Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(N(C(C)C)CC)(C)C.CN(C(O[N:44]1[N:52]=[N:51][C:46]2[CH:47]=[CH:48]C=N[C:45]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.NC1C=CN=NC=1>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([NH:51][C:46]1[CH:47]=[CH:48][N:52]=[N:44][CH:45]=1)=[O:8]
Reactant: O=C(O)c1cc(Cl)c(C(=O)N2CCOCC2)cc1OCc1ccccc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1ccnnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccnnc1)c1cc(Cl)c(C(=O)N2CCOCC2)cc1OCc1ccccc1
Reaction time: 2 h

Procedure:
To a solution of 5-chloro-4-(4-morpholinylcarbonyl)-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 67; 90 mg, 0.24 mmol) in N,N-dimethylformamide (3 ml) was added diisopropylethylamine (0.08 ml, 0.48 mmol), HATU (164 mg, 0.43 mmol) and 4-aminopyridazine (26.8 mg, 0.29 mmol). The solution was stirred for 2 hours and the solvent removed in vacuo. The residue was purified by column chromatography (SiO2, Isolute, 1:1 ethyl acetate/cyclohexane) to give the title compound as a white solid. 71 mg.
Reaction SMILES: [Na].Cl[C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][S:6][N:7]=1.[CH2:14]([OH:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>>[CH2:14]([O:22][C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][S:6][N:7]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCO
Reactant: Clc1nsnc1-c1cccnc1
Agent: [Na]
Product: CCCCCCCCOc1nsnc1-c1cccnc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of sodium (350 mg, 15 mmol) in 1-octanol (10 ml) was added 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (590 mg, 3 mmol). The mixture was stirred at 50° C. for 1 h and evaporated. The residue was dissolved in water and extracted with methylene chloride. The combined organic phases were dried and evaporated to give the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:37])[CH:15]([N:20]3[C:25](=[O:26])[CH:24]=[C:23](ON4C5C=CC=CC=5N=N4)[CH:22]=[N:21]3)[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:45]1[C:53]2[CH:52]=[CH:51][CH:50]=[C:49]([OH:54])[C:48]=2[CH:47]=[CH:46]1>CN(C)C=O>[CH3:1][C:2]1([CH3:38])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:37])[CH:15]([N:20]3[C:25](=[O:26])[CH:24]=[C:23]([N:45]4[C:53]5[C:48](=[C:49]([OH:54])[CH:50]=[CH:51][CH:52]=5)[CH:47]=[CH:46]4)[CH:22]=[N:21]3)[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1
Reactant: Oc1cccc2[nH]ccc12
Reactant: CC(C)CC(C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)n1ncc(On2nnc3ccccc32)cc1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)CC(C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)n1ncc(-n2ccc3c(O)cccc32)cc1=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 13.3 %

Procedure:
A solution of 2-[4-(benzotriazol-1-yloxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide (Example 109, Step 1, 0.50 g, 0.95 mmol) in N,N-dimethylformamide (4 mL, 0.24M) was treated with cesium carbonate (0.62 g, 1.90 mmol) and 1H-indol-4-ol (0.15 g, 1.13 mmol). The resulting reaction mixture was stirred at 80° C. overnight. The reaction mixture was then concentrated in vacuo, diluted with water (100 mL), and acidified with a 1N aqueous hydrochloric acid solution. Ethyl acetate (75 mL) was added, and the mixture was filtered through filter paper, rinsing with water and ethyl acetate. The layers were separated, and the aqueous layer was back extracted with ethyl acetate (75 mL). The combined organics were washed with a saturated aqueous sodium chloride solution (100 mL), dried over magnesium sulfate, filtered, rinsed, and concentrated in vacuo. Silica gel column chromatography (AnaLogix 40 g, 1-10% methanol/methylene chloride) followed by chromatography (Pursuit C-18 column 5×25 cm, 0.05% trifluoroacetic acid/water/acetonitrile linear gradient, 50 ml/min, 45 min run) afforded impure 2-[4-(4-hydroxy-indol-1-yl)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide (66 mg).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:19](OCC)=[O:20].[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1>C(Cl)Cl>[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:30][C:19]([C:3]2[CH:4]=[N:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][C:9]([CH2:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:8][CH:7]=3)=[O:20])=[CH:27][CH:26]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2ccc(CC3CCOCC3)cc2c1O
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(CC3CCOCC3)cc2c1O
Temperature: 65 °C

Procedure:
A solution of ethyl 4-hydroxy-6-(tetrahydro-2H-pyran-4-ylmethyl)-3-quinolinecarboxylate (0.315 g) from Preparation No. 51 and 4-chlorobenzylamine (0.61 nL) is heated to 180° C. for 1 h. The reaction mixture is cooled to 65° C. and diluted with CH2Cl2. Hexanes are added to initiate precipitation of the product. The resulting solid is collected and dried to yield 0.33 g of N-(4-chlorobenzyl)-4-hydroxy-6-(tetrahydro-2H-pyran-4-ylmethyl)-3-quinolinecarboxamide as an off-white solid.
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].C(N(CC)CC)C.Cl.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[N:22][CH:21]=1>O1CCCC1.C(Cl)Cl>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:19]([NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([NH2:10])=[O:9])=[O:26])[CH:21]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: NC(=O)c1ccccc1N
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)c1ccccc1NC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 79.1 %

Procedure:
To a solution of anthranilamide (8.2 g, being on sale) and triethylamine (18.0 g)in 100 mL of tetrahydrofuran/methylene chloride (1:1), was added nicotinoyl chloride hydrochloride (10.8 g). The mixture was allowed to stir at room temperature, under nitrogen atmosphere, for six hours. The solution was then concentrated under reduced pressure. The concentrate was taken up in ethyl acetate and water and the mixture filtered. The solid material was triturated in ether and filtered to give the title compound (11.5 g) as a yellow powder having the following physical data.
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5][N:4]1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:29][NH:30][CH3:31].O>O1CCOCC1.ClCCl>[CH3:29][N:30]([CH2:2][CH:3]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5][N:4]1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:31]
Reactant: ClCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: CNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: CN(C)CC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A 6 g portion of 2-chloromethyl-1,4-bis(phenylmethyl)piperazine was dissolved in 20 ml of dioxane. To this was added 3.14 g of potassium carbonate and 68 ml of 40% aqueous dimethylamine. The mixture was stirred in a sealed pressure bottle at 80° C. for 18 hours and then taken to dryness in vacuo. The gummy residue was mixed with water and dichloromethane. The aqueous layer was washed twice with dichloromethane. The organic solutions were combined, dried, filtered and evaporated, giving 6.23 g of 2-dimethylaminomethyl-1,4-bis(phenylmethyl)piperazine as a gum.
Reaction SMILES: C([O:8][N:9]([CH3:37])[C:10]([C@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][N:13]1[S:18]([N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([F:36])[CH:34]=3)[NH:29][CH:28]=2)[CH2:23][CH2:22]1)(=[O:20])=[O:19])=[O:11])C1C=CC=CC=1>C(O)C.O1CCCC1.[Pd]>[OH:8][N:9]([CH3:37])[C:10]([C@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][N:13]1[S:18]([N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([F:36])[CH:34]=3)[NH:29][CH:28]=2)[CH2:23][CH2:22]1)(=[O:20])=[O:19])=[O:11]
Reactant: CN(OCc1ccccc1)C(=O)[C@H]1CCCCN1S(=O)(=O)N1CCC(c2c[nH]c3ccc(F)cc23)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CN(O)C(=O)[C@H]1CCCCN1S(=O)(=O)N1CCC(c2c[nH]c3ccc(F)cc23)CC1
Reaction time: 1.17 h
Yield: 83 %

Procedure:
A suspension of 10% Pd/C (0.20 g) and N-benzyloxy-N-methyl-1-[4-(5-fluoroindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxamide (0.40 g, 0.75 mmol) [prepared as described in Step 4 above] in 80% ethanol/tetrahydrofuran (6 ml) was stirred under a hydrogen atmosphere (1 atm) for 70 min. The reaction was degassed with nitrogen, filtered through Celite and the filtrate was concentrated in vacuo. The residue was chromatographed (PTLC, SiO2, 10% methanol/methylene chloride) to give N-hydroxy-N-methyl-1-[4-(5-fluoroindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxamide (83%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:15](Cl)(=O)C(Cl)=O>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:7][C:3]=1[C:4]([O:6][CH3:15])=[O:5]
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(F)(F)F)ccc1Cl
Yield: 100.4 %

Procedure:
To a solution of 2-chloro-5-(trifluoromethyl)benzoic acid (15 g, 66.8 mmol) in methylene chloride (200 mL) was added oxalyl chloride (12.7 g, 100 mmol) drop wise followed by the addition of 5-6 drops of DMF. The reaction mixture was concentrated, the residue partitioned between methylene chloride and 5% aq. sodium carbonate. The organic layer was dried (MgSO4) and concentrated to give the title compound as a pale oil (16 g).
Reaction SMILES: [C:1]([C:4]1[N:11]2[C:7](=[N:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=32)[S:6][N:5]=1)([OH:3])=[O:2].[OH-].[Na+:17]>CO.O>[C:1]([C:4]1[N:11]2[C:7](=[N:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=32)[S:6][N:5]=1)([O-:3])=[O:2].[Na+:17]
Reactant: O=C(O)c1nsc2nc3ccccc3n12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C([O-])c1nsc2nc3ccccc3n12
Reaction time: 4 h
Yield: 95 %

Procedure:
To a suspension of 3-carboxy-1,2,4-thiadiazolo[4,5-a]benzimidazole (10.00 g, 45.62 mmol) in methanol (150 ml) and water (100 ml), 1M NaOH (45.6 ml) was added over a period of 1 h. After 4 h, the solution turned clear and the methanol was removed under reduced pressure. The aqueous solution was extracted with chloroform, the aqueous phase was freeze-dried to give the title compound (10.4 g, 95%) as a white solid: mp 225-227° C.; 1H NMR (DMSO-d6) δ 7.68 (d, 1H), 7.05 (d, 1H), 6.95 (t, 1H), 6.80 (t, 1H) ppm; 13C NMR (DMSO-d6) δ 167.20, 161.76, 149.68, 148.84, 129.52, 126.23, 122.74, 118.37, 116.06 ppm; IR (KBr) ν 3395, 3243, 1663, 1641, 1522, 1443, 1334, 827, 729 cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[N+](=[CH2:14])=[N-]>CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:11])[CH:10]=1)[C:5]([O:7][CH3:14])=[O:6]
Reactant: O=C(O)c1cc(Br)cc(Br)c1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)c1cc(Br)cc(Br)c1
Reaction time: 0.33 h

Procedure:
To a solution of 3,5-dibromobenzoic acid (1 eq.) in ether was added dropwise a solution of diazomethane in ether until gas evolution had ceased. The reaction was stirred for 20 min and concentrated in vacuo to afford the title compound.
Reaction SMILES: Cl[C:2]1[C:3]([C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:16][O:17][CH2:18][CH2:19][NH2:20]>COCCOC>[CH3:16][O:17][CH2:18][CH2:19][NH:20][C:2]1[C:3]([C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: O=C(c1cccnc1)c1nccnc1Cl
Reactant: COCCN
Solvent: COCCOC
Product: COCCNc1nccnc1C(=O)c1cccnc1
Temperature: 120 °C

Procedure:
A microwave tube is charged with (3-chloro-pyrazin-2-yl)-pyridin-3-yl-methanone (85 mg, 0.39 mmol), DME (2 ml) and 2-methoxyethylamine (0.95 g, 4.26 mmol) and the tube is sealed with a microwave cap. The mixture is heated at 120° C. for 15 hours, then the solvent is removed in vacuo. [3-(2-Methoxy-ethylamino)-pyrazin-2-yl]-pyridin-3-yl-methanone is obtained by flash chromatography (SiO2, toluene/EtOAc, 2:1)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C:12]([CH3:15])([CH3:14])[N:11]([CH2:16][C:17]2[CH:22]=[C:21](Br)[N:20]=[C:19]3[N:24]([CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][O:29]4)[N:25]=[C:26]([CH3:27])[C:18]=23)[CH2:10][C:9]1([CH2:35][CH3:36])[CH3:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:37][C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][C:12]([CH3:15])([CH3:14])[N:11]([CH2:16][C:17]2[CH:22]=[C:21]([C:41]3[CH:42]=[CH:43][C:38]([OH:37])=[CH:39][CH:40]=3)[N:20]=[C:19]3[N:24]([CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][O:29]4)[N:25]=[C:26]([CH3:27])[C:18]=23)[CH2:10][C:9]1([CH2:35][CH3:36])[CH3:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccc(O)cc1
Reactant: CCC1(C)CN(Cc2cc(Br)nc3c2c(C)nn3C2CCCCO2)C(C)(C)CN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCC1(C)CN(Cc2cc(-c3ccc(O)cc3)nc3c2c(C)nn3C2CCCCO2)C(C)(C)CN1C(=O)OC(C)(C)C
Temperature: 85 °C
Reaction time: 1.25 h
Yield: 26.5 %

Procedure:
To a degassed mixture of 70 mg 4-[6-bromo-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-ylmethyl]-2-ethyl-2,5,5-trimethyl-piperazine-1-carboxylic acid tert-butyl ester, 21 mg 4-hydroxyphenylboronic acid and 19 mg potassium carbonate in DME/water (v/v=2/1, 0.7 mL) at r.t. and under Ar-atmosphere 2 mg palladium(0) bis(tri-tert-butylphosphine) was added and the mixture was stirred at 85° C. for 75 min in a microwave reactor. To the mixture water and ethyl acetate were added, the phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were concentrated in vacuo and the resulting residue was purified by flash chromatography (silica, heptane/ethyl acetate). 19 mg (27%) of the title compound were obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[F:15][C:16]1[CH:17]=[C:18]([S:23](Cl)(=[O:25])=[O:24])[CH:19]=[C:20]([F:22])[CH:21]=1.[CH:27]1([C:30]2[CH:31]=[C:32]([CH:34]=[CH:35][CH:36]=2)[NH2:33])[CH2:29][CH2:28]1>>[CH:27]1([C:30]2[CH:31]=[C:32]([NH:33][C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][CH:12]=[CH:13][C:4]=4[NH:1][S:23]([C:18]4[CH:17]=[C:16]([F:15])[CH:21]=[C:20]([F:22])[CH:19]=4)(=[O:25])=[O:24])[N:9]=3)[CH:34]=[CH:35][CH:36]=2)[CH2:29][CH2:28]1
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Reactant: Nc1cccc(C2CC2)c1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Product: O=S(=O)(Nc1cccc2nc(Nc3cccc(C4CC4)c3)ccc12)c1cc(F)cc(F)c1

Procedure:
The title compound, MS: m/e=452.0 (M+H+), was prepared in accordance with the general method of example 89 from 5-nitro-2-chloroquinoline, 3,5-difluorobenzenesulfonylchloride and 3-cyclopropylaniline.
Reaction SMILES: [CH2:1]([O:3][C:4]([P:6](=[O:21])([O:14]C1C=CC=CC=1)[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5])[CH3:2].C(=O)([O-])O.[Na+:26]>O>[CH2:1]([O:3][C:4]([P:6](=[O:14])([O-:21])[O:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:5])[CH3:2].[Na+:26]
Reactant: CCOC(=O)P(=O)(Oc1ccccc1)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)P(=O)([O-])Oc1ccccc1
Yield: 26.6 %

Procedure:
Diphenyl ethoxycarbonylphosphonate (3.06 g) and sodium hydrogencarbonate (0.84 g) were stirred in water (10 ml) at room temperature for about 24 hours. The solvent was evaporated and the residue extracted with ethanol. The ethanol was evaporated and the residue was washed with ether. The residue was recrystallized twice from isopropanol. Colourless crystals (0.67 g, 27%) were obtained. Thin layer chromatography on silica gel, eluted with ethanol and developed with iodine vapor: Rf 0.66. By t.l.c. the compound was estimated to contain <0.4% of trisodium oxycarbonylphosphonate.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH2:11][C:10](=[O:20])[CH:9]1[CH2:8][N:7]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:6]2)=[O:4].[CH:28]([C:31]1[CH:36]=[CH:35][C:34]([Mg]Br)=[CH:33][CH:32]=1)([CH3:30])[CH3:29].BrC1C=CC(C(C)C)=CC=1.[Mg]>C(OCC)C>[CH3:1][O:2][C:3]([C:5]12[CH:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:12][CH2:11][C:10]([C:34]3[CH:35]=[CH:36][C:31]([CH:28]([CH3:30])[CH3:29])=[CH:32][CH:33]=3)([OH:20])[CH:9]1[CH2:8][N:7]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:6]2)=[O:4]
Reactant: COC(=O)C12CN(Cc3ccccc3)CC1C(=O)CCC2c1ccccc1
Reactant: CC(C)c1ccc([Mg]Br)cc1
Agent: CC(C)c1ccc(Br)cc1
Agent: [Mg]
Solvent: CCOCC
Product: COC(=O)C12CN(Cc3ccccc3)CC1C(O)(c1ccc(C(C)C)cc1)CCC2c1ccccc1
Yield: 41 %

Procedure:
By carrying out the reaction as in Stage A of Example 1, but from 6 g of methyl(3aRS,4SR,7aRS)-2-benzyl-7-oxo-4-phenyloctahydroisoindole-3a-carboxylate in 60 cm3 of dry diethyl ether and from a solution of 4-isopropylphenylmagnesium bromide, prepared at the time of use from 4 g of 4-bromoisopropylbenzene and 0.52 g of magnesium turnings in 7 cm3 of dry diethyl ether, for eighteen hours at room temperature, 3.3 g (41%) of methyl(3aRS,4SR,7RS,7aRS)-2-benzyl-7-(4-isopropylphenyl)-7-hydroxy-4-phenyloctahydroisoindole-3a-carboxylate were obtained, after purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with a gradient of mixtures of cyclohexane and of ethyl acetate (from 98/2 to 80/20 by volume), in the form of a yellow oil, the characteristic of which was as follows:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([NH2:14])[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2.[F:17][C:18]([F:30])([F:29])[C:19]1[N:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:16][C:2]([F:1])([F:15])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([NH:14][S:25]([C:22]3[CH:23]=[N:24][C:19]([C:18]([F:30])([F:17])[F:29])=[CH:20][CH:21]=3)(=[O:27])=[O:26])[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: Nc1cc(OC(F)(F)F)cc2cccnc12
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)nc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1cc(OC(F)(F)F)cc2cccnc12)c1ccc(C(F)(F)F)nc1
Yield: 42.9 %

Procedure:
In a similar fashion using route 14 general procedure 27, 6-trifluoromethoxy-quinolin-8-ylamine (Intermediate 46) (75 mg, 0.32 mmol), 6-(trifluoromethyl)pyridine-3-sulfonyl chloride (96 mg, 0.39 mmol), DMAP (cat.), pyridine (0.05 ml, 0.65 mmol) and DCM (2 ml) gave the title compound (60 mg, 42%) after purification by column chromatography with n-hexane/EtOAc (90:10) as the eluent.
Reaction SMILES: [CH3:1][C:2]1[NH:8][C:7]([NH2:9])=[N:6][C:4](=[O:5])[CH:3]=1.[C:10]([O:15][CH2:16][CH2:17][N:18]=[C:19]=[O:20])(=[O:14])[C:11]([CH3:13])=C.[CH2:21]([Sn](=O)CCCC)CCC>CC(N(C)C)=O>[CH3:1][C:2]1[NH:8][C:7]([NH:9][C:19]([NH:18][CH2:17][CH2:16][O:15][C:10](=[O:14])[CH:11]=[CH:13][CH3:21])=[O:20])=[N:6][C:4](=[O:5])[CH:3]=1
Reactant: CCCC[Sn](=O)CCCC
Reactant: Cc1cc(=O)nc(N)[nH]1
Reactant: C=C(C)C(=O)OCCN=C=O
Solvent: CC(=O)N(C)C
Product: CC=CC(=O)OCCNC(=O)Nc1nc(=O)cc(C)[nH]1
Temperature: 90 °C

Procedure:
37.5 g (0.3 mol) 6-methylisocytosine, 55.8 g (0.36 mol) 2-isocyanatoethyl methacrylate and 3.7 g (0.015 mmol) dibutyltin oxide were added to 400 ml dimethylacetamide. 100 mg BHT was added and the mixture was heated to 90° C. for one hour. The mixture was filtered at 90° C. Upon cooling down to room temperature 2-methyl-2-propenoic acid-2-[[[(1,4-dihydro-6-methyl-4-oxo-2-pyrimidinyl)amino]carbonyl]amino]ethyl ester started to crystallize. The mixture was stirred for two and a half hour. 500 ml acetone was added and 3-methyl-2-propenoic acid-2-[[[(1,4-dihydro-6-methyl-4-oxo-2-pyrimidinyl)amino]carbonyl]amino]ethyl ester was isolated by filtration. 2-methyl-2-propenoic acid-2-[[[(1,4-dihydro-6-methyl-4-oxo-2-pyrimidinyl)amino]carbonyl]amino]ethyl ester was treated with 500 ml acetone, again isolated by filtration and dried. 68.6 g (82%) of 2-methyl-2-propenoic acid-2-[[[(1,4-dihydro-6-methyl-4-oxo-2-pyrimidinyl)amino]carbonyl]amino]ethyl ester was isolated (m.p.:208° C.).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]2[O:10][CH2:9][CH2:8][O:7]2)=[CH:2]1.[CH2:11]([Sn:15](Cl)([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH3:14]>CCOCC.C([Li])CCC.O1CCCC1>[CH2:20]([Sn:15]([CH2:11][CH2:12][CH2:13][CH3:14])([CH2:16][CH2:17][CH2:18][CH3:19])[C:2]1[S:1][CH:5]=[CH:4][C:3]=1[CH:6]1[O:10][CH2:9][CH2:8][O:7]1)[CH2:21][CH2:22][CH3:23]
Reactant: c1cc(C2OCCO2)cs1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1sccc1C1OCCO1
Temperature: -78 °C
Yield: 76.7 %

Procedure:
To a stirred solution of 15.6 g (0.10 mol) of 2-(3-thienyl)-1,3-dioxolane in 100 ml of anhydrous ether, n-butyl-lithium (1.48N, in hexane, 74.3 ml) is added dropwise under nitrogen at room temperature. After being refluxed for 15 minutes, the reaction mixture is cooled to -78° C. and tri-n-butyltin chloride (34.18 g, 0.105 mol) in 100 ml of dry tetrahydrofuran is added dropwise. After the addition is complete, the mixture is warmed to room temperature and the solvent evaporated. To the oily residue 100 ml of hexane is added, and the resulting precipitate (LiCl) is filtered off. The filtrate is evaporated and the residue distilled at reduced pressure, giving 34.16 g (77%) of the desired product.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(N(CC)CC)C>O1CCCC1>[CH2:12]([O:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[S:3][C:4]=2[CH:10]=1)[CH3:13]
Reactant: CCOc1ccc2nc(Cl)sc2c1
Reactant: C1CNCCN1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOc1ccc2nc(N3CCNCC3)sc2c1
Temperature: 160 °C

Procedure:
A mixture of 1.36 mmol 2-chloro-6-ethoxy-benzothiazole (CA=[79071-17-3]), 3.00 mmol of piperazine and 3.00 mmol of triethylamine in 5 ml of tetrahydrofuran in a sealed tube was heated at 160° C. for 5 min under microwave irradiation. The reaction mixture was concentrated, and the residue was purified by chromatography (SiO2, methanol/dichloromethane) to yield the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[N:6][C:5]([O:8][CH3:9])=[C:4]2[O:10][C:11]([C:13]3([O:19][CH3:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:12][C:3]=12.[CH:21](O)=O.C=O>[OH-].[Na+]>[Br:1][C:2]1[CH:7]=[N:6][C:5]([O:8][CH3:9])=[C:4]2[O:10][C:11]([C:13]3([O:19][CH3:20])[CH2:18][CH2:17][N:16]([CH3:21])[CH2:15][CH2:14]3)=[CH:12][C:3]=12
Reactant: O=CO
Reactant: COc1ncc(Br)c2cc(C3(OC)CCNCC3)oc12
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Product: COc1ncc(Br)c2cc(C3(OC)CCN(C)CC3)oc12
Temperature: 95 °C

Procedure:
4-Bromo-7-methoxy-2-(4-methoxypiperidin-4-yl)furo[2,3-c]pyridine (1.2 g), formic acid (0.76 ml) and formaldehyde (37% w/w aqueous solution) (0.66 g) were combined and heated to 95° C. for 24 hours. The reaction mixture was then diluted with 2N sodium hydroxide solution (100 ml) and extracted with ethyl acetate (3×50 ml). The combined extracts were then dried over magnesium sulphate and evaporated in vacuo to give the title compound (0.96 g) as a pale yellow oil.