Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([Cl:11])[S:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1.[C:14]([NH2:23])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:16])[CH3:15]>C(O)C>[Cl:11][C:9]1[S:10][C:5]2[S:4](=[O:13])(=[O:12])[N:3]=[C:2]([NH:23][C:14]([CH3:16])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:15])[NH:7][C:6]=2[CH:8]=1
Reactant: O=S1(=O)N=C(Cl)Nc2cc(Cl)sc21
Reactant: CC(C)(N)c1ccccc1
Solvent: CCO
Product: CC(C)(NC1=NS(=O)(=O)c2sc(Cl)cc2N1)c1ccccc1
Yield: 20 %

Procedure:
A solution of 3,6-dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (1.0 g, 3.9 mmol) and cumylamine (1.06 g, 7.8 mmol) in ethanol (6 ml) was stirred for 31 h at 120° C. in a sealed flask. The cooled solution was concentrated in vacuo and the residue dissolved in 1N sodium hydroxide (50 ml) followed by treatment with decolourising charcoal. After filtration, the clear solution was acidified to pH <2 with 4M hydrochloric acid and the precipitate was filtered off and recrystallised from ethanol to give 278 mg (20%) of the title compound; mp ca. 360° C. (decomposes gradually above 200° C.); 1H-NMR (DMSO-d6): δ1.68 (s, 6H), 7.12 (s, 1H), 7.17-7.41 (m, 6H), 10.72 (br s, 1H); MS: m/e 355/357 (M+); (C14H14ClN3O2S2) calc C, 47,25; H, 3.97; N, 11.81; found C, 46.82; H, 3.96; N, 11.62.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]([CH3:14])[C:10](=[O:15])[CH:9]=2)=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][CH2:19][Cl:20]>>[Cl:20][CH2:19][CH2:18][CH2:17][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]([CH3:14])[C:10](=[O:15])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: ClCCCBr
Reactant: Cn1ncc(-c2ccc(O)cc2)cc1=O
Product: Cn1ncc(-c2ccc(OCCCCl)cc2)cc1=O

Procedure:
5-[4-(3-Chloro-propoxy)-phenyl]-2-methyl-2H-pyridazin-3-one was prepared from 5-(4-hydroxy-phenyl)-2-methyl-2H-pyridazin-3-one with 1-bromo-3-chloro-propane using the procedure described in Example 86 Step 3; Mp 90-91° C.; MS m/z 279 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[N:21]=[CH:20][C:19]([CH2:22][N:23]5[CH2:28][CH2:27][O:26][CH2:25][C:24]5=[O:29])=[CH:18][CH:17]=4)[S:15][C:8]=23)=[C:4]([F:32])[CH:3]=1.ClC(Cl)(O[C:37](=[O:43])OC(Cl)(Cl)Cl)Cl.[CH:45]1([NH2:48])[CH2:47][CH2:46]1>C1COCC1.C(Cl)Cl>[CH:45]1([NH:48][C:37]([NH:1][C:2]2[CH:31]=[CH:30][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]4[CH:13]=[C:14]([C:16]5[CH:17]=[CH:18][C:19]([CH2:22][N:23]6[CH2:28][CH2:27][O:26][CH2:25][C:24]6=[O:29])=[CH:20][N:21]=5)[S:15][C:8]=34)=[C:4]([F:32])[CH:3]=2)=[O:43])[CH2:47][CH2:46]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NC1CC1
Reactant: Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCOCC5=O)cn4)sc23)c(F)c1
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCOCC5=O)cn4)sc23)c(F)c1)NC1CC1
Temperature: 25 °C
Yield: 23.4 %

Procedure:
To a solution of 122 (65 mg, 0.144 mmol) in THF (7 mL) was added TEA (0.06 mL, 0.433 mmol) and triphosgene (42.8 mg, 0.144 mmol) in THF (2 mL) and the mixture was stirred at RT for an hour. Cyclopropylamine (16.48 mg, 0.289 mmol) was added and the reaction mixture was stirred at RT overnight. The reaction mixture was diluted with DCM and washed with saturated NH4Cl solution. The organic phase was collected, dried over anhydrous Na2SO4, filtered and concentrated. The resultant solid was triturated with acetone to afford title compound 123 (18 mg, 23% yield) as an olive colored solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.69 (s, 1H), 8.55 (s, 1H), 8.51 (d, J=5.48 Hz, 1H), 8.34 (s, 1H), 8.25 (d, J=8.22 Hz, 1H), 7.82 (m, 1H), 7.71 (m, 1H), 7.36 (t, J=8.99 Hz, 1H), 7.19 (m, 1H), 6.63 (d, J=5.48 Hz, 1H), 6.55 (s, 1H), 4.60 (s, 2H), 4.12 (s, 2H), 3.83 (m, 2H), 3.36 (m, 2H), 2.49 (m, 1H), 0.64 (m, 2H), 0.42 (m, 2H). MS (m/z)=534.51 (M+H)
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].CCN(C(C)C)C(C)C.[NH:23]1[CH2:28][CH2:27][CH:26]([C:29]([NH2:31])=[O:30])[CH2:25][CH2:24]1>C(#N)C>[C:29]([CH:26]1[CH2:27][CH2:28][N:23]([CH:2]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:24][CH2:25]1)(=[O:30])[NH2:31]
Reactant: CCOC(=O)C(Br)c1ccccc1
Reactant: NC(=O)C1CCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(c1ccccc1)N1CCC(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.9 %

Procedure:
Ethyl 2-bromo-2-phenylacetate (0.22 ml, 1.23 mmol) was dissolved in acetonitrile (4 ml). DIPEA (0.28 ml, 1.60 mmol) and piperidine-4-carboxamide (0.21 g, 1.60 mmol) were sequentially added. The reaction was stirred at room temperature overnight. The mixture was evaporated and the residue was purified by flash chromatography (DCM/Acetone=8/2). The solid was triturated with i-Pr2O to obtain ethyl 2-(4-carbamoylpiperidin-1-yl)-2-phenylacetate (239 mg, 66.7% yield) as a pale yellow solid.
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]#[CH:20])[CH:12]=O.C([CH2:24][C:25]([NH:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30]([OH:32])=[O:31])=[O:26])(O)=O>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[CH:24]/[C:25]([NH:27][C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30]([OH:32])=[O:31])=[O:26])[CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]#[CH:20]
Reactant: C#CCOc1ccc(C=O)cc1OC
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: C#CCOc1ccc(/C=C/C(=O)Nc2ccccc2C(=O)O)cc1OC
Temperature: 25 °C
Yield: 61.1 %

Procedure:
Piperidine (158 mL, 1.59 mol) was added to a suspension of 3-methoxy-4-propargyloxybenzaldehyde (302 g, 1.59 mol) and 2-[(carboxyacetyl)amino]benzoic acid (322 g, 1.44 mol) in toluene (1.5 L). The reaction flask was fitted with a Dean-Stark apparatus and heated to reflux for 30 min. The reaction was then cooled to rt and the resulting suspension was filtered and washed with toluene. The piperidinium salt was dissolved in MeOH (4 L) and water (1 L) at 50° C. and the solution was acidified with 50% aqueous AcOH. The precipitate was filtered and the crude product was recrystallised from EtOH (35 mL/g), filtered and washed with cooled EtOH to afford (E)-2-[[3-(3-methoxy-4-propargyloxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (309 g, 61%) as a yellow crystalline solid; mp 201-203° C.; δH (400 MHz, DMSO-d6) 3.59 (t, J=2.4 Hz, 1H, C≡CH), 3.84 (s, 3H, OCH3), 4.84 (d, J=2.4 Hz, 2H, OCH2), 6.81 (d, J=15.6 Hz, 1H, CH═CHCO), 7.05 (d, J5,6=8.4 Hz, 1H, H5′), 7.16 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.25 (d, J5′,6′=8.4 Hz, 1H, H6′), 7.41 (s, 1H, H2′), 7.56 (d, J=15.6 Hz, 1H, CH═CHCO), 7.61 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 8.00 (d, J3,4=8.0 Hz, 1H, H3), 8.62 (d, J5,6=8.0 Hz, 1H, H6), 11.31 (s, 1H, NH), 13.57 (br s, 1H, CO2H); δC (100 MHz, DMSO-d6) 55.6, 55.9, 78.6, 79.1, 110.8, 113.5, 116.6, 120.4, 120.4, 122.2, 122.7, 128.2, 131.2, 134.0, 141.0, 141.5, 148.3, 149.3, 164.1, 169.5; HRMS (ESI) calculated for C20H17NO5 [M+H]+ 352.1179, found 352.1187; νmax 755, 1010, 1140, 1253, 1502, 1582, 1657, 3278, 3522 cm−1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=4[O:27][CH3:28])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35]OS(C)(=O)=O>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:14][CH2:15][CH:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=4[O:27][CH3:28])[CH2:17][CH2:18]3)=[O:12])=[CH:7][N:8]2[CH2:35][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=2)=[CH:4][CH:3]=1
Reactant: COc1cccc(OC)c1C1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Reactant: CS(=O)(=O)OCc1ccccn1
Product: COc1cccc(OC)c1C1CCN(C(=O)c2cn(Cc3ccccn3)c3cc(Cl)ccc23)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone (preparation described herein), with methanesulfonic acid pyridin-2-ylmethyl ester (described in WO 9955318) gave the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7]2[C:8]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:9]=3[N:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11](=[O:13])[CH2:12][C:6]2=[N:5][N:4]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1.C(Cl)Cl>[C:25]([O:1][CH2:2][C:3]1[N:7]2[C:8]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:9]=3[N:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11](=[O:13])[CH2:12][C:6]2=[N:5][N:4]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1Cc2nnc(CO)n2-c2ccc(Cl)cc2N1c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCc1nnc2n1-c1ccc(Cl)cc1N(c1ccccc1)C(=O)C2
Temperature: 25 °C
Reaction time: 10 h

Procedure:
3.4 g of 1-(hydroxymethyl)-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one and 1.0 g of acetic anhydride in 10 ml of pyridine are warmed in a steam bath for 0.2 hour and stirred at room temperature for 10 hours. The reaction mixture is cooled, diluted with 100 ml methylene chloride and washed with 100 ml water containing 0.84 g sodium bicarbonate. The organic phase is washed four times with water, dried and evaporated. The residue is triturated with a minimum amount of ether and the title compound filtered off, dried and recrystallized from methylene chloride and ether.
Reaction SMILES: [N:1]1[C:13]2[N:4]([C:5](=[O:14])[N:6]=[C:7]3[C:12]=2[CH:11]=[CH:10][CH:9]=[CH:8]3)[NH:3][C:2]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].OS(O)(=O)=O.[N+:25]([O-])([OH:27])=[O:26]>>[N+:25]([C:10]1[CH:9]=[CH:8][C:7]2[C:12](=[C:13]3[N:1]=[C:2]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[NH:3][N:4]3[C:5](=[O:14])[N:6]=2)[CH:11]=1)([O-:27])=[O:26]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1nc2c3ccccc3nc(=O)n2[nH]1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1nc2c3cc([N+](=O)[O-])ccc3nc(=O)n2[nH]1
Temperature: 0 °C

Procedure:
2.0 g (0.008 mole) of ethyl 1,2,4-triazolo[1,5-c]quinazolin-5-one-2-carboxylate were introduced into 20 ml of concentrated H2SO4 at 20° C., whilst stirring, and 0.3 ml of 100% strength HNO3 was added dropwise. The mixture was stirred for a further 3 hours at 20° C. and then introduced onto 100 ml of ice water. The precipitate was filtered off and dissolved in methylene chloride/methanol, the solution was treated with active charcoal and filtered, and the solvent was stripped off. Yield: 1.4 g (60%), mp. 280° C.
Reaction SMILES: [Br:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.CC[N:17](CC)CC.ClC(OCC)=O.N.O>C1COCC1>[Br:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH2:17])=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1
Reactant: O=C(O)c1cc(Cl)c(Br)cc1[N+](=O)[O-]
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)c1cc(Cl)c(Br)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
A mixture of 4-bromo-5-chloro-2-nitrobenzoic acid (1.3 g, 4.63 mmol), Et3N (1.4 g, 13.9 mmol) in THF (20 mL) at 0° C., ethyl chloroformate (1.5 g, 13.9 mmol) was added. The resulting mixture was stirred at 0° C. for 1 h. Then NH3.H2O (4 mL) was added and stirred for 0.5 h. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford the crude product (900 mg).
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]CC=C)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[C:20]([OH:24])([CH3:23])([CH3:22])C.S(OS([O-])=O)([O-])=[O:26].[Na+].[Na+]>CCCCCC.C(OCC)(=O)C>[CH2:1]([O:8][C@@H:9]([CH3:10])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:22][C@@H:20]([OH:24])[CH2:23][OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)O
Reactant: C=CCCCCCC[C@H](C)OCc1ccccc1
Reactant: O=S([O-])OS(=O)[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H](CCCCCC[C@@H](O)CO)OCc1ccccc1
Temperature: -10 °C
Reaction time: 40 h
Yield: 62 %

Procedure:
A vigorously stirred solution of 6.0 g (24.3 mmol) (S)-2-benzyloxydec-9-ene in 300 ml of a 1:1 mixture of water and tert-butanol was cooled to −10° C. After addition of 29.2 g AD-Mix β (i.e. 1.2 g per mmol alkene) the mixture was stirred at 4° C. for 40 h. Subsequently, 30.0 g (158 mmol) sodium disulfite were added, and the mixture was stirred at 20° C. for another hour. The brownish suspension was extracted three times with 250 ml ethyl acetate. The organic layers were combined, dried over magnesium sulphate, and concentrated in vacuo. Flash chromatography (ethyl acetate and hexane 1:1) furnished 4.2 g (15 mmol, 62%) (2R,9S)-9-benzyloxydecan-1,2-diol as a colorless oil.
Reaction SMILES: [H-].[Na+].[O:3]1[C:11]2[CH:10]=[CH:9][NH:8][C:7](=[O:12])[C:6]=2[CH:5]=[CH:4]1.C([O:15][CH:16]([O:19]CC)[CH2:17]Br)C.O>CN(C=O)C>[OH:15][CH:16]([OH:19])[CH2:17][N:8]1[CH:9]=[CH:10][C:11]2[O:3][CH:4]=[CH:5][C:6]=2[C:7]1=[O:12]
Reactant: O=c1[nH]ccc2occc12
Reactant: CCOC(CBr)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2ccoc2ccn1CC(O)O
Temperature: 0 °C

Procedure:
Sodium hydride (60% in oil, 0.36 g) was suspended in DMF(10 ml), and was cooled to 0° C. in an ice water bath. 5H-Furo[3,2-c]pyridin-4-one(1.0 g) was added thereto at the same temperature, and the mixture was stirred at 0° C. for an hour. Bromoacetaldehyde diethylacetal(2.6 ml) was added thereto, and the mixture was stirred at 80° C. for 5 hours. Water was added to the reaction liquid, followed by extraction by ethyl acetate. The organic layer was dried over sodium sulfate, and condensed under reduced pressure. A 3N-hydrochloric acid(5.8 ml) was added to an acetone solution (20 ml) of the residue, and the liquid was stirred at 60° C. for 5 hours. Water was added to the reaction liquid and stirred at room temperature. The precipitated insoluble matter was separated, washed with water, and dried to give the title compound(0.90 g) as a white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH:19]4[CH2:21][CH2:20]4)[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:28][S-:29].[Na+]>CN(C=O)C.CCOC(C)=O>[CH:19]1([CH2:18][N:15]2[CH2:16][CH2:17][N:12]([CH2:11][C:9]3[S:10][C:5]4[C:4]([N:22]5[CH2:27][CH2:26][O:25][CH2:24][CH2:23]5)=[N:3][C:2]([S:29][CH3:28])=[N:7][C:6]=4[CH:8]=3)[CH2:13][CH2:14]2)[CH2:21][CH2:20]1
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCN(CC4CC4)CC3)cc2n1
Reactant: C[S-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1nc(N2CCOCC2)c2sc(CN3CCN(CC4CC4)CC3)cc2n1
Temperature: 100 °C
Yield: 97.3 %

Procedure:
2-Chloro-6-(4-(cyclopropylmethyl)piperazin-1-ylmethyl)-4-morpholin-4-ylthieno[3,2-d]pyrimidine (0.2 g, 0.49 mmol) in DMF (3 mL) was treated with sodium thiomethoxide (0.12 g, 1.71 mmol) in a sealed tube and the reaction mixture heated at 100° C. with stirring. After 2 hours the contents of the tube were diluted with EtOAc then washed with saturated aqueous NaHCO3 (×2) followed by brine and the organic phase was isolated, dried (Na2SO4), filtered and concentrated to afford 6-(4-(cyclopropylmethyl)piperazin-1-ylmethyl)-2-methylsulfanyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine as a pale yellow solid (0.2 g, 97%). LCMS (Method D): RT=2.04 min, [M+H]+ 419
Reaction SMILES: [C:1]([C:9]1[C:10]([CH3:28])=[N:11][C:12]([CH2:26][CH3:27])=[CH:13][C:14]=1[NH:15]S(C1C=CC(C)=CC=1)(=O)=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(OCC)=O>C1(C)C(C)=CC=CC=1>[NH2:15][C:14]1[CH:13]=[C:12]([CH2:26][CH3:27])[N:11]=[C:10]([CH3:28])[C:9]=1[C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1cc(NS(=O)(=O)c2ccc(C)cc2)c(C(=O)c2ccccc2)c(C)n1
Agent: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1C
Product: CCc1cc(N)c(C(=O)c2ccccc2)c(C)n1
Yield: 46.3 %

Procedure:
A mixture of compound C (1.1 g) and (carbethoxymethylene)triphenylphosphorane (6 g) in xylene (200 ml) was stirred and heated at reflux for 4 hours. The solution was then concentrated by evaporation and a solution of sodium (2.6 g) in methanol (200 ml) was added. The mixture was stirred and heated at reflux for 4 hours. Volatile material was removed by evaporation and water was added to the residue. The mixture was then acidified by the addition of concentrated hydrochloric acid and extracted twice with ether. The ether extracts were discarded. The aqueous phase was basified with solid potassium carbonate and extracted twice with ethyl acetate. The combined extracts were washed with water, saturated sodium chloride solution and dried (MgSO4). Solvent was removed by evaporation to leave a residue which was recrystallised from acetone to give 5,7-diethyl-4-methyl-1,6-naphthyridin-2(1H)-one (D) (0.31 g) as a solid, m.p. 220°-223° C.; NMR (d6 -DMSO): 1.22(t, 3H), 1.24(t, 3H), 2.62(s, 3H), 2.69(q, 2H), 3.16(q, 2H), 6.33(s, 1H), 6.91(s, 1H), 11.68(s, 1H); mass spectrum (CI, ammonia): 217 (M+H)+ ; microanalysis, found: C, 71.5; H, 7.1; N, 12.9%; C13H16N2O requires: C, 72.2; H, 7.5; N, 13.0%.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[Cl:13])[N:3]=1.[O:14]([CH3:16])[K].CCOC(C)=O>CO>[Cl:1][C:2]1[CH:11]=[C:10]([O:14][CH3:16])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[Cl:13])[N:3]=1
Reactant: CO[K]
Reactant: Clc1cc(Cl)c2c(Cl)cccc2n1
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(Cl)nc2cccc(Cl)c12
Temperature: 25 °C

Procedure:
To 2.4,5-trichloroquinoline (0.79 g, 3.4 mmol) was added KOMe (20.4 ml of a 0.5 M suspension in MeOH). The mixture was heated under reflux for 2.5 h. EtOAc was added and the solution was allowed to cool to room temperature. The solvent was evaporated in vacuo and the residue submitted to column chromatography (silica gel, EtOAc:hexanes 1:6→1:3). 4,5-Dichloro-2-methoxyquinoline eluted first, then 2,4,5-trichloroquinoline. followed by the title compound, a colourless solid, (0.43 g, 44%). δH (CDCl3) 4.04 (s, 3H), 6.77 (s, 1H), 7.50-7.60 (m, 2H), 7.85 (dd, J=6.7, 3.0, 1H); MS (AP+) 228 (MH+, 100%).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)C(=O)[C:3]=1[C:23](=O)[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]([F:34])([F:33])[F:32].O.[NH2:37][NH2:38].[C:39](=[O:42])([O-])O.[Na+]>CN(C=O)C>[F:33][C:31]([F:34])([F:32])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH2:24][C:23]1[C:3]2[C:39](=[O:42])[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:19])[F:21])[CH:13]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:38][N:37]=1
Reactant: NN
Reactant: O=C(Cc1ccccc1C(F)(F)F)c1c(O)c2cccnc2n(-c2cccc(C(F)(F)F)c2)c1=O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c(Cc3ccccc3C(F)(F)F)n[nH]c2c2cccnc2n1-c1cccc(C(F)(F)F)c1
Temperature: 105 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
To a suspension of 4-hydroxy-1-(3-trifluoromethylphenyl)-3-(2-trifluoromethylphenylacetyl)-1,8-naphthyridin-2(1H)-one (740 mg, 1.5 mmol) produced in Synthesis Example 14 in DMF (5 mL) was added hydrazine monohydrate (purity of 80%, 291 μL), and the mixture was stirred at 100 to 110° C. for 1 hour. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration, recrystallized from ethanol, and dried to give 3-(2-trifluoromethylbenzyl)-5-(3-trifluoromethylphenyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one (489 mg, yield 67%).
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:28])[C@H:10]([NH2:27])[C:11]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]2[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:13]=2[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:30]1[N:38]=[CH:37][N:36]=[C:35]2[C:31]=1[N:32]=[CH:33][N:34]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[CH2:1]([O:8][C@H:9]([CH3:28])[C@H:10]([NH:27][C:30]1[N:38]=[CH:37][N:36]=[C:35]2[C:31]=1[NH:32][CH:33]=[N:34]2)[C:11]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]2[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:13]=2[N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@@H](OCc1ccccc1)[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@@H](OCc1ccccc1)[C@H](Nc1ncnc2nc[nH]c12)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 90 °C
Yield: 96.1 %

Procedure:
A mixture of (1R,2R)-2-benzyloxy-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)propylamine (100 mg, 0.27 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (65 mg, 0.27 mmol) and DIPEA (240 μL, 1.35 mmol) in n-butanol (1 mL) was heated at 90° C. in a sealed vial for 18 h. After cooling to RT, the volatiles were removed in vacuo and the resulting residue loaded onto an Isolute® SCX-2 cartridge then washed with MeOH followed by 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) to afford the title compound (128 mg, 96%). LCMS (Method J): RT 3.19 min [M+H]+ 494.1.
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][C:10]1=[O:15].[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:27]=[C:26]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[N:25]([CH2:35][C:36](Cl)=[O:37])[N:24]=2)=[CH:19][CH:18]=1.C(N(CC)CC)C>ClCCl>[F:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[N:27]=[C:26]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[N:25]([CH2:35][C:36]([N:12]3[CH2:13][CH2:14][N:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=4)[C:10](=[O:15])[CH2:11]3)=[O:37])[N:24]=2)=[CH:21][CH:22]=1
Reactant: O=C1CNCCN1c1ccccn1
Reactant: O=C(Cl)Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1)N1CCN(c2ccccn2)C(=O)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 30.6 %

Procedure:
160 mg 1-pyridin-2-yl-piperazin-2-one dihydrochloride was added to 216 mg (3,5-bis-(4-fluoro-phenyl)-(1,2,4)triazol-1-yl)-acetyl chloride and 300 μL triethylamine in 10 mL dichlormethane. The reaction was stirred for 1 day at RT, the solvent was evaporated and the residue was purified by HPLC to yield 93 mg of the desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[CH:13]=1)([O-])=O.O.O.[Sn](Cl)Cl>C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[CH:13]=1
Reactant: Nc1nc2cc([N+](=O)[O-])ccc2s1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc2sc(N)nc2c1
Temperature: 80 °C
Yield: 74.4 %

Procedure:
To a solution of ethanol (36 mL) was added 5-nitro-benzothiazol-2-ylamine (Example 15, 78 mg, 0.35 mmol) and tin dichloride dihydrate (449 mg, 2 mmol). The resulting mixture was heated at 80° C. for 4 hours. The solution was cooled to room temperature and the solvent was removed. The residue was dissolved in ethyl acetate and poured onto 50 mL of 1.5 N NaOH solution and extracted using ethyl acetate (3×30 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to give a solid (43 mg, 66%). 1H NMR (DMSO d) δ: 7.23–7.19 (m, 3H), 6.59 (d, 1H, J=1.96 Hz), 6.32 (dd, 1H, J=2.18, 8.28 Hz), 4.88 (br s, 2H); MS (ESI) 166 (M+1, 100%).