17])[NH2:9]
Reactant: S
Reactant: Cc1ccncc1C#N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccncc1C(N)=S
Temperature: 25 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
To a solution of compound (14)(9.2 g, 77.9 mmol) in dimethylformamide (500 ml) was added triethylamine (800 mg, 7.79 mmol; 10 mol %), and the mixture was stirred at room temperature for 16 hrs. while introducing hydrogen sulfide gas. The solvent was concentrated and the obtained residue was partitioned between dichloromethane and brine. The aqueous layer was extracted with dichloromethane. The extracts were combined and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was recrystallized from a small amount of ethyl acetate to give the title compound (10.2 g, 86%).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([OH:12])=[O:11])[C:5]=12.S(Cl)(Cl)=O.[CH3:17]O>>[CH3:17][O:11][C:10]([C:6]1[C:5]2[N:4]([CH:3]=[CH:2][N:1]=2)[CH:9]=[CH:8][CH:7]=1)=[O:12]
Reactant: O=C(O)c1cccn2ccnc12
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccn2ccnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of imidazo[1,2-a]pyridine-8-carboxylic acid (3.8 g, 23 mmol) in methanol (100 mL) is added thionylchloride (8.36 g, 70.3 mmol) and the mixture is warmed at reflux. After 8 hours, the reaction mixture is cooled to room temperature and quenched with saturated aqueous NaHCO3, and extracted with EtOAc (3×250 mL). The combined organic layers are washed with water, brine, dried over Na2SO4 and concentrated. The crude material is purified by silica gel chromatography eluting with 3% MeOH in CH2Cl2 to afford imidazo[1,2-a]pyridine-8-carboxylic acid methyl ester. Mp: 71-73° C.
Reaction SMILES: F[C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[C:4]([F:11])[N:3]=1.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][CH2:20][O:21][CH2:22][C:23]([NH2:25])=[NH:24]>>[F:11][C:4]1[CH:5]=[CH:6][C:7]2[C:8](=[O:10])[NH:25][C:23]([CH2:22][O:21][CH2:20][CH2:19][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[F:12])=[N:24][C:2]=2[N:3]=1
Reactant: O=C(O)c1ccc(F)nc1F
Reactant: N=C(N)COCCc1ccccc1F
Product: O=c1[nH]c(COCCc2ccccc2F)nc2nc(F)ccc12
Yield: 80 %

Procedure:
The title compound was synthesized in analogy to example 85 using 2,6-difluoropyridine-3-carboxylic acid and 2-[2-(2-fluorophenyl)-ethoxy]-acetamidine to give 7-fluoro-2-[2-(2-fluorophenyl)-ethoxymethyl]-3H-pyrido[2,3-d]pyrimidin-4-one as the desired product (80%) as a white solid. MS: m/e=318.2 [M+H+].