Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4](Cl)=[O:5].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[N:15]=1.O1CCOCC1>C(Cl)Cl>[NH2:13][C:14]1[N:15]=[C:16]([NH:20][C:4](=[O:5])[C:3]2[C:2]([F:1])=[CH:10][C:9]([F:11])=[CH:8][C:7]=2[F:12])[CH:17]=[CH:18][CH:19]=1
Reactant: Nc1cccc(N)n1
Reactant: O=C(Cl)c1c(F)cc(F)cc1F
Solvent: C1COCCO1
Solvent: ClCCl
Product: Nc1cccc(NC(=O)c2c(F)cc(F)cc2F)n1
Temperature: 40 °C
Yield: 73.9 %

Procedure:
Combine 2,4,6-trifluorobenzoyl chloride (3.891 g, 20 mmol), 2,6-diaminopyridine (6.548 g, 60 mmol) and dioxane (25 mL) and stir for 1 hr. at room temperature followed by heating at 40° C. overnight. Dilute the reaction mixture with CH2Cl2 (100 mL), and wash with 0.1N NaOH solution. Extract the aqueous layer three times with CH2Cl2. Combine the organic layers, dry over Na2SO4, filter, and concentrate to a residue. Chromatography on silica gel, eluting with a gradient of 40-50% ethylacetate in hexanes gives the title intermediate (3.95 g, 74%): mass spectrum (ion spray): m/z=267.9 (M+1); 1H NMR (CDCl3, ppm): 8.28 (s, br, 1H), 7.66 (d, 1H), 7.52 (t, 1H), 6.78 (m, 2H), 6.31 (d, 1H), 4.36 (s, br, 2H).
Reaction SMILES: [NH2:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[Cl:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([Cl:39])[CH:38]=1)[C:33](Cl)=[O:34]>>[Cl:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([Cl:39])[CH:38]=1)[C:33]([NH:1][C@H:2]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:12]=2)[CH2:7][CH2:6]1)=[O:34]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NC(=O)c3cc(Cl)cc(Cl)c3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 3,5-dichlorobenzoyl chloride: ESMS m/e: 552.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][C:15](=[O:18])[CH2:16][NH2:17])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C1CCNCC1.[CH:27]([C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1)([CH3:29])[CH3:28].N.S(Cl)(Cl)(=O)=O>>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH2:8][CH2:9][CH:10]([CH2:13][NH:14][C:15](=[O:18])[CH2:16][NH:17][S:36]([C:33]3[CH:34]=[CH:35][C:30]([CH:27]([CH3:29])[CH3:28])=[CH:31][CH:32]=3)(=[O:38])=[O:37])[CH2:11][CH2:12]2)=[CH:4][CH:3]=1
Reactant: NCC(=O)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: N
Solvent: O=S(=O)(Cl)Cl
Solvent: C1CCNCC1
Product: CC(C)c1ccc(S(=O)(=O)NCC(=O)NCC2CCN(Cc3ccc(Cl)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1-(4-chlorobenzyl)-4-{(glycylamino)methyl}piperidine (14.8 mg, 0.05 mmol) in CHC3 (2 mL) was treated with (piperidinomethyl)polystyrene resin (28 mg, 2.8 mmol/g), 4-isopropylbenzenesulfonyl chloride (1.5 equiv.) and stirred at 25° C. for 16 h. (Aminomethyl)polystyrene was added to scavenge the residual sulfonyl chloride and the reaction mixture was stirred at 25° C. for 16 h. Filtration and concentration afforded 1-(4-chlorobenzyl)-4-[{(4-isopropylphenylsulfonyl)glycyl}aminomethyl]piperidine (compound No. 869) (22.1 mg, 92%): The purity was determined, by RPLC/MS (86%); ESI/MS m/e 478 (M++H, C24H32ClN3O3S).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].CN(C=O)C.[H-].[Na+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>O1CCCC1>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11])[CH3:26]
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(C=O)cc1[N+](=O)[O-]

Procedure:
To a solution of 4-hydroxy-3-nitrobenzaldehyde (10.0 g, 59.8 mmol) in tetrahydrofuran (600 mL)) and DMF (240 mL) was added dry sodium hydride (1.58 g, 65.82 mmol) and ethyl bromoacetate (7.30 mL, 65.82 mmol). The reaction was refluxed for 24 hours. The reaction was then concentrated and diluted with ethyl acetate (500 mL) and acidified to pH 2 with 1N HCl. The organic layer was then washed with saturated sodium bicarbonate (2×200 mL), sodium chloride (2×200 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield a dark red oil. The oil was used in the next step without purification. 1H NMR (d6-DMSO) δ 1.18 (t, 3H), 4.15 (q, 2H), 5.14 (s, 2H), 7.49 (d, 1H), 8.11 (dd, 1H), 8.41 (s, 1H), 9.93 (s, 1H). MS: M+−1=252.1 Da.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:12][N:13]1[C:21]2[C:16](=[CH:17][C:18]([CH:22]=[O:23])=[CH:19][CH:20]=2)[CH:15]=[N:14]1>C1COCC1>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([CH:22]([C:18]3[CH:17]=[C:16]4[C:21](=[CH:20][CH:19]=3)[N:13]([CH3:12])[N:14]=[CH:15]4)[OH:23])=[CH:3][N:4]=2)[N:7]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: Cn1ncc2cc(C=O)ccc21
Solvent: C1CCOC1
Product: Cn1ncc2cc(C(O)c3cnc4ccc(Cl)nn34)ccc21
Temperature: -10 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
To a solution of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (232.0 mg, 1.00 mmol) in THF (5 mL) was added EtMaBr (1M in THF, 1.50 mL, 1.50 mmol) at −10° C. After stirring at −10° C. for 1 h, 1-methyl-1H-indazole-5-carbaldehyde (240.0 mg, 1.50 mmol) was added. The mixture was allowed to warm to it slowly and stirred for 2 h. The reaction was quenched with saturated NH4Cl solution and concentrated under reduced pressure. The residue was diluted with water and extracted with EtOAc twice. The organic layers were combined, dried over Na2SO4 and concentrated. The crude product was washed with DCM to give the title compound as a white solid (230 mg, 70%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.21 (d, 1H), 8.02 (s, 1H), 7.81 (s, 1H), 7.59 (d, 1H), 7.56 (s, 1H), 7.49 (d, 1H), 7.35 (d, 1H), 6.29 (d, 1H), 6.21 (d, 1H), 4.02 (s, 3H). LCMS (method A): [MH]+=314, tR=4.44 min.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:4][CH3:5].[H-].[Na+].Br[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>C1COCC1>[C:9]([O:8][C:7]([NH:6][C@@H:3]([CH2:4][CH3:5])[CH2:2][O:1][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:13])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC[C@@H](CO)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@@H](COCC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-tert-butyl 1-hydroxybutan-2-ylcarbamate (1 eq, from the previous step) in THF (0.23 M) at 0° C. was added portionwise 60% wt NaH (2 eq). The reaction was stirred at 0° C. for 30 minutes, and then a solution of tert-butyl 2-bromoacetate (1 eq) in THF (0.12 M) was added dropwise. The reaction was warmed to room temperature and stirred for 1 hour. The reaction was quenched slowly with saturated aqueous NH4Cl solution and diluted with ether. The organic layer was washed with water, brine, dried over anhydrous MgSO4, and concentrated en vaccuo. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using a gradient of 0-40% ethyl acetate in hexanes to give the product as an oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]2[C:21](=[O:28])[NH:22][NH:23][C:24]=2[CH:25]([CH3:27])[CH3:26])=[C:15]([CH3:29])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][C:31]([O:33][CH2:34][C@H:35]1[O:40][C@H:39](Br)[C@H:38]([O:42][C:43]([CH3:45])=[O:44])[C@@H:37]([O:46][C:47]([CH3:49])=[O:48])[C@H:36]1[O:50][C:51]([CH3:53])=[O:52])=[O:32].CC(OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O)=O>>[C:43]([O:42][C@@H:38]1[C@@H:37]([O:46][C:47](=[O:48])[CH3:49])[C@@H:36]([O:50][C:51](=[O:52])[CH3:53])[C@@H:35]([CH2:34][O:33][C:31](=[O:32])[CH3:30])[O:40][C@H:39]1[O:28][C:21]1[C:20]([CH2:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:14][C:15]=2[CH3:29])=[C:24]([CH:25]([CH3:27])[CH3:26])[NH:23][N:22]=1)(=[O:44])[CH3:45]
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: Cc1cc(OCCCOCc2ccccc2)ccc1Cc1c(C(C)C)[nH][nH]c1=O
Agent: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCOCc3ccccc3)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 17 using 4-{[4-(3-benzyloxypropoxy)-2-methylphenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one and acetobromo-α-D-galactose instead of 4-{[4-(3-benzyloxypropoxy)phenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one and acetobromo-α-D-glucose, respectively.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH:5]=[CH:6][CH:7]=1.C1(CCC(O)=O)CCCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:4]1([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH2:3][CH2:2][CH2:7][CH2:6][CH2:5]1
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: O=C(O)CCC1CCCCC1
Product: C[C@H]1CC[C@H](N(CCCC2CCCCC2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 3-cyclohexyl-propionic acid and (2-aminothiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: S(Cl)(Cl)=O.O[CH:6]([C:12]1[N:16]2[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]2=[N:14][C:13]=1[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][O:29][CH3:30])=[CH:24][CH:23]=1)[C:7]([N:9]([CH3:11])[CH3:10])=[O:8].C(S([O-])=O)O.[Na+]>C(Cl)Cl>[CH3:11][N:9]([CH3:10])[C:7](=[O:8])[CH2:6][C:12]1[N:16]2[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]2=[N:14][C:13]=1[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][O:29][CH3:30])=[CH:24][CH:23]=1
Reactant: COCc1ccc(-c2nc3ccc(C)cn3c2C(O)C(=O)N(C)C)cc1
Agent: O=S([O-])CO
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COCc1ccc(-c2nc3ccc(C)cn3c2CC(=O)N(C)C)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
8.5 ml of thionyl chloride are added dropwise to 1.5 g (4.2×10-3 mol) of α-hydroxy-N,N-dimethyl-6-methyl-2-[4-(methoxymethyl)phenyl]imidazo[1,2-a]pyridine-3-acetamide (IX) dissolved in 85 ml of dry methylene chloride. The mixture is left stirred for 15 h at room temperature and evaporated to dryness, the residue is taken up with pentane, crystallized and dried under vacuum. A white solid is obtained which is dissolved in 120 ml of methylene chloride, 1.9 g (1.2×10-2 mol, 3 eq) of Rongalite are added and the mixture is left stirred for 4 h at room temperature. The mixture is then filtered and the filtrate washed with bicarbonate water and then with water to neutral pH, dried and evaporated. The product is purified by chromatography and crystallized in ether.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH:18]4[CH2:19][CH2:20][CH:14]3[CH2:15][O:16][CH2:17]4)[N:10]=[C:9]([C:21]3[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.ClC(Cl)(O[C:32](=[O:38])OC(Cl)(Cl)Cl)Cl.[NH2:40][C:41]1[CH:49]=[CH:48][C:44]([CH2:45][CH2:46][OH:47])=[CH:43][CH:42]=1>>[OH:47][CH2:46][CH2:45][C:44]1[CH:48]=[CH:49][C:41]([NH:40][C:32]([NH:25][C:24]2[CH:26]=[CH:27][C:21]([C:9]3[N:8]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[N:12]=[C:11]([N:13]4[CH:14]5[CH2:20][CH2:19][CH:18]4[CH2:17][O:16][CH2:15]5)[N:10]=3)=[CH:22][CH:23]=2)=[O:38])=[CH:42][CH:43]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(CCO)cc1
Reactant: Nc1ccc(-c2nc(N3CCOCC3)nc(N3C4CCC3COC4)n2)cc1
Product: O=C(Nc1ccc(CCO)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3C4CCC3COC4)n2)cc1
Yield: 33.2 %

Procedure:
Following the procedure described in example 34, reaction of 4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]aniline (22 mg, 0.06 mmol) (22 mg, 0.06 mmol, triphosgene (18 mg, 0.06 mmol) and 4-aminophenethyl alcohol (24 mg, 0.18 mmol) gave the title compound as off-white solid (10.6 mg, 33% yield). MS (ESI) m/z 532.5.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:27])[C@@H:6]([O:24][CH2:25][CH3:26])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)=[CH:10][CH:9]=1)[CH3:3].ClCCl.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(N(CC)CC)C>C(OCC)(=O)C>[CH2:2]([O:4][C:5](=[O:27])[C@@H:6]([O:24][CH2:25][CH3:26])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([NH:23][S:32]([CH3:31])(=[O:34])=[O:33])=[CH:21][CH:22]=2)=[CH:10][CH:9]=1)[CH3:3]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCc2ccc(N)cc2)cc1)OCC
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](Cc1ccc(OCCc2ccc(NS(C)(=O)=O)cc2)cc1)OCC
Reaction time: 3 h
Yield: 32.8 %

Procedure:
3-{4-[2-(4-Aminophenyl)ethoxy]phenyl}-(S)-2-ethoxypropanoic acid ethyl ester hydro chloride (described in Example 41b) (0.45 g; 1.26 mmole), dichloromethane (10 ml), methanesulfonyl chloride (0.216 g; 1.88 mmole) and triethylamine (0.318 g; 3.14 mmole) were mixed at 0° C. and stirred for 3 hours at that temperature and then at room temperature over night. The reaction mixture was poured into ethyl acetate (50 ml). Triethylamine hydrochloride salt was filtered off and the filtrate evaporated. The residue was redissolved and extracted with ethyl acetate and water. The organic phase was washed once more with water, dried with sodium sulfate and evaporated. Chromatography with diethyl ether:petroleum ether (1:3, 1:1, 3:1) as eluant gave 0.18 g (32.8% yield) of (S)-2-ethoxy-3-[4-{2-(4-[methylsulfonylamino]phenyl)ethoxy}phenyl]propanoic acid ethyl ester.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1C(C1C=C(C)C=CC=1C1C=NN(C)C=1)=O.[F:25][C:26]1[C:27]([O:35][CH3:36])=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([OH:31])=O>>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:29]([C:28]1[CH:32]=[CH:33][CH:34]=[C:26]([F:25])[C:27]=1[O:35][CH3:36])=[O:31]
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: COc1c(F)cccc1C(=O)O
Product: COc1c(F)cccc1C(=O)N1CCC[C@@H](C)[C@H]1CN

Procedure:
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1 using 3-fluoro-2-methoxybenzoic acid. MS (ESI) 281 (M+H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].C(N(CC)CC)C.[CH2:27]([S:31](Cl)(=[O:33])=[O:32])[CH2:28][CH2:29][CH3:30]>ClCCl>[CH2:27]([S:31]([NH:1][C@@H:2]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=1)[C:3]([O:5][C:6]([CH3:9])([CH3:7])[CH3:8])=[O:4])(=[O:33])=[O:32])[CH2:28][CH2:29][CH3:30]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc([N+](=O)[O-])cc1
Reactant: CCCCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCS(=O)(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.4 %

Procedure:
To an ice-cold solution of the product of step (a) (6.9 g) and triethylamine (3.64 ml) in dichloromethane (100 ml) was added, with stirring, dropwise over 15 minutes a solution of butanesulphonyl chloride (4.1 g) in dichloromethane (10 ml). The reaction mixture was stirred at low temperature for 2 hours and then at ambient temperature for a further 2 hours. The solvents were removed in vacuo and the residue was partitioned between ethyl acetate (100 ml) and water (100 ml). The organic layer was separated and washed with water, dilute KHSO4 (aq.), dilute NaHCO3 (aq.), brine, dried (MgSO4) and evaporated. The solid residue was collected and washed with hexane containing a small volume of ether to give t-butyl (2S)-2-(n-butylsulphonylamino)-3-(4-nitrophenyl)propionate (6.65 g) as an off-white solid: NMR Spectrum (CDCl3) 0.90 (3H, t), 1.36 (2H, m), 1.45 (9H, s), 1.68 (2H, m), 2.88 (2H, m), 3.18 (2H, m), 4.28 (1H, m), 5.01 (1H, d), 7.43 (2H, d), 8.19 (2H, d).
Reaction SMILES: C[O-].[Na+].Cl.[NH2:5][C:6]([NH2:8])=[NH:7].[CH3:9][S:10]([C:13]1[CH:14]=[C:15]([CH:20]=[C:21]([N:23]2[CH:27]=[CH:26][CH:25]=[CH:24]2)[CH:22]=1)[C:16](OC)=[O:17])(=[O:12])=[O:11]>CO>[CH3:9][S:10]([C:13]1[CH:14]=[C:15]([CH:20]=[C:21]([N:23]2[CH:27]=[CH:26][CH:25]=[CH:24]2)[CH:22]=1)[C:16]([N:7]=[C:6]([NH2:8])[NH2:5])=[O:17])(=[O:12])=[O:11]
Reactant: N=C(N)N
Reactant: COC(=O)c1cc(-n2cccc2)cc(S(C)(=O)=O)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CS(=O)(=O)c1cc(C(=O)N=C(N)N)cc(-n2cccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.1 %

Procedure:
28% Methanolic sodium methoxide (6.2 ml) was added to a solution of guanidine hydrochloride (3.2 g) in dry methanol (40.0 ml) and the mixture was stirred for 30 minutes at ambient temperature. To the mixture was added methyl 3-methylsulfonyl-5-(pyrrol-1-yl)benzoate (1.9 g) and the mixture was stirred for 7 hours at the same temperature. The solvent was removed by concentration and the residue was added to a mixture of ethyl acetate, tetrahydrofuran and water. The separated organic layer was washed with brine and dried over magnesium sulfate. The residue was obtained by evaporating a solvent, and purified by column chromatography on alumina eluting with a mixture of chloroform and methanol (19:1, V/V). The fractions containing the desired product were collected and evaporated in vacuo. The residue was recrystallized from a mixture of methanol and diisopropyl ether to give 2-[3-methylsulfonyl-5-(pyrrol-1-yl)benzoyl]guanidine (0.44 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:10][CH:11]([CH3:13])[CH3:12])[C:5]([CH2:8][OH:9])=[N:6][CH:7]=1.[H-].[Na+].I[CH3:17]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:10][CH:11]([CH3:13])[CH3:12])[C:5]([CH2:8][O:9][CH3:17])=[N:6][CH:7]=1
Reactant: CI
Reactant: CC(C)Oc1cc(Br)cnc1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1ncc(Br)cc1OC(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (5-bromo-3-isopropoxy-pyridin-2-yl)-methanol (stage 190.1.2, 0.61 mmol) in DMF (3 ml) was added 55% NaH in oil (0.688 mmol) was added. The RM was stirred for 30 min at rt then was added iodomethane (0.684 mmol). The RM was stirred for 2.5 h at rt then was quenched with MeOH and purified by preparative HPLC. The fractions containing product were combined, basified with NaHCO3, concentrated and extracted with dichloromethane (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to dryness to give the title compound as a yellow oil. (HPLC: tR 2.83 min (Method A); M+H=260, 262 MS-ES).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][N:12]1[C:16](=[O:17])[CH2:15][CH2:14][C@@H:13]1[C:18]([OH:20])=O.[NH2:21][CH:22]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:23]([OH:27])[C:24]([NH2:26])=[O:25].O[NH-].O=[N-]>>[NH2:26][C:24](=[O:25])[C:23](=[O:27])[CH:22]([NH:21][C:18]([C@H:13]1[CH2:14][CH2:15][C:16](=[O:17])[N:12]1[CH2:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)=[O:20])[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Reactant: O=C(O)[C@H]1CCC(=O)N1Cc1ccc2ccccc2c1
Agent: [N-]=O
Agent: [NH-]O
Product: NC(=O)C(=O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccc2ccccc2c1

Procedure:
Coupling of (R)-1-naphthalen-2-ylmethyl-5-oxo-pyrrolidine-2-carboxylic acid with 3-amino-2-hydroxy-4-phenylbutanamide and oxidation of the resulting hydroxyamide intermediate to the corresponding ketoamide.
Reaction SMILES: [CH2:1]([OH:7])[C@H:2]([OH:6])[CH2:3][CH2:4][OH:5].[CH3:8][C:9]([CH3:11])=O>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>[CH3:8][C:9]1([CH3:11])[O:6][C@H:2]([CH2:3][CH2:4][OH:5])[CH2:1][O:7]1
Reactant: CC(C)=O
Reactant: OCC[C@@H](O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(C)OC[C@@H](CCO)O1
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 72.3 %

Procedure:
A mixture of (R)-(+)-1,2,4-butanetriol (30 g, 283 mmol), acetone (200 ml, 2724 mmol) and p-toluenesulfonic acid monohydrate (1.4 g, 7.36 mmol) was stirred at room temperature for 16.5 hours. To the reaction mixture, triethylamine was added and the mixture was concentrated. The crude product was purified by silica gel column chromatography (silica gel, elution solvent: heptane/ethyl acetate=1/0→1/1→1/3 gradient). Desired fractions were concentrated to obtain the title compound (29.9 g, 72.3% yield) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[CH2:10][CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([S:19][CH3:20])[N:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:26]>C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:11]2[CH2:10][CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([S:19]([CH3:20])=[O:26])[N:3]=1
Reactant: CSc1nc(N)c2c(n1)CCC(c1ccccc1Cl)C2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CS(=O)c1nc(N)c2c(n1)CCC(c1ccccc1Cl)C2
Temperature: -10 °C
Reaction time: 18 h

Procedure:
A stirred solution of 1.5 grams (0.005 mole) of 4-amino-2-methylthio-6-(2-chlorophenyl)-5,6,7,8-tetrahydroquinazoline (prepared as in Example 16) in 20 mL of chloroform is cooled to -10° C., and a solution of 1.7 grams (0.005 mole) of 50-60% 3-chloroperoxybenzoic acid in 30 mL of chloroform is added dropwise at a rate to maintain the reaction mixture temperature at -10° C. Upon completion of addition, the reaction mixture is maintained at -10° C. for one hour. After this time the reaction mixture is allowed to warm to ambient temperature, where it stands for about 18 hours. The reaction mixture is then washed with an aqueous 10% solution of potassium carbonate. The organic layer is dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure to a residue. The residue is subjected to column chromatography on silica gel, yielding 4-amino-2-methylsulfinyl-6-(2-chlorophenyl)-5,6,7,8-tetrahydroquinazoline.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:18]3[C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[O:15][C:14]=3[C:13]([O:23][CH:24]([F:26])[F:25])=[CH:12][CH:11]=2)=[O:9])=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:35])C=1>C(Cl)(Cl)Cl>[N:1]1[CH:6]=[CH:5][C:4]([NH+:7]([O-:35])[C:8]([C:10]2[C:18]3[C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[O:15][C:14]=3[C:13]([O:23][CH:24]([F:26])[F:25])=[CH:12][CH:11]=2)=[O:9])=[CH:3][CH:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(Nc1ccncc1)c1ccc(OC(F)F)c2oc3ccccc3c12
Solvent: ClC(Cl)Cl
Product: O=C(c1ccc(OC(F)F)c2oc3ccccc3c12)[NH+]([O-])c1ccncc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.9 %

Procedure:
A suspension of N-(pyrid-4-yl)-4-difluoromethoxy-dibenzo[b,d]furan-1-carboxamide (50 mg, 0.14 mmol) (example 21) and m-chloroperbenzoic acid (50-55%) (120 mg, 0.70 mmol) in chloroform (10 ml) was stirred at room temperature for 16 h. Chloroform was evaporated and the resulting solid was stirred in saturated sodium bicarbonate solution, filtered, dried and purified by column chromatography using 40% acetone-chloroform as the eluent to give 30 mg of N-(pyrid-4-yl)-4-difluoromethoxy-dibenzo[b,d]furan-1-carboxamide-N1-oxide as white solid; mp: 244° C.