Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[F:13][C:14]([F:22])([F:21])[CH:15]([OH:20])[C:16]([F:19])([F:18])[F:17].C(N(C(C)C)C(C)C)C.[CH3:32][C@@H:33]1[NH:38][CH2:37][CH2:36][N:35]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[CH:42][C:41]=2[C:52]([F:55])([F:54])[F:53])[CH2:34]1>CN(C)C1C=CN=CC=1.O.ClCCl>[CH3:32][C@H:33]1[CH2:34][N:35]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[CH:42][C:41]=2[C:52]([F:55])([F:53])[F:54])[CH2:36][CH2:37][N:38]1[C:2]([O:20][CH:15]([C:16]([F:19])([F:18])[F:17])[C:14]([F:22])([F:21])[F:13])=[O:4]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OC(C(F)(F)F)C(F)(F)F
Reactant: C[C@H]1CN(Cc2ccc(N3CCOCC3)cc2C(F)(F)F)CCN1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(Cc2ccc(N3CCOCC3)cc2C(F)(F)F)CCN1C(=O)OC(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.5 %

Procedure:
A 100 mL round-bottom flask was charged with triphosgene (121 mg, 0.410 mmol, 0.70 equiv), dichloromethane (20 mL), 1,1,1,3,3,3-hexafluoropropan-2-ol (196 mg, 1.17 mmol, 2.00 equiv) and N-ethyl-N-isopropylpropan-2-amine (602 mg, 4.66 mmol, 8.00 equiv) were added at 0° C. The mixture was stirred for 2 h at room temperature. 4-(4-[[(3S)-3-methylpiperazin-1-yl]methyl]-3-(trifluoromethyl)phenyl)morpholine (200 mg, 0.580 mmol, 1.00 equiv) and 4-dimethylaminopyridine (71.0 mg, 0.580 mmol, 1.00 equiv) were added. The resulting solution was stirred overnight at room temperature, diluted with H2O (10 mL), extracted with dichloromethane (3×10 mL). The organic layers were combined and washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product (500 mg) was purified by preparative HPLC using the following gradient conditions: 20% CH3CN/80% Phase A increasing to 80% CH3CN over 10 min, then to 100% CH3CN over 0.1 min, holding at 100% CH3CN for 1.9 min, then reducing to 20% CH3CN over 0.1 min, and holding at 20% for 1.9 min, on a Waters 2767-5 Chromatograph. Column: Xbridge Prep C18, 19*150 mm 5 um; Mobile phase: Phase A: aqueous NH4HCO3 (0.05%); Phase B: CH3CN; Detector, UV220 & 254 nm. Purification resulted in 228 mg (73% yield) of 1,1,1,3,3,3-hexafluoropropan-2-yl(2S)-2-methyl-4-[[4-(morpholin-4-yl)-2-(trifluoromethyl)phenyl]methyl]piperazine-1-carboxylate as yellow oil. 1H NMR 300 MHz (CDCl3) δ 7.58 (d, J=8.7 Hz, 1H), 7.14 (s, 1H), 7.01-7.05 (m, 1H), 5.72-5.84 (m, 1H), 4.27 (br, 1H), 3.87 (t, J=4.8 Hz, 5H), 3.55 (s, 2H), 3.26 (br, 1H), 3.20 (t, J=4.8 Hz, 4H), 2.79 (d, J=10.5 Hz, 1H), 2.63 (d, J=11.4 Hz, 1H), 2.25-2.30 (m, 1H), 2.08-2.16 (m, 1H), 1.31 (d, J=6.6 Hz, 3H). LCMS: (ESI, m/z): 538 [M+H]+.
Reaction SMILES: [CH2:1]1N2CN3CN(C2)[CH2:3][N:2]1[CH2:9]3.[C:11]([OH:14])(=O)[CH3:12].[C:15]1(C)[CH:20]=CC=[CH:17][CH:16]=1>>[CH3:1][N:2]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:20][C:12]=1[CH:11]=[O:14])[CH3:3]
Reactant: CC(=O)O
Reactant: Cc1ccccc1
Reactant: C1N2CN3CN1CN(C2)C3
Product: CN(C)c1ccccc1C=O

Procedure:
This example demonstrates that the reaction of N,N-dimethylaniline with hexamethylenetetramine can be carried out with the addition of toluene to the reaction medium to give dimethylaminobenzaldehyde directly in high yield in one step. There is no need for an additional hydrolysis step since the initially formed Schiff's base is converted to the desired product, p-dimethylaminobenzaldehyde (DMAB) under the reaction conditions. In addition, there is substantial reduction in the amounts of hexamethylenetetramine (0.5 compared to 1.5 mol) and acetic acid (2-3 compared to 7 mol) required to obtain comparable yields of dimethylaminobenzaldehyde when toluene is added compared to its absence. The inventive process gives very high selectivity (>90%) to the desired product, which affords efficient utilization of starting materials.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH:3]1[CH2:8][CH2:7][C:6]([C:9]2[CH:10]=[C:11]([NH2:16])[CH:12]=[C:13]([F:15])[CH:14]=2)=[CH:5][CH2:4]1.[Cl:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>O1CCOCC1>[ClH:18].[Cl:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:20]=1[C:21]([NH:16][C:11]1[CH:12]=[C:13]([F:15])[CH:14]=[C:9]([C:6]2[CH2:7][CH2:8][CH:3]([N:2]([CH3:17])[CH3:1])[CH2:4][CH:5]=2)[CH:10]=1)=[O:22]
Reactant: CN(C)C1CC=C(c2cc(N)cc(F)c2)CC1
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Solvent: C1COCCO1
Product: CN(C)C1CC=C(c2cc(F)cc(NC(=O)c3ccc(F)cc3Cl)c2)CC1
Product: Cl
Temperature: 25 °C
Yield: 99.5 %

Procedure:
Combine chiral 3-(4-dimethylamino-cyclohex-1-enyl)-5-fluoro-phenylamine (isomer 5A, preparation 5, 0.25 g, 1.07 mmol), 2-chloro-4-fluoro-benzoyl chloride (0.31 g, 1.6 mmol) and 1,4-dioxane (5 mL) and heat to reflux for 3 hr. Cool to ambient temperature and remove volatiles. Purify the residue by flash chromatography (silica gel, 10% 2M NH3/MeOH in DCM) to obtain the free base of the title compound (0.34 g, 81%). Convert to the hydrochloride salt by dissolving in ether and treating with 1M HCl in ether: MS (ES) m/z=391 (M+H)+; 1H NMR of free base (CDCl3): δ 8.19 (s, 1H), 7.72 (m, 1H), 7.42 (d, 1H, J=10 Hz), 7.26 (s, 1H), 7.16 (m, 1H), 7.06 (m, 1H), 6.86 (d, 1H, J=10 Hz), 6.09 (bs, 1H), 2.40 (m, 4H), 2.32 (s, 6H), 2.11 (m, 2H), 1.53 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][NH2:20])[O:16][C:15]2=[O:21])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:35])[CH2:30][CH2:31][C:32](O)=[O:33])=[CH:25][CH:24]=1.C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][NH:20][C:32](=[O:33])[CH2:31][CH2:30][C:29]([C:26]3[CH:25]=[CH:24][C:23]([Cl:22])=[CH:28][CH:27]=3)=[O:35])[O:16][C:15]2=[O:21])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1
Reactant: NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Reactant: O=C(O)CCC(=O)c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: O=C(CCC(=O)c1ccc(Cl)cc1)NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Temperature: 0 °C
Reaction time: 24 h
Yield: 42 %

Procedure:
(S)-N-[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl amine (0.100 gm, 0.00034 moles) was taken up in 1:1 THF-water mixture (20 ml). To this was added 4-(4-chlorophenyl)-4-oxobutanoic acid (0.072 g, 0.00034 moles and HOBt (0.046 g, 0.00034 moles). The resulting mixture was cooled to 0° C., and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.071 gm, 0.00037 moles) was added. The resulting mixture was allowed to warm to room temperature and then stirred for 24 hr. The reaction mixture was concentrated and 2 ml of saturated aqueous sodium bicarbonate solution was added, stirred for 15 min and then extracted with dichloromethane. The organic layer was separated and evaporated off. The residue was chromatographed over silica gel (100-200 mesh, 20 g) and eluted with mixture of ethyl acetate:hexane, and finally with ethyl acetate. The combined fractions were concentrated to give (0.070 gm, 42%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]3[NH:19][CH:20]=[C:21]([CH2:25][CH3:26])[C:22](=[O:24])[N:23]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:27]([F:30])([F:29])[F:28].[CH3:31][CH2:32]N(C(C)C)C(C)C.C(I)C>ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][O:17][C:18]3[N:19]([CH2:31][CH3:32])[CH:20]=[C:21]([CH2:25][CH3:26])[C:22](=[O:24])[N:23]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[C:27]([F:28])([F:30])[F:29]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCc1c[nH]c(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)nc1=O
Solvent: CCI
Solvent: ClCCCl
Product: CCc1cn(CC)c(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)nc1=O
Temperature: 40 °C
Yield: 39.4 %

Procedure:
To a solution of 2-{[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl]oxy}-5-ethyl-4(1H)-pyrimidinone (60 mg, 0.137 mmol), DIPEA (0.036 mL, 0.205 mmol) in DCE (2 mL) was added EtI (0.013 mL, 0.164 mmol). The mixture was heated at 40° C. for 1 h. Purification via reverse phase flash chromatography then afforded the title compound (25 mg, 0.054 mmol, 39.2% yield). LCMS: rt=3.80 min, [M+H+]=467
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)([S:4]([O:7][CH2:8][CH3:9])(=[O:6])=[O:5])[CH3:3].[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(Cl)(=O)C1C=CC=CC=1>[CH3:1][C:2]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][Br:17])=[CH:12][CH:11]=1)([S:4]([O:7][CH2:8][CH3:9])(=[O:5])=[O:6])[CH3:3]
Reactant: CCOS(=O)(=O)C(C)(C)c1ccc(C)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: O=C(Cl)c1ccccc1
Product: CCOS(=O)(=O)C(C)(C)c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 105.4 %

Procedure:
To a solution of ethyl 1-methyl-1-(4-methylphenyl)ethanesulfonate (0.458 g, 1.89 mmol) in carbon tetrachloride (8 mL) was added N-bromosuccinimide (0.370 g, 2.08 mmol) and benzoyl chloride (0.009 g). The mixture was heated under reflux for 1.5 hours, cooled to rt, and filtered. The filtrate was washed with aqueous sodium bicarbonate and brine, dried, filtered and evaporated to give crude ethyl 1-methyl-1-(4-bromomethylphenyl)ethanesulfonate (0.64 g, 100%) which was used directly in the next reaction.
Reaction SMILES: [NH2:1]C(OCC)=O.C[O-].[Na+].[CH3:10][O:11][CH2:12][CH:13]1[CH2:17][O:16][C:15](=O)[O:14]1>CN(C)C=O>[CH3:10][O:11][CH2:12][CH:13]1[O:14][C:15](=[O:16])[NH:1][CH2:17]1
Reactant: COCC1COC(=O)O1
Reactant: CCOC(N)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC1CNC(=O)O1
Temperature: 140 °C
Reaction time: 80 h
Yield: 43.3 %

Procedure:
Urethane (10.0 g, 113 mmol) was dissolved in N,N-dimethylformamide (40 ml), and thereto were added sodium methoxide (409 mg, 7.57 mmol) and 4-methoxymethyl-1,3-dioxolan-2-one (10.0 g, 75.7 mmol), in order. The mixture was stirred for 80 hours at 140° C. under an atmosphere of argon. After filtering off the insoluble materials, the filtrate was condensed in vacuo, and the residue was purified by silica gel chromatography to give the subject 5-methoxymethyloxazolidin-2-one (4.3 g, yield 43.3%).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[N:15]([CH3:16])[C:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[N:13][N:12]=1)(=O)=O.[F:24][C:25]([F:39])([F:38])[C:26]1[CH:31]=[CH:30][C:29]([C@:32]23[CH2:37][C@H:36]2[CH2:35][NH:34][CH2:33]3)=[CH:28][CH:27]=1>>[ClH:23].[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C:14]2[N:15]([CH3:16])[C:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][N:34]3[CH2:35][C@H:36]4[C@:32]([C:29]5[CH:28]=[CH:27][C:26]([C:25]([F:24])([F:39])[F:38])=[CH:31][CH:30]=5)([CH2:37]4)[CH2:33]3)=[N:12][N:13]=2)=[CH:18][CH:19]=1
Reactant: Cn1c(CCCCCOS(C)(=O)=O)nnc1-c1ccc(Cl)cc1
Reactant: FC(F)(F)c1ccc([C@@]23CNC[C@@H]2C3)cc1
Product: Cl
Product: Cn1c(CCCCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)nnc1-c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the method described in Example 14 in 19 mg yield as a white solid starting from 5-[5-(4-chlorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl]pentyl methanesulfonate (31 mg) and (1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (21 mg ).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7]2[CH:8]=[C:9](B(O)O)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:15])[O:3]1.Br[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1>>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:9]2[CH:10]=[CH:11][C:6]3[NH:5][C:4](=[O:15])[O:3][C:2]([CH3:16])([CH3:1])[C:7]=3[CH:8]=2)=[CH:19][CH:20]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Product: CC1(C)OC(=O)Nc2ccc(-c3ccc(F)cc3)cc21

Procedure:
6-(4-Fluoro-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one was prepared, according to the procedure of Example 5 from (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and 1-bromo-4-fluorobenzene, as off-white crystals: mp 232-233° C.; 1H-NMR (DMSO-d6) δ 10.3 (s, 1H), 7.74 (m, 2H), 7.53 (m, 2H), 7.28 (m, 2H), 6.96 (d, 1H, J=8.9 Hz), 1.63 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH:11]=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29](=[O:42])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)[CH:31]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH:11]=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29](=[O:42])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)[CH:31]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)ccc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Product: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)ccc1NC(=O)CC(=O)c1cccc(-c2cccnc2)c1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-phenyl]-carbamic acid tert-butyl ester (Example J13) (230 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as a light brown solid (362 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5](P(OC)(OC)=O)[NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:4].[CH3:23][C:24]([CH3:30])([CH:28]=[CH2:29])[CH2:25][CH:26]=O.C1CCN2C(=NCCC2)CC1>C1COCC1.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:4])[C:5]([NH:6][C:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8])=[CH:29][CH2:28][C:24]([CH3:30])([CH3:23])[CH:25]=[CH2:26]
Reactant: C=CC(C)(C)CC=O
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: C=CC(C)(C)CC=C(NC(=O)OCc1ccccc1)C(=O)OC
Temperature: 0 °C
Reaction time: 16 h

Procedure:
N-(Benzyloxycarbonyl)-α-phosphonoglycine trimethyl ester (34.3 g, 103 mmol, 1.0 equiv) was dissolved in dry THF (250 mL) and the solution was cooled to 0° C. 3,3-Dimethyl-pent-4-en-al (11.6 g, 103 mmol, 1.0 equiv) and DBU (15.5 mL, 103 mmol, 1.0 equiv) were added and the reaction mixture was stirred for 16 h. The solution was diluted with 500 mL of CH2Cl2 and washed with 1×150 mL water, and 1×150 mL brine. The organic layer was dried over Na2SO4, decanted and concentrated in vacuo to provide 2-benzyloxycarbonylamino-5,5-dimethyl-hept-2,6-dienoic acid methyl ester as a thick oil (31 g, 95% crude). The enamide is purified by flash chromatography on silica using hexanes/EtOAc as mobile phase to yield 2-benzyloxyearbonylamino-5,5-dimethyl-hept-2,6-dienoic acid methyl ester as a thick oil that solidifies on standing.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([NH:12]C(C2C=NC3C(C=2Cl)=C(F)C=C(F)C=3)=O)[CH2:8][CH2:7]1>C(N(CC)CC)C>[ClH:3].[CH3:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([NH2:12])[CH2:8][CH2:7]1
Reactant: C[C@H]1CC[C@H](NC(=O)c2cnc3cc(F)cc(F)c3c2Cl)CC1
Reactant: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: C[C@H]1CC[C@H](N)CC1
Product: Cl

Procedure:
The crude acid (500 mg,), thionyl chloride, trans-4-methylcyclohexylamine hydrochloride (250 mg, 1.67 mmol), and triethylamine (0.3 mLs) afforded crude N-(trans-4-methylcyclohexyl)-4-chloro-5,7-difluoroquinoline-3-carboxamide.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([CH3:17])[C:3]=1[C:4]#[N:5].Cl.[CH3:19][O:20][C:21]1[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=1[O:23][CH2:24][CH2:25][NH2:26].C(=O)([O-])O.[Na+].CS(C)=O>O>[CH3:19][O:20][C:21]1[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=1[O:23][CH2:24][CH2:25][NH:26][C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([CH3:17])[C:3]=1[C:4]#[N:5]
Reactant: COc1ccccc1OCCN
Reactant: Cc1cc(Nc2cc(C)c(C#N)c(Cl)n2)n[nH]1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccccc1OCCNc1nc(Nc2cc(C)[nH]n2)cc(C)c1C#N
Temperature: 100 °C
Reaction time: 27 h
Yield: 14.4 %

Procedure:
Compound A (400 mg, 1.63 mmol), 2-(2-methoxyphenoxy)ethylamine hydrochloride (1.10 g) and sodium hydrogencarbonate (1.37 g) were added to DMSO (12 ml), and the mixture was stirred at 100° C. for 27 hr. After stirring, the reaction mixture was added to cold water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and concentrated, and the residue was washed by suspending in ethyl acetate to give the object compound of 2-(2-(2-methoxyphenoxy)ethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)-4-methylnicotinonitrile (89 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([N:11]([CH2:16][CH2:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:12](=[O:15])[O:13][CH3:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:26][C:27](=[CH2:31])[CH2:28][Mg]Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([N:11]([CH2:16][CH2:17][C:18]([OH:25])([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:28][C:27]([CH3:31])=[CH2:26])[C:12](=[O:15])[O:13][CH3:14])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: COC(=O)N(CCC(=O)c1ccccc1)C1(c2ccc(Br)cc2)CC1
Reactant: C=C(C)C[Mg]Cl
Solvent: C1CCOC1
Product: C=C(C)CC(O)(CCN(C(=O)OC)C1(c2ccc(Br)cc2)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 41 %

Procedure:
A solution of methyl 1-(4-bromophenyl)cyclopropyl(3-oxo-3-phenylpropyl)carbamate (127 mg, 0.316 mmol) in dry THF (10 mL) was cooled to −78° C. A solution of 0.5M 2-methylallylmagnesium chloride in THF (1.9 mL, 3 equiv) was added. After 10min, the reaction mixture was warmed to rt slowly and stirred for 1 h. LC-MS found the reaction was complete. The mixture was quenched with satd aq NH4Cl (3 mL), diluted with ether (40 mL), washed with 1% aq HCl (8 mL), satd aq NaHCO3 (7 mL), and brine (5 mL), and dried over Na2SO4. After filtration and concentration, the residue was purified by chromatography on a 12-g silica gel column, eluted with a 0˜30% EtOAc in hexanes gradient, to afford methyl 1-(4-bromophenyl)cyclopropyl(3-hydroxy-5-methyl-3-phenylhex-5-enyl)carbamate (58.8 mg, 41%).
Reaction SMILES: [CH2:1]([O:3][C:4]([O:6][C@H:7]([N:9]1[N:13]=[N:12][C:11]([C:14]2[N:18]([CH3:19])[N:17]=[CH:16][C:15]=2[C:20]2[CH:48]=[CH:47][C:23]([C:24]([N:26]([C:40]3[C:45]([CH3:46])=[CH:44][CH:43]=[CH:42][N:41]=3)[C@@H:27]3[CH2:32][CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28]3)=[O:25])=[CH:22][CH:21]=2)=[N:10]1)[CH3:8])=[O:5])[CH3:2].Cl.O1CCOCC1>C(#N)C>[C:4](=[O:5])([O:6][C@H:7]([N:9]1[N:13]=[N:12][C:11]([C:14]2[N:18]([CH3:19])[N:17]=[CH:16][C:15]=2[C:20]2[CH:48]=[CH:47][C:23]([C:24](=[O:25])[N:26]([C:40]3[C:45]([CH3:46])=[CH:44][CH:43]=[CH:42][N:41]=3)[C@@H:27]3[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]3)=[CH:22][CH:21]=2)=[N:10]1)[CH3:8])[O:3][CH2:1][CH3:2]
Reactant: CCOC(=O)O[C@@H](C)n1nnc(-c2c(-c3ccc(C(=O)N(c4ncccc4C)[C@@H]4CCCN(C(=O)OC(C)(C)C)C4)cc3)cnn2C)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: CCOC(=O)O[C@@H](C)n1nnc(-c2c(-c3ccc(C(=O)N(c4ncccc4C)[C@@H]4CCCNC4)cc3)cnn2C)n1
Temperature: 80 °C
Reaction time: 1 h
Yield: 65.1 %

Procedure:
Preparation 27, tert-butyl (3R)-3-[{4-[5-(2-{(1S)-1-[(ethoxycarbonyl)oxy]ethyl}-2H-tetrazol-5-yl)-1-methyl-1H-pyrazol-4-yl]benzoyl}(3-methylpyridin-2-yl)amino]piperidine-1-carboxylate (438 mg, 0.664 mmol) was dissolved in acetonitrile (3.3 mL). To this was added HCl in dioxane (2.49 mL, 4M solution, 15 eq.) dropwise at room temperature. After 1 h, the reaction was concentrated in vacuo, and concentrated with toluene (3×15 mL). The crude material was suspended in EtOAc and heated to 80° C. for 16 h. Filtration of the material provided the hydrochloride salt of ethyl (1S)-1-{5-[1-methyl-4-(4-{(3-methylpyridin-2-yl)[(3R)-piperidin-3-yl]carbamoyl}phenyl)-1H-pyrazol-5-yl]-2H-tetrazol-2-yl}ethyl carbonate (242 mg, 65%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:30]([F:31])=[CH:29][C:28]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:27][C:26]=3[F:36])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:37][CH3:38].Cl[C:40]([O:42][CH2:43][CH3:44])=[O:41].CCN(CC)CC>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:26]([F:36])=[CH:27][C:28]([S:32]([NH:35][C:40](=[O:41])[O:42][CH2:43][CH3:44])(=[O:34])=[O:33])=[CH:29][C:30]=3[F:31])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:37][CH3:38]
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(S(N)(=O)=O)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)NS(=O)(=O)c1cc(F)c(CSc2ncc(C(C)(C)c3ccc(Cl)c(OC)c3)n2-c2ccc(F)cc2)c(F)c1
Reaction time: 3 h
Yield: 68.3 %

Procedure:
To a mixture of 4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorobenzenesulfonamide (100 mg, 0.17 mmol, 1.0 eq) and ethyl chloroformate (0.022 mL, 0.21 mmol, 1.2 eq) in DCM was added Et3N (0.05 mL, 0.34 mmol, 2.0 eq). After stirring 3 h, the reaction mixture was diluted with EtOAc, washed with water and brine, and purified by chromatography (silica, 0 to 80% EtOAc/Hex, then 10% MeOH/DCM) to provide the title compound (76 mg, 68%). MS (EI) m/z 655 (MH+).
Reaction SMILES: [CH3:1][C@@:2]12[C:8]([CH3:10])([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[C:4](=O)[C:3]2=O.COP([CH2:19][C:20]([C:22]1[CH:23]=[N:24][N:25]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:26]=1[CH3:27])=O)(=O)OC.O.[NH2:36][NH2:37]>>[CH2:28]([N:25]1[C:26]([CH3:27])=[C:22]([C:20]2[CH:19]=[C:4]3[C:3]([C@:2]4([CH3:1])[C:8]([CH3:10])([CH3:9])[C@H:5]3[CH2:6][CH2:7]4)=[N:37][N:36]=2)[CH:23]=[N:24]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2=O
Reactant: COP(=O)(CC(=O)c1cnn(Cc2ccccc2)c1C)OC
Reactant: NN
Solvent: O
Product: Cc1c(-c2cc3c(nn2)[C@@]2(C)CC[C@@H]3C2(C)C)cnn1Cc1ccccc1

Procedure:
light brown amorphous solid. MS (ESI): 359.1 (MH+). Prepared from (1S,4R)-1,7,7-trimethyl-bicyclo[2.2.1]heptane-2,3-dione, [2-(1-Benzyl-5-methyl-1H-pyrazol-4-yl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: C(O[C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[N:9]2[CH:18]=[C:19]([C:21]#[N:22])[CH:20]=[C:8]2[C:7]=1[OH:23])=O)C.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:27][C:26]=1[S:36]([NH2:39])(=[O:38])=[O:37].N12CCCN=C1CCCCC2>N1C=CC=CC=1>[C:21]([C:19]1[CH:20]=[C:8]2[C:7]([OH:23])=[C:6]([C:4]3[NH:24][C:25]4[CH:30]=[CH:29][C:28]([NH:31][S:32]([CH3:35])(=[O:33])=[O:34])=[CH:27][C:26]=4[S:36](=[O:38])(=[O:37])[N:39]=3)[C:11](=[O:12])[N:10]([CH2:13][CH2:14][CH:15]([CH3:16])[CH3:17])[N:9]2[CH:18]=1)#[N:22]
Reactant: CS(=O)(=O)Nc1ccc(N)c(S(N)(=O)=O)c1
Reactant: CCOC(=O)c1c(O)c2cc(C#N)cn2n(CCC(C)C)c1=O
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)c(O)c2cc(C#N)cn21
Temperature: 120 °C
Yield: 6.7 %

Procedure:
A solution of 6-cyano-4-hydroxy-1-(3-methyl-butyl)-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (Example 15e, 0.25 g, 0.788 mmol) and 2-amino-5-methanesulfonylamino-benzenesulfonamide (Example 3d, 0.209 g, 0.788 mmol) in pyridine (4 mL) was heated to 120° C. for 3 h. 1,8-Diazabicyclo[5.4.0]undec-7-ene (200 μL) was added and the mixture was heated at 120° C. for 16 h. The reaction mixture was passed through a plug of silica gel and eluted with 50%-100% ethyl acetate in hexanes. The solvents were removed in vacuo and purification by preparative HPLC (Column Luna 5μ C18 (2) 100 Å size 150×21.2 mm, 5 micron, 40%-95% in 11 min 25 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water) afforded the desired product, N-{3-[6-cyano-4-hydroxy-1-(3-methyl-butyl)-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (0.0275 g, 0.0531 mmol, 6.7% yield). 1H NMR (400 MHz, DMSO-d6) δ: 0.94 (3H, s), 0.96 (3H, s), 1.17-1.23 (2H, m), 1.51-1.57 (2H, m), 1.65-1.75 (1H, m), 5.74 (1H, s), 3.05 (3H, s), 7.40 (1H, s), 7.49-7.57 (3H, m), 8.51 (1H, s), 10.12 (1H, s), 13.75 (1H, s). LC-MS (ESI) calcd for C21H22N6O6S2 518.10. found 519.4 [M+H+].