Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[C:14](=[O:26])[C:13]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:12][CH:11]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[I:1][C:11]1[CH:12]=[C:13]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:14](=[O:26])[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:23])[F:24])[CH:17]=2)[C:10]=1[CH3:9]
Reactant: O=C1CCC(=O)N1I
Reactant: CCOC(=O)c1ccc(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc(I)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 25 °C
Reaction time: 19 h
Yield: 82.8 %

Procedure:
N-Iodosuccinimide (6.89 g, 30.6 mmol) was added to a solution of ethyl 6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylate (9.9 g, 30.5 mmol) in DCM (45 ml) and TFA (38 ml) under a nitrogen atmosphere. After 19 h stirring at ambient temperature the solvent was concentrated in vacuo. Saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the residue to neutralize the remaining TFA. The organic phase was collected, washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica eluting with DCM/methanol (10:0.2) to give the title compound as a yellow solid (11.4 g, 83%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([NH:16][C:17]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:18]=2[C:19](O)=[O:20])=[O:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[O:15][C:19](=[O:20])[C:18]3[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Nc2ccc(Cl)cc2C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2nc3ccc(Cl)cc3c(=O)o2)CC1
Reaction time: 0.5 h
Yield: 56.4 %

Procedure:
To a stirring solution of 2-[(4-Boc-piperazin-1-ylcarbonyl)amino]-5-chlorobenzoic acid (1.6 g, 4.17 mmol) in DMF (30 mL) was added 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (2.4 g, 12.51 mmol). After 30 min, the solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The layers were separated and the organic phase was washed consecutively with 1 M citric acid, brine, sat. aq sodium bicarbonate, and brine, then dried with MgSO4, filtered and concentrated in vacuo. The residue was then suspended in diethyl ether, sonicated, filtered and dried in vacuo to give 0.86 g (58%) of the title compound as a white solid.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[OH:5][C:6]1[C:7]2[C:11]([CH:12]=[CH:13][CH:14]=1)=[N:10][N:9]([CH3:15])[C:8]=2[S:16]([NH2:19])(=[O:18])=[O:17].C(=O)([O-])O.[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH2:1]([O:5][C:6]1[C:7]2[C:11]([CH:12]=[CH:13][CH:14]=1)=[N:10][N:9]([CH3:15])[C:8]=2[S:16]([NH2:19])(=[O:18])=[O:17])[CH:2]=[CH2:3]
Reactant: Cn1nc2cccc(O)c2c1S(N)(=O)=O
Reactant: C=CCBr
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1cccc2nn(C)c(S(N)(=O)=O)c12
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.1 %

Procedure:
1.3 g of allyl bromide was added to a mixture comprising 5 g (22 mmol) of 4-hydroxy-2-methyl-2H-indazole-3-sulfonamide and 50 ml of a DMF solution of 1.9 g (22 mmol) of sodium hydrogencarbonate, and the mixture was stirred at room temperature for 12 hours. The mixture was poured into ice water, acidified with citric acid and extracted with ethyl acetate. The organic layer was washed, then concentrated and purified by column chromatography (hexane/ethyl acetate=2/1) to obtain 1.9 g (yield: 32.5%) of the desired product. Melting point: 143°-144° C.
Reaction SMILES: [O:1]1[CH2:5][C@H:4]([OH:6])[C@@H:3]([OH:7])[CH2:2]1.[C:8]([Si:12]([CH3:15])([CH3:14])Cl)([CH3:11])([CH3:10])[CH3:9]>ClCCl>[Si:12]([O:6][C@H:4]1[CH2:5][O:1][CH2:2][C@@H:3]1[OH:7])([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:15])[CH3:14]
Reactant: O[C@H]1COC[C@@H]1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H]1COC[C@@H]1O
Temperature: 25 °C
Reaction time: 96 h
Yield: 18.7 %

Procedure:
A mixture of (3S,4S)-tetrahydrofuran-3,4-diol (9.35 g, 89.8 mmol), t-butyldimethylchlorosilane (14.9 g, 98.8 mmol), TEA (13.8 mL, 98.8 mmol), and dichloromethane (100 mL) is stirred at room temperature for 4 days. The reaction is concentrated in vacuo and purified on silica gel (330 g, 35-80% EtOAc/hexanes, observed on TLC using KMnO4 staining) to give 3.66 g (19%) of the title compound as a light yellow oil. GC-MS m/z 161 (M-tBu)+.
Reaction SMILES: [CH3:1][C:2]1[N:10]([C:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([O:20][CH3:21])=[CH:5][C:4]=2[C:3]=1[CH2:22][C:23](O)=[O:24].[OH:26][CH2:27][CH2:28][CH2:29][CH2:30][NH2:31].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[OH:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:23](=[O:24])[CH2:22][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([O:20][CH3:21])[CH:5]=2)[N:10]([C:11](=[O:12])[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:2]=1[CH3:1]
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Reactant: NCCCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(CC(=O)NCCCCO)c(C)n2C(=O)c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 58.3 %

Procedure:
To a stirred solution of indomethacin (3.57 g, 10 mmol) in DMF was added 4-hydroxybutylamine (4.64 g), HOBt (2.02 g, 15 mmol), DIPEA (3.88 g, 30 mmol), EDCl (2.10 g, 11 mmol) at 25° C. The resultant solution was stirred for 16 h at 25° C. Removal of solvent in vacuo afforded a residue, where 100 mL water was added and extracted with EtOAc (3×75 mL). Combined organic layers were dried over Na2SO4. Solvent was evaporated completely and the obtained mass was dissolved in CH2Cl2 (40 mL), then HCl (gas) was bubbled for 2 h at 25° C. Removal of solvent in vacuo afforded a yellow residue, where n-hexane was added (20 mL) and stirred for 30 min to a make good slurry, which was filtered to afford the desired N-(4-hydroxybutyl)-2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetamide as yellow solid (2.5 g, 70%). 1H NMR (500 MHz, DMSO-d6) δ 1.44-1.52 (m, 2H, CCH2CC), 1.53-1.59 (m, 2H, CCCH2C), 2.23 (s, 3H, CH3), 3.03-3.08 (m, 2H, CH2CCC), 3.52 (s, 2H, CH2CO), 3.75 (s, 3H, OCH3), 3.77-3.78 (m, 2H, CCCCH2), 4.53 (br s, 1H, OH), 6.684 (dd, J=9, 2.4 Hz, 1H, indolyl H-6), 6.916 (d, J=9 Hz, 1H, indolyl H-7), 7.144 (d, J=2.4 Hz, 1H, indolyl H-4), 7.64 (d, J=8.7 Hz, 2H, p-chlorobenzoyl H-3, H-5), 7.67 (d, J=8.7 Hz, 2H, p-chlorobenzoyl H-2, H-6), 8.24 (br s, 1H, NHCO). Mass (ESI) (M+Na) calcd for C23H25ClN2O4Na 451.15. found 451.04.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](O)[CH:5]=[C:4]([C:9]2([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=1.C(N(C(C)C)C(C)C)C.P(Cl)(Cl)([Cl:32])=O>C(#N)C>[Cl:32][C:6]1[CH:5]=[C:4]([C:9]2([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1nc(O)cc(C2(c3ccc(Cl)cc3)CCCC2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Nc1nc(Cl)cc(C2(c3ccc(Cl)cc3)CCCC2)n1

Procedure:
360 mg of 2-amino-6-[1-(4-chlorophenyl)cyclopentyl]pyrimidin-4-ol are dissolved in 10 ml of acetonitrile, and 0.8 ml of N-ethyldiisopropylamine is added under nitrogen. 0.5 ml of phosphoryl chloride are subsequently added slowly. The batch is boiled under reflux for 8 h in order to complete the reaction. All volatile constituents are subsequently removed in vacuo, and the batch is added to ice-water and dichloromethane. The organic phase is dried over sodium sulfate, filtered and evaporated. The residue obtained is employed in the subsequent reaction without further purification. (Rt: 2.694 min.; M+H+: 308.2+310.2).
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH3:8])=[N:5][N:4]=[C:3]1[C:9]1[S:10][CH:11]=[CH:12][CH:13]=1.ClC1C=C(C=CC=1)C(OO)=[O:19]>C(Cl)Cl>[S:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[C:3]1[N:2]([CH3:1])[C:6]([S:7]([CH3:8])=[O:19])=[N:5][N:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nnc(-c2cccs2)n1C
Solvent: ClCCl
Product: Cn1c(-c2cccs2)nnc1S(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred, 0° C., solution of 4-methyl-5-methylthio-3-(2-thienyl)-4H-1,2,4-triazole (4.85 g, 2.29×10-2 mole) and CH2Cl2 (170 ml) was added portionwise m-chloroperoxybenzoic acid (4.95 g, 2.29×10-2 mole). After stirring at room temperature overnight the reaction was washed two times with saturated aqueous NaHCO3 and one time with saturated aqueous NaCl, and dried over anhydrous N2SO4. The drying agent was removed by filtration and the filtrate was evaporated at reduced pressure yielding an off-white solid which was purified by flash chromatography (40% acetone/EtOAc). Crystallization from EtOAc afforded small colorless plates: 2.78 g (53%), mp 105°-107° C.
Reaction SMILES: C([BH3-])#N.[Na+].[CH3:5][C:6]1[C:14]2[C:13]([OH:15])=[CH:12][CH:11]=[CH:10][C:9]=2[NH:8][CH:7]=1.O>C(O)(=O)C>[OH:15][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]=1[CH:6]([CH3:5])[CH2:7][NH:8]2
Reactant: Cc1c[nH]c2cccc(O)c12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC1CNc2cccc(O)c21
Temperature: 15 °C
Reaction time: 16.5 h
Yield: 44.4 %

Procedure:
1.35 g of sodium cyanoborohydride are gradually added to a solution of 1.0 g of 3-methyl-1H-indol-4-ol in 35 ml of acetic acid under argon cooled to a temperature of about 15° C. The reaction mixture is allowed to warm up to ambient temperature. After 16.5 hours, the reaction mixture is treated with 15 ml of water, and then concentrated to dryness under reduced pressure. The residue is taken up in 75 ml of ethyl acetate, and then treated with 60 ml of a saturated sodium hydrogen carbonate solution. After stirring for 1 hour and then settling out, the organic phase is separated and the aqueous phase is extracted with 50 ml of ethyl acetate. The organic phases are combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. The residue is purified by chromatography on a 70 g cartridge of 15-40 μm silica, elution being carried out with an 80/20 v/v cyclohexane/ethyl acetate mixture, with a flow rate of 80 ml/min. 0.45 g of 4-hydroxy-3-methylindoline is thus obtained in the form of a pale yellow solid, the characteristics of which are the following:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C@@:7]2([OH:14])[CH2:12][CH2:11][CH2:10][CH2:9][C@@H:8]2[OH:13])=[CH:5][CH:4]=[N:3]1.CN(C1C=CC=CN=1)C.[C:24](N1C=CN=C1)(N1C=CN=C1)=[O:25]>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:6]([C@@:7]23[CH2:12][CH2:11][CH2:10][CH2:9][C@@H:8]2[O:13][C:24](=[O:25])[O:14]3)=[CH:5][CH:4]=[N:3]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cn1nccc1[C@@]1(O)CCCC[C@@H]1O
Agent: CN(C)c1ccccn1
Solvent: Cc1ccccc1
Product: Cn1nccc1[C@@]12CCCC[C@@H]1OC(=O)O2
Reaction time: 3 h
Yield: 86.1 %

Procedure:
A solution of the (1S,2S)-1-(1-methyl-1H-pyrazol-5-yl)cyclohexane-1,2-diol (1.21 g, 6.17 mmol) prepared in Example 123c, dimethylaminopyridine (75.3 mg, 0.62 mmol) and carbonyldiimidazole (2.0 g, 12.3 mmol) in toluene (20 mL) was stirred for 3 hours under heated reflux. To the reaction solution, carbonyldiimidazole (1.0 g, 6.17 mmol) was added, and the reaction solution was further stirred for 3 hours under heated reflux. To the reaction solution, carbonyldiimidazole (0.50 g, 3.08 mmol) was further added, and the reaction solution was stirred for 3 hours under heated reflux. After allowing to cool, the reaction solution was vacuum concentrated, and the residue was purified with silica gel chromatography (hexane/ethyl acetate=7:3) to yield the title compound (1.18 g, 86%) as a colorless solid.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C@@H:6]([C:10]([OH:12])=[O:11])[CH2:7][CH2:8][CH3:9].[CH3:13]O>>[CH3:13][O:11][C:10](=[O:12])[C@@H:6]([CH2:7][CH2:8][CH3:9])[NH2:5]
Reactant: CO
Reactant: CCC[C@@H](N)C(=O)O
Solvent: O=S(Cl)Cl
Product: CCC[C@@H](N)C(=O)OC
Temperature: -5 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
Thionyl chloride (47.7 mL) was added dropwise to methanol (300 mL) under stirring at −5° C. over 2 hours and 15 minutes. D-Norvaline (35.00 g) was added to the resulting light yellow solution under stirring at −4° C. The solution was stirred at room temperature for 18 hours and then methanol was removed under reduced pressure. Disopropyl ether (90 mL) was added to the precipitated crystals, which were filtered and washed twice with diisopropyl ether (30 mL) to give (R)-norvaline methyl ester (47.74 g, 95% yield) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:26][C:27](=[O:29])[CH3:28])[CH:5]=[CH:6][C:7]=1[O:8][Si:9]([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(NC(C)C)(C)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>ClCCl>[C:27]([O:26][C:4]1[CH:5]=[CH:6][C:7]([O:8][Si:9]([C:22]([CH3:25])([CH3:23])[CH3:24])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:2]([NH:1][S:38]([CH3:37])(=[O:40])=[O:39])[CH:3]=1)(=[O:29])[CH3:28]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)Oc1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(N)c1
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: CC(=O)Oc1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(NS(C)(=O)=O)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
Acetic acid 3-amino-4-(t-butyl-diphenyl-silanyloxy)-phenyl ester (3.5 g, 8.6 mmol) was dissolved in anhydrous dichloromethane (150 mL) and anhydrous N,N-diisoproplyamine (1.5 mL) added. The solution was cooled to −78° C. and methanesulfonyl chloride (1.08 g, 9.05 mmol) added. The solution was stirred for 30 minutes and allowed to come to room temperature. The solution was stirred overnight. The reaction mixture was washed with water. The organic solvent was dried over anhydrous magnesium sulfate. The solution was filtered and the solvent evaporated to dryness in vacuo to yield the title compound as a solid (2.8 g, 5.7 mmol).
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[C:8]([Cl:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12][Br:14])=[C:8]([Cl:13])[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(Cl)cnn(C(C)(C)C)c1=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)n1ncc(Cl)c(CBr)c1=O

Procedure:
2-tert-butyl-4-methyl-5-chloro 3(2H)-pyridazinone (3 g, 15 mmol) is dissolved in 25 ml of carbon tetrachloride and to it is added N-bromosuccinimide (2.6 g, 15 mmol) and benzoyl peroxide (14 mg). The mixture is then refluxed for 6 hours after which it is cooled and filtered. The filtrate is washed with water and dried. After removing the organic solvent the crude residue obtained is purified by flash chromatography (silica gel; ethyl acetate/hexanes: 9:1) to obtain the product.
Reaction SMILES: N1C2C(=NC=CC=2)N([O:10][C:11]([C:13]2[C:17]([CH3:18])=[C:16](/[CH:19]=[C:20]3\[C:21](=[O:41])[NH:22][C:23]4[C:28]\3=[CH:27][C:26]([S:29]([CH2:32][C:33]3[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:40])(=[O:31])=[O:30])=[CH:25][CH:24]=4)[NH:15][C:14]=2[CH3:42])=O)N=1.[NH:43]1[CH2:48][CH2:47][S:46][CH2:45][CH2:44]1>CC(N(C)C)=O>[Cl:39][C:38]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:40])[C:33]=1[CH2:32][S:29]([C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:41])/[C:20]/2=[CH:19]\[C:16]1[NH:15][C:14]([CH3:42])=[C:13]([C:11]([N:43]2[CH2:48][CH2:47][S:46][CH2:45][CH2:44]2)=[O:10])[C:17]=1[CH3:18])(=[O:30])=[O:31]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)On1nnc2cccnc21
Reactant: C1CSCCN1
Solvent: CC(=O)N(C)C
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)N1CCSCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [1,2,3]triazolo[4,5-b]pyridin-3-yl ester (100 mg, 0.162 mmol) in DMA (2 mL) was added thiomorpholine (33 mg, 2 eq.). The mixture was stirred at rt for 2 hours. The reaction was concentrated, diluted with DCM, washed with sat. NaHCO3 and water, concentrated and triturated with methanol to give the titled compound as an orange solid.
Reaction SMILES: [CH:1](=O)[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[NH2:8][NH:9][C:10]([NH:12][NH2:13])=[S:11]>CO>[CH:1](=[N:8][NH:9][C:10]([NH:12][NH2:13])=[S:11])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNC(=S)NN
Reactant: O=Cc1ccco1
Solvent: CO
Product: NNC(=S)NN=Cc1ccco1
Reaction time: 0.5 h
Yield: 65.4 %

Procedure:
24 g of furfural and 26.5 g of thiocarbohydrazide in 150 ml of methanol are vigorously stirred. Stirring is continued for 30 minutes after the exothermic reaction has died down. The precipitate is suction filtered and recrystallised from methanol. 30.1 g of furfurylidene thiocarbohydrazide, melting at 186° to 187° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[F:35][C:36]1[CH:41]=[CH:40][C:39]([N:42]2[C:46]3([CH2:51][CH2:50][NH:49][CH2:48][CH2:47]3)[C:45](=[O:52])[NH:44][CH2:43]2)=[CH:38][CH:37]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:49]3[CH2:48][CH2:47][C:46]4([N:42]([C:39]5[CH:38]=[CH:37][C:36]([F:35])=[CH:41][CH:40]=5)[CH2:43][NH:44][C:45]4=[O:52])[CH2:51][CH2:50]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: O=C1NCN(c2ccc(F)cc2)C12CCNCC2
Product: COc1cc(C(=O)N2CCC(CCN3CCC4(CC3)C(=O)NCN4c3ccc(F)cc3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.3 using 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (5 mmol) and 1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(#N)C>[CH2:18]([O:11][C:3]1[CH:4]=[CH:5][C:6]([C:8](=[O:9])[CH3:10])=[CH:7][C:2]=1[CH3:1])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1ccc(O)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)c1ccc(OCc2ccccc2)c(C)c1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
A mixture of 4-hydroxy-3-methylacetophenone (5.0 g) in dry acetonitrile (50 ml) was treated with potassium carbonate (5.06 g) and benzyl bromide (3.96 ml) and the reaction mixture heated at 40° C. After 3 hours the reaction was allowed to cool and was concentrated. The residue was partitioned between water and ethyl acetate; the aqueous layer separated and extracted twice more with ethyl acetate. The organic solutions were combined and were dried with brine and over magnesium sulfate and concentrated to give the title compound as a colourless oil
Reaction SMILES: C(=O)([O-])O.[Na+].[F:6][C:7]1[CH:8]=[C:9]([NH2:19])[CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]=[N:16][C:15]([CH3:18])=[N:14]1.Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>C1COCC1>[CH2:24]([O:23][C:21](=[O:22])[NH:19][C:9]1[CH:10]=[CH:11][C:12]([N:13]2[CH:17]=[N:16][C:15]([CH3:18])=[N:14]2)=[C:7]([F:6])[CH:8]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1ncn(-c2ccc(N)cc2F)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ncn(-c2ccc(NC(=O)OCc3ccccc3)cc2F)n1
Temperature: -20 °C
Yield: 84.4 %

Procedure:
Saturated aqueous sodium hydrogencarbonate solution (375 ml) was added to a solution of 3-fluoro-4-(3-methyl-1,2,4-triazol-1-yl)phenylamine (Intermediate 27) (50.8 g, 0.265 mol) in THF (1 1). The mixture was cooled to −20° C. and benzyl chloroformate (48 ml, 0.336 mol) was added. The reaction mixture was stirred under N2, allowed to warm to room temperature and stirred for 2 days. The mixture was concentrated to approximately half the volume and diluted with ethyl acetate (1 l). The organic layer was separated and washed with water (2×), brine (2×), dried over sodium sulfate and concentrated in vacuo. Recrystallisation from ethyl acetate/hexanes (300 ml/200 ml) gave the title compound (73.0 g), m.p. 152.6-154.9° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.[C:9](Cl)(=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11]>O1CCOCC1>[NH2:8][C:4]1[N:3]=[C:2]([NH:1][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(N)n1
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1COCCO1
Product: CC(C)(C)C(=O)Nc1cccc(N)n1
Reaction time: 2 h
Yield: 73.9 %

Procedure:
To a solution of 2,6-diaminopyridine (50.0 g, 0.46 mol) in dioxane (250 mL) was added slowly (1 h) pivaloylchloride (27.9 g, 0.23 mol), dissolved in dioxane (50 mL). The resulting mixture was stirred for 2 h and the white precipitate (2,6-diaminopyridine hydrochloride) filtered off. The organic phase was evaporated to dryness in vacuo, and the crude product recrystalized from n-hexane/ethyl acetate to give the desired product (32.83 g, 74%) as colorless crystals (mp 140-141° C.). 1H NMR (DMSO-d6): δ 8.93 (s, 1H), 7.34 (t, 7.9 Hz, 1H), 7.19 (d, 7.6 Hz, 1H), 6.18 (d, 7.6 Hz, 1H), 5.75 (br. s, 2H), 1.19 (s, 9H). 13C NMR (DMSO-d6): δ 176.5, 158.5, 150.4, 138.4, 103.6, 101.5, 39.4, 27.1. FAB+ MS (m/z): 193.88 M+H+, calc. for C10H15N3O+H+ 194.1293.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][C@H:24](OS(C)(=O)=O)[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][C@@H:24]([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CC[C@H](OS(C)(=O)=O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](n2cc(B3OC(C)(C)C(C)(C)O3)cn2)C1
Temperature: 25 °C
Yield: 33.6 %

Procedure:
A solution of 4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.856 g, 4.41 mmol), (S)-3-methanesulfonyloxy-pyrrolidine-1-carboxylic acid tert-butyl ester (1.17 g, 4.41 mmol) and Cs2CO3 (2.16 g, 6.61 mmol) in anhydrous DMF (11.7 mL) was heated to 100° C. for 16 h. The reaction mixture was allowed to cool to rt and was partitioned between EtOAc and H2O and separated. The aqueous was re-extracted with EtOAc (3×) and the combined organic fractions were washed with H2O (3×), brine (2×), dried over Na2SO4, filtered and concentrated in vacuo resulting in a crude brown oil. The reaction mixture was purified by chromatography on silica gel [eluting with 12% EtOAc in CHCl3]resulting in 538 mg, 33% yield of the title compound as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ 1.31 (s, 12H), 1.46 (s, 9H), 2.36 (q, J=7.0 Hz, 2H), 3.46-3.78 (m, 3H), 3.80-3.91 (m, 1H), 4.89 (quint, J=6.1 Hz, 1H), 7.73 (s, 1H), 7.80 (s, 1H).