Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[CH2:5]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:16])[CH:6]1[O:8][CH2:7]1>C(O)C>[Cl:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[O:9][CH2:5][CH:6]([OH:8])[CH2:7][NH:3][CH2:2][CH2:1][NH2:4]
Reactant: Clc1ccccc1OCC1CO1
Reactant: NCCN
Solvent: CCO
Product: NCCNCC(O)COc1ccccc1Cl

Procedure:
120 g of ethylenediamine are dissolved in 150 ml of ethanol. A solution of 20 g of o-chlorophenyl glycidyl ether ##STR18## in 40 ml of ethanol is added to the above solution, and the mixture is heated under reflux for 20 hours. Excess ethylenediamine and ethanol are then distilled off in vacuo, and the residue is then distilled in vacuo. The N-[3-(o-chlorophenoxy)-2-hydroxy-propyl]-ethylenediamine is thus obtained as an oil which can be distilled at a boiling point of 190° C./0.4 mm. The 4,5-dichloro-pyridazin-3-one used as the starting material is prepared in a known manner by the reaction of muccochloric acid with hydrazine (for example according to K. Dury, Angew. Chemie 77, page 282 (1965).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]([S:14][CH2:15][CH2:16][C:17]([O:19]C)=[O:18])=[CH:12][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]([S:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:12][N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCSc1cnc(NC(=O)OC(C)(C)C)s1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ncc(SCCC(=O)O)s1
Yield: 81.3 %

Procedure:
Methyl 3-[2-(tert-butoxycarbonylamino)thiazol-5-yl]sulfanylpropanoate (9.0 g, 28.3 mmol) was dissolved in THF/H2O (3:1, 200 ml) and LiOH (1.4 g, 57.0 mmol) and the reaction mixture stirred at ambient temperature for 18 hours. The solvent was evaporated under vacuum then diluted with water and acidified with 1 M HCl to pH (4˜5). The solid formed was filtered, and washed with water and dried to give the title compound as a yellow solid (7.0 g, 80% yield) 1H NMR (400 Mz, CDCl3) δ1.57 (s, 9H), 2.69 (t, 2H), 2.98 (t, 2H), 7.33 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([CH:20]=O)[CH:14]=1)[CH2:8][CH:9]1[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH:30]1([NH2:33])[CH2:32][CH2:31]1.[BH4-].[Na+].C([O-])(O)=O.[Na+]>CO>[C:1]([O:5][C:6](=[O:22])[N:7]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([CH2:20][NH:33][CH:30]2[CH2:32][CH2:31]2)[CH:14]=1)[CH2:8][CH:9]1[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(Cl)c(C=O)c1)CC1CC1
Reactant: NC1CC1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)OC(=O)N(Cc1ccc(Cl)c(CNC2CC2)c1)CC1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.4 %

Procedure:
A mixture of (4-chloro-3-formyl-benzyl)-cyclopropylmethyl-carbamic acid tert-butyl ester (1.00 g, 3.09 mmol), Et3N (0.646 mL, 4.64 mmol) and cyclopropylamine (0.325 mL, 4.64 mmol) in MeOH (10.5 mL) was heated to reflux for 4 h. The mixture was allowed to cool to rt, and NaBH4 (292 mg, 7.71 mmol) was added. The mixture was stirred for 1 h, and aq. sat. NaHCO3 was added. The mixture was extracted with EtOAc (2×). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (MeOH/CH2Cl2 1:49) yielded the title compound (535 mg, 48%). LC-MS: tR=0.81 min; ES+: 406.20.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([C:12]1[S:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1)=O.[NH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1>O1CCCC1.C(OCC)(=O)C.[Na].[Ti]>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10](=[N:21][CH:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1)[C:12]1[S:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1
Reactant: CN1CCC(N)CC1
Reactant: O=C(c1cc2ccccc2o1)c1nc2ccccc2s1
Agent: [Ti]
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN1CCC(N=C(c2cc3ccccc3o2)c2nc3ccccc3s2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (benzofuran-2-yl)(benzothiazol-2-yl)methanone (1.4 g) and 4-amino-1-methylpiperidine (0.57 g) in tetrahydrofurane (8 mL) is added dropwise titanium tetraisopropoxyde (1.78 g). The suspension is stirred for 24 h at room temperature, diluted with ethyl acetate and 1N sodium hydroxyde. The precipitate is filtered over a clarcel pad and rinsed with ethyl acetate. The pooled filtrates are washed with saturated sodium chloride solution, dried and concentrated under reduced pressure. The residue is purified over silica gel (gradiant dichloromethane/methanol from 100/0 to 90/10) to afford [(benzofuran-2-yl)(benzothiazol-2-yl)methylene](1-methylpiperidin-4-yl)amine.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH2:20][CH2:21][NH2:22])=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:34])[CH:31]([CH3:33])[CH3:32]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:32][CH:31]([CH3:33])[C:30]([NH:22][CH2:21][CH2:20][O:19][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[N:10]([S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:9])=[O:8])[CH:11]=[CH:12]2)=[O:34]
Reactant: NCCOc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Reactant: CC(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(=O)NCCOc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 264.7 %

Procedure:
2-{[1-(Phenylsulfonyl)-1H-indol-5-yl]oxy}ethanamine (Intermediate 24, 0.20 g, 0.63 mmol) in DCM (100 mL) was treated with triethylamine (0.27 mL, 1.9 mmol) and 4-dimethylaminopyridine (39 mg, 0.32 mmol). The solution was cooled to 0° C. and was treated with isobutyryl chloride (0.14 g, 0.13 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was washed with saturated aqueous NaHCO3 (50 mL) and 1 M HCl (2×40 mL). The organic phase was dried (MgSO4) and concentrated in vacuo to give the title compound (133 mg). MS m/z 387 [M+H]+.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:23])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH3:15])[C:10](=[O:16])[C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:8]2)=[O:4].[NH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28].C[O-].[Na+]>>[OH:23][C:6]1[C:5]([C:3]([NH:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[O:4])=[N:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[C:9]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:10](=[O:16])[N:11]2[CH3:15]
Reactant: NCCC(=O)O
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2C)c1O
Agent: C[O-]
Agent: [Na+]
Product: Cn1c(=O)c(-c2ccccc2)cc2c(O)c(C(=O)NCCC(=O)O)ncc21
Temperature: 25 °C
Yield: 74.2 %

Procedure:
A mixture of 5-hydroxy-1-methyl-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (35 mg, 0.11 mmol), β-alanine (805 mg, 9.0 mmol) and NaOMe solution (13.5 mL, 6.8 mmol, 0.5 M in MeOH) was refluxed for 48 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 1. The organic layer was dried over MgSO4 and concentrated. The residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH 2 with 6 M HCl, and the resulting suspension was extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated to give 30 mg of the title compound as a light yellow solid. MS: (−) m/z 366.28 (M−1).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([CH2:6][OH:7])[CH2:2]1.F[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.C(N(CC)CC)C>CO>[N:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[N:1]1[CH2:5][CH2:4][C@H:3]([CH2:6][OH:7])[CH2:2]1
Reactant: OC[C@H]1CCNC1
Reactant: Fc1ccccn1
Solvent: CO
Solvent: CCN(CC)CC
Product: OC[C@H]1CCN(c2ccccn2)C1
Temperature: 150 °C
Yield: 58.4 %

Procedure:
(S)-Pyrrolidin-3-ylmethanol (9.89 mmol, 1 g), 2-fluoropyridine (29.7 mmol, 2.88 g) and triethylamine (49.4 mmol, 6.89 ml, 5.00 g) were dissolved in MeOH (2.5 ml) and heated to 150° C. for 1 hour in the microwave. The resulting residue was purified by silica chromatography, eluting with DCM—5% MeOH/DCM to afford (S)-(1-(pyridin-2-yl)pyrrolidin-3-yl)methanol (1.03 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[NH2:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][CH2:35][OH:36].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[OH:36][CH2:35][CH2:34][CH2:33][O:32][CH2:31][CH2:30][NH:29][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:27])([F:28])[F:26])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: NCCOCCCO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCCOCCCO)ccc21
Yield: 83.1 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-(3-hydroxy-propoxy)-ethyl]-amide (85 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (82 mg), 3-(2-amino-ethoxy)-propan-1-ol (48 mg), HBTU (91 mg), and DIEA (52 uL). LC/MS: m/z 510.0.
Reaction SMILES: [N+:1]([C:4]1[C:10]([CH2:11][P:12]([O:17]CC)([O:14]CC)=[O:13])=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-])=O.Cl.[CH2:21]([OH:23])[CH3:22]>[Pd]>[OH:23][CH2:21][C:22]1[NH:1][C:4]2[C:10]([CH2:11][P:12]([OH:14])([OH:17])=[O:13])=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: CCO
Reactant: CCOP(=O)(Cc1cccc(N)c1[N+](=O)[O-])OCC
Agent: [Pd]
Agent: Cl
Product: O=P(O)(O)Cc1cccc2nc(CO)[nH]c12

Procedure:
2-Nitro-3-(diethylphosphonomethyl)aniline (3.2 gm) in ethanol (60 mL) was combined with 10% Pd on carbon and concentrated HCl (ca. 1 mL) and hydrogenated at 55 psi for 3 hours. Additional ethanol was added and the mixture filtered through diatomaceous earth and concentrated to a solid. The solid was combined with 6N HCl and heated to reflux for 16 hours. The reaction was concentrated to a reddish solid combined with water and reconcentrated. The solid was then combined with glyoxalic acid (1.4 gm) and water (30 mL) and heated to reflux for 16 hours. The reaction mixture was concentrated to a solid. H NMR data: D2O (HDO at 4.81 ppm) 3.26 (d,2H), 4.92 (s, 2H), 7.26 (m, 3H).
Reaction SMILES: CN([S+](N(C)C)N(C)C)C.C[Si-](F)(F)(C)C.[N+:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([O-:19])=[O:18].[O:26]1[CH2:30][CH2:29][CH:28]=[C:27]1[O:31][Si](C)(C)C.BrBr>C(#N)C.C1COCC1>[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([CH:28]2[CH2:29][CH2:30][O:26][C:27]2=[O:31])=[CH:22][CH:21]=1)([O-:19])=[O:18]
Reactant: C[Si](C)(C)OC1=CCCO1
Reactant: O=[N+]([O-])c1ccccc1
Agent: BrBr
Agent: CN(C)[S+](N(C)C)N(C)C
Agent: C[Si-](C)(C)(F)F
Solvent: C1CCOC1
Solvent: CC#N
Product: O=C1OCCC1c1ccc([N+](=O)[O-])cc1
Reaction time: 20 h
Yield: 31.9 %

Procedure:
A solution of 2.75 g (10 mmol) of TASF in 3 mL of acetonitrile and 3 mL of THF was added to a solution of 1.02 mL (10 mmol) of nitrobenzene and 1.93 mL (10.50 mmol) of [(oxacyclopent-2-ene-2-yl)oxy]trimethylsilane (OCS) in 12 mL of anhydrous THF at -78° C. over 10 min. The last traces of TASF from the dropping funnel were washed down with additional 5 mL of THF. The mixture was stirred for 20 hrs. at -78° C. Then, 0.460 mL (8.98 mmol) of bromine was added from a dropping funnel. The mixture was stirred at -78° C. for 15 min, and then the cold bath was removed. Stirring was continued for 1 hr. Thirty mL of freshly prepared saturated sodium bisulfite was added, and the product was extracted into four 60 mL portions of ether. Combined ether extracts were washed with saturated potassium hydrogen phosphate and sodium chloride. Concentration and chromatography on silica yielded two products identified as the ortho and para addition products. The ortho-adduct yielded 0.660 g (32%) of product which had a melting point of 112°-117° C. (dec). The para-adduct yielded 0.282 g (14%) of product which had a melting point of 76° to 78° C. Both the o- and p-products were analyzed by ultraviolet absorption, infrared spectroscopy, nuclear magnetic resonance spectroscopy, and mass spectrometry.
Reaction SMILES: Cl([O-])=O.[Na+].S(=O)(=O)(O)N.[F:10][C:11]1[CH:18]=[C:17]([N:19]([CH:23]2[C:27]3[CH:28]=[C:29]4[C:34](=[CH:35][C:26]=3[CH2:25][CH2:24]2)[N:33]=[C:32]([CH3:36])[N:31]([CH2:37][O:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])[C:30]4=[O:45])[CH2:20][C:21]#[CH:22])[CH:16]=[CH:15][C:12]=1[CH:13]=[O:14].C([O-])(=[O:48])C.[Na+]>C(O)(=O)C.C(O)(C)(C)C>[F:10][C:11]1[CH:18]=[C:17]([N:19]([CH:23]2[C:27]3[CH:28]=[C:29]4[C:34](=[CH:35][C:26]=3[CH2:25][CH2:24]2)[N:33]=[C:32]([CH3:36])[N:31]([CH2:37][O:38][C:39](=[O:44])[C:40]([CH3:41])([CH3:43])[CH3:42])[C:30]4=[O:45])[CH2:20][C:21]#[CH:22])[CH:16]=[CH:15][C:12]=1[C:13]([OH:48])=[O:14]
Reactant: CC(=O)[O-]
Reactant: C#CCN(c1ccc(C=O)c(F)c1)C1CCc2cc3nc(C)n(COC(=O)C(C)(C)C)c(=O)c3cc21
Agent: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Product: C#CCN(c1ccc(C(=O)O)c(F)c1)C1CCc2cc3nc(C)n(COC(=O)C(C)(C)C)c(=O)c3cc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Sodium chlorite (0.28 g) and sulphamic acid (0.24 g) were added portionwise to a stirred mixture of o-fluoro-p-[N-((6RS)-2-methyl-4-oxo-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]benzaldehyde (0.47 g), 0.2M sodium acetate in acetic acid buffer (pH 4, 70 ml) and tert-butanol (70 ml). The mixture was stirred at ambient temperature for 24 hours. The mixture was partitioned between methylene chloride and a saturated aqueous sodium dihydrogen phosphate solution. The organic phase was washed with brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography to give o-fluoro-p-[N-((6RS)-2-methyl-4-oxo-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]benzoic acid (0.41 g);
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:16]([C:18]3([NH:21][C:22](=[O:27])[C:23]([O:25]C)=O)[CH2:20][CH2:19]3)=[O:17])=[C:10]([F:28])[CH:9]=2)[C:3]=1[C:29]([O:31][CH3:32])=[O:30].[NH3:33]>C(Cl)Cl.CO>[NH2:33][C:23](=[O:25])[C:22]([NH:21][C:18]1([C:16]([NH:15][CH2:14][C:11]2[CH:12]=[CH:13][C:8]([C:4]3[C:3]([C:29]([O:31][CH3:32])=[O:30])=[C:2]([F:1])[CH:7]=[CH:6][CH:5]=3)=[CH:9][C:10]=2[F:28])=[O:17])[CH2:20][CH2:19]1)=[O:27]
Reactant: COC(=O)C(=O)NC1(C(=O)NCc2ccc(-c3cccc(F)c3C(=O)OC)cc2F)CC1
Reactant: N
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1c(F)cccc1-c1ccc(CNC(=O)C2(NC(=O)C(N)=O)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 3,3′-difluoro-4′-({[(1-{[methoxy(oxo)acetyl]-amino}cyclopropyl)carbonyl]amino}methyl)-1,1′-biphenyl-2-carboxylate (0.02 g, 0.045 mmol, Example 5) in methylene chloride (2 mL) at room temperature was added ammonia (0.224 mL of a 2M solution in methanol, 0.45 mmol). The reaction mixture was stirred at room temperature for 4 hrs and then concentrated to obtain the crude product. This crude product was purified by reverse phase HPLC (Vydac column #218TP1022, gradient elution 5–95% acetonitrile:water containing 0.1% TFA). The pure fractions were lyophilized to afford the title compound as a solid. Purity was determined by LCMS (ES MS, M++H found:432) and proton NMR (400 MHz, CDCl3: δ 7.86 (1H,s), 7.45(1H,dt, J=5.7 and 8.1 Hz), 7.35 (1H, t, J=7.8 Hz), 7.20–7.00 (4H,m), 6.59 (1H, m), 5.61(1H, s), 4.54 (2H, d,J=6.0 Hz), 3.74(3H,s), 1.68(2H,m), 1.12 (2H,m) ppm.
Reaction SMILES: [I:1][C:2]1[CH:14]=[N:13][C:5]2[N:6]([CH3:12])[C:7](=[O:11])O[C:9](=[O:10])[C:4]=2[CH:3]=1.IC1C=NC(NC)=[C:20](C=1)[C:21]([O:23][CH3:24])=[O:22].IC1C=NC(NC)=C(C=1)C(OCC)=O.ClC(OC(Cl)(Cl)Cl)=O>ClCCCl.O1CCOCC1>[OH:10][C:9]1[C:4]2[C:5](=[N:13][CH:14]=[C:2]([I:1])[CH:3]=2)[N:6]([CH3:12])[C:7](=[O:11])[C:20]=1[C:21]([O:23][CH3:24])=[O:22]
Reactant: Cn1c(=O)oc(=O)c2cc(I)cnc21
Reactant: CNc1ncc(I)cc1C(=O)OC
Agent: CCOC(=O)c1cc(I)cnc1NC
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Solvent: ClCCCl
Product: COC(=O)c1c(O)c2cc(I)cnc2n(C)c1=O
Temperature: 80 °C

Procedure:
6-Iodo-1-methyl-1H-pyrido[2,3-d][1,3]oxazine-2,4-dione. To a mixture of methyl 5-iodo-2-(methylamino)nicotinate and ethyl 5-iodo-2-(methylamino)nicotinate (10.5 g) and 1,4-dioxane (10 mL) in anhydrous 1,2-dichloroethane (1000 mL) was added trichloromethyl chloroformate (15.43 mL, 128.45 mmol) dropwise over 1 hour, with stirring and heating at 80° C. After addition, the reaction mixture was stirred at 80° C. for 4 hours, and was allowed to reach room temperature. The solvent was evaporated, and the residue was washed with a 1:1 mixture of EtOAc/hexanes (100 mL) and dried in vacuo to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[N:9]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH2:8][CH2:7][C:6]=2[CH:19]=1.Cl[C:21]1[N:26]=[CH:25][N:24]=[C:23]([C:27]([N:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:31][CH2:30]2)=[O:28])[CH:22]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[N:9]([CH:13]3[CH2:14][CH2:15][N:16]([C:21]4[CH:22]=[C:23]([C:27]([N:29]5[C:37]6[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=6)[CH2:31][CH2:30]5)=[O:28])[N:24]=[CH:25][N:26]=4)[CH2:17][CH2:18]3)[CH2:8][CH2:7][C:6]=2[CH:19]=1
Reactant: O=C(c1cc(Cl)ncn1)N1CCc2ccccc21
Reactant: O=C1Nc2ccc(Cl)cc2CCN1C1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(N2CCC(N3CCc4cc(Cl)ccc4NC3=O)CC2)ncn1)N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
110 mg (0.36 mmol) 7-chloro-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one were added to 87.6 mg (0.34 mmol) (6-chloropyrimidin-4-yl)-(2,3-dihydro-indol-1-yl)-methanone and 63 μL (0.37 mmol) DIPEA in 2.5 mL DMF. The reaction mixture was stirred overnight at RT, then concentrated by rotary evaporation using the rotary evaporator and purified by preparative HPLC. The corresponding product fractions were combined and evaporated down using the rotary evaporator. The residue was taken up in DMF and combined with methanol. The substance was precipitated, suction filtered, washed with a little methanol and dried.
Reaction SMILES: Cl.[NH2:2][C:3]1([CH3:22])[CH2:7][CH2:6][CH2:5][CH:4]1[NH:8][C:9](=[O:21])[O:10][C@@H:11]1[CH2:16][C@H:15]([CH3:17])[CH2:14][CH2:13][C@H:12]1[CH:18]([CH3:20])[CH3:19].F[C:24]1[C:29]([F:30])=[CH:28][C:27]([C:31]([F:34])([F:33])[F:32])=[CH:26][N:25]=1.CCN(C(C)C)C(C)C>CS(C)=O>[F:30][C:29]1[C:24]([NH:2][C:3]2([CH3:22])[CH2:7][CH2:6][CH2:5][CH:4]2[NH:8][C:9](=[O:21])[O:10][C@@H:11]2[CH2:16][C@H:15]([CH3:17])[CH2:14][CH2:13][C@H:12]2[CH:18]([CH3:19])[CH3:20])=[N:25][CH:26]=[C:27]([C:31]([F:33])([F:32])[F:34])[CH:28]=1
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)NC1CCCC1(C)N
Reactant: Fc1cc(C(F)(F)F)cnc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)NC1CCCC1(C)Nc1ncc(C(F)(F)F)cc1F

Procedure:
A solution of (1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl N-(2-amino-2-methylcyclopentyl)carbamate hydrochloride (Intermediate 27; 1.00 g, 3.00 mmol), 2,3-difluoro-5-(trifluoromethyl)pyridine (CAS number 89402-42-6; 0.412 ml, 3.30 mmol) and DIPEA (1.57 ml, 9.01 mmol) in DMSO (10 ml) was subjected to microwave irradiation at 140° C. for 3 hours. The reaction was then partitioned between ethyl acetate (10 ml) and water (10 ml), filtered through a hydrophobic frit and concentrated in vacuo. The residue was purified by column chromatography (silica, 0-12% diethyl ether/petrol) to afford the title compound as a single trans-enantiomer.
Reaction SMILES: ClCCl.C(O[C@@:8]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28])([C@H:15]([S:17](Cl)(=[O:19])=[O:18])[CH3:16])[CH2:9][N:10]1[CH:14]=[N:13][CH:12]=[N:11]1)(=O)C.[NH3:29]>C(OCC)(=O)C>[F:28][C:22]1[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=1[C:8]([CH2:9][N:10]1[CH:14]=[N:13][CH:12]=[N:11]1)=[C:15]([S:17]([NH2:29])(=[O:19])=[O:18])[CH3:16]
Reactant: CC(=O)O[C@@](Cn1cncn1)(c1ccc(F)cc1F)[C@@H](C)S(=O)(=O)Cl
Reactant: N
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=C(Cn1cncn1)c1ccc(F)cc1F)S(N)(=O)=O

Procedure:
A dichloromethane (30 ml) solution of (2R,3R)-3-chlorosulfonyl-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butyl acetate (2.0 g) was cooled to -30° C., to which was introduced ammonia for 10 minutes. To the mixture was introduced nitrogen to eliminate ammonia. To the reaction mixture was added ethyl acetate (50 ml), then precipitating crystals were collected by filtration, followed by recrystallization from methanol to give 3-(2,4-difluorophenyl)-4-(1H-1,2,4-triazol-1-yl)-2-butene-2-sulfonamide (isomer A, Compound 36, 0.54 g) as colorless crystals.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[NH2:10][C:11]1[C:12]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])=[N:13][C:14](Br)=[CH:15][N:16]=1>CN(C=O)C>[NH2:10][C:11]1[C:12]([C:18]([NH:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:19])=[N:13][C:14]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:15][N:16]=1
Reactant: Oc1ccccc1
Reactant: Nc1ncc(Br)nc1C(=O)Nc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncc(Oc2ccccc2)nc1C(=O)Nc1ccccc1
Temperature: 100 °C
Yield: 11.8 %

Procedure:
Phenol (62.60 mg, 59.06 μL, 0.6652 mmol) was added slowly to a suspension of sodium hydride (60% dispersion in mineral oil) (15.96 mg, 17.73 μL, 0.6652 mmol) in anhydrous DMF (1.3 mL) at 0° C. The reaction mixture was stirred until the evolution of H2 ceased. 3-Amino-6-bromo-N-phenyl-pyrazine-2-carboxamide (130 mg, 0.4435 mmol) was added followed by Cu2O (15.87 mg, 0.1109 mmol) and reaction mixture heated to 100° C. overnight. The reaction mixture was cooled to ambient temperature and quenched with crushed ice. The aqueous layer was extracted with EtOAc (×3) and the combined organic extracts washed with ammonium hydroxide (×1), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound as a yellow solid (16 mg, 12% Yield). 1H NMR (400.0 MHz, DMSO) δ 7.15-7.17 (m, 4H), 7.34-7.47 (m, 6H), 7.66-7.68 (m, 2H), 8.24 (s, 1H) and 9.92 (s, 1H) ppm; MS (ES+) 306.99.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[C:7]([F:15])[CH:6]=1.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C(O)C>[F:15][C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=1)[O:4][CH2:3][CH2:2][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CS(=O)(=O)c1cc(F)cc(OCCBr)c1
Reactant: C1CCNCC1
Solvent: CCO
Product: CS(=O)(=O)c1cc(F)cc(OCCN2CCCCC2)c1
Yield: 94.8 %

Procedure:
Preparation according to Example 1 but performed in one portion: 1-(2-bromoethoxy)-3-fluoro-5-methylsulfonyl-benzene (0.5 g, 1.68 mmol) and piperidine (1.33 ml, 13.46 mmol) in ethanol (5 ml). Purification by flash column chromatography (ethyl acetate/methanol, 100:0 to 85:15) gave the title compound (480 mg, 94.7%). The amine was converted to the hydrochloric acid salt and re-crystallized from methanol/diethyl ether: M.p. 194.6° C. MS m/z (relative intensity, 70 eV) 301(M+, 1), 99 (8), 98 (bp), 96 (4), 55 (5).