Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:6])[C:3]([OH:5])=O.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:27](=[O:28])[CH2:26][C:25](=[O:29])[NH:24][C:23]3[C:30]4[C:35]([CH:36]=[CH:37][C:22]2=3)=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:17][CH:16]=1.CC(OC1C=CC=CC=1)(C)C(Cl)=O>>[CH3:6][C:2]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:1])[C:3]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:27](=[O:28])[CH2:26][C:25](=[O:29])[NH:24][C:23]3[C:30]4[C:35]([CH:36]=[CH:37][C:22]2=3)=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:17][CH:16]=1)=[O:5]
Reactant: CC(C)(Oc1ccccc1)C(=O)O
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: CC(C)(Oc1ccccc1)C(=O)Cl
Product: CC(C)(Oc1ccccc1)C(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 101 %

Procedure:
2-Methyl-2-phenoxypropionic acid (34 mg, 0.189 mmol) was made into acid chloride in a conventional manner. By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30 mg, 0.095 mmol) obtained in Example 1, (3), and 2-methyl-2-phenoxypropionic acid chloride mentioned above, the title compound (46 mg, yield 100%) was obtained in the same manner as that of Example 1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:12][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(F)ccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(F)ccc1CBr

Procedure:
With no precautions to maintain a dry atmosphere, methyl 5-fluoro-2-methylbenzoate (Maybridge, 5 g, 29.7 mmole) was dissolved in CCl4 (50 mL). N-bromosuccinimide (5.82 g, 32.7 mmol) and benzoyl peroxide (0.36 g, 1.48 mmole) were added and the reaction brought to reflux overnight. An additional 0.3 eq of NBS and 0.01 eq of benzoyl peroxide was added and the reaction refluxed for 4 hrs, then cooled, filtered and concentrated. The residue was chromatographed on silica eluting with a gradient of 0-10% EtOAc/Hexanes. The fractions were collected to give the product, which was a mixture of mono and bis-brominated materials, as a clear oil.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:14])[C@@H:10](Br)[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:15]=[N+:16]=[N-:17].[Na+].O.C([O-])(O)=O.[Na+]>CN(C)C=O>[N:15]([C@H:10]([CH2:11][OH:12])[C:9]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:14])=[N+:16]=[N-:17]
Reactant: O=C(NCc1ccccc1)[C@@H](Br)CO
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=N[C@H](CO)C(=O)NCc1ccccc1
Temperature: 52.5 °C
Yield: 99.62 %

Procedure:
To a reaction flask was charged (2S)-N-benzyl-2-bromo-3-hydroxypropanamide (80.0 g) and sodium azide (30.23 g) in N,N-dimethylformamide (480 ml) and raised the temperature to 50-55° C. and maintained for 4-5 hours. Stopped heating and cooled the reaction mixture to 20-25° C. and charged DM water (400 ml), adjusted pH of the reaction mixture to 9-9.5 using 5% NaHCO3 solution. Extracted the reaction mass with ethyl acetate (1×800 ml, 2×280 ml). Separated the organic layer and combined all ethyl acetate layers, washed with saturated ammonium chloride solution (2×240 ml). Concentrated the solvent ethyl acetate under reduced pressure to get oily compound of (2R)-2-azido-N-benzyl-3 -hydroxypropanamide.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:22]=[CH:21][C:14]([C:15]([NH:17][CH2:18][CH2:19][CH3:20])=[O:16])=[CH:13][C:12]=1[O:23][CH3:24].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:22]=[CH:21][C:14]([C:15]([NH:17][CH2:18][CH2:19][CH3:20])=[O:16])=[CH:13][C:12]=2[O:23][CH3:24])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CCCNC(=O)c1ccc(N)c(OC)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCCNC(=O)c1ccc(Nc2nc(Cl)ncc2Cl)c(OC)c1

Procedure:
2,4,5-Trichloropyrimidine (1.0 g, 5.4 mmol), 4-amino-3-methoxy-N-propylbenzamide (778 mg, 3.74 mmol), and N,N-diisopropylethylamine (1.19 g, 9.21 mmol) were combined in isopropanol (40 mL) and reacted in a microwave (120° C.) for 5½ hours. The 4-(2,5-dichloropyrimidin-4-ylamino)-3-methoxy-N-propylbenzamide that formed as a yellow solid (1.33 g, 71%) was isolated by filtration. A small amount of this material (50 mg, 0.10 mmol) was combined with 7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine (35 mg, 0.14 mmol) and 10-camphorsulfonic acid (36 mg, 0.15 mmol) in isopropanol (3 mL) to which had been added 0.05 mL water. The mixture was heated in a microwave (130° C.) for 3 hours and on cooling was concentrated. The organics were extracted into dichloromethane which was washed with saturated sodium bicarbonate solution and subsequently dried (sodium sulfate). Concentration followed by ISCO chromatography (gradient elution: 1 to 10% MeOH:dichloromethane) afforded 4-[5-Chloro-2-(7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-3-methoxy-N-propyl-benzamide as a white solid (58 mg, 70%). Mp: 193-7° C. (dec). LCMS (m/e) 565 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.58 (d, J=8 Hz, 1H), 8.11 (s, 1H), 8.05 (s, 1H), 7.50 (s, 1H), 7.35 (s, 1H), 7.31 (m, 1H), 7.25 (m, 1H), 7.10 (d, J=8 Hz, 1H), 6.96 (s, 1H), 6.11 (m, 1H), 4.03 (s, 3H), 3.72 (m, 4H), 3.48 (m, 2H), 2.86 (m, 2H), 2.70 (m, 2H), 2.57 (s, 4H), 2.10 (m, 2H), 1.68 (m, 3H), 1.47 (m, 2H), 1.03 (t. J=7 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][C@H:8]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O)([CH3:4])([CH3:3])[CH3:2].ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.Cl.[Cl:52][CH2:53][CH2:54][NH:55][CH2:56][CH2:57][Cl:58].C(N(CC)CC)C>C(#N)C>[Cl:52][CH2:53][CH2:54][N:55]([CH2:56][CH2:57][Cl:58])[C:12]([C:11]1[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=1[CH2:9][C@@H:8]([NH:19][C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:27])=[O:14]
Reactant: ClCCNCCCl
Reactant: CC(C)(C)OC(=O)C[C@@H](Cc1ccccc1C(=O)O)NC(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)C[C@@H](Cc1ccccc1C(=O)N(CCCl)CCCl)NC(=O)OC(C)(C)C
Reaction time: 12 h

Procedure:
Adapting a literature known protocol (Levi and Weed, U.S. Pat. No. 3,235,594), to a reaction mixture of 2-[(2R)-4-tert-butoxy-2-(tert-butoxycarbonylamino)-4-oxo-butyl]benzoic acid (23b) (759 mg, 2.0 mmol), N-hydroxysuccinimide (NHS, HOSu) (235 mg, 2.2 mmol) in anhydrous acetonitrile (MeCN) (10 mL) is added solid dicyclohexylcarbodiimide (DCC) (433 mg, 2.1 mmol) in small portions at about room temperature. The reaction mixture is stirred for about 12 hours and the precipitated dicyclohexylurea side product is filtered off using a Büchner funnel. The filtrate is treated with commercial di-(2-chloroethyl)amine hydrochloride (2-chloro-N-(2-chloroethyl)ethanamine hydrochloride; HN(CH2—CH2—Cl)2.HCl) (393 mg, 2.2 mmol) followed by neat triethylamine (Et3N, TEA) (321 μL, 233 mg, 2.3 mmol). The reaction mixture is stirred for about 12 hours at room temperature. The reaction is followed by TLC and/or LC/MS to completion. Acidic aqueous work-up and purification by silica gel column chromatography furnish the title compound tert-butyl(3R)-4-[2-[bis(2-chloroethyl)carbamoyl]phenyl]-3-(tert-butoxycarbonylamino)butanoate (23c).
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:20][C@@H:19]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[C:18]2[C:13](=[CH:14][C:15](Cl)=[CH:16][C:17]=2Cl)[NH:12]1)=[O:10])C1C=CC=CC=1.[OH-].[Na+]>CO.O>[CH2:24]([O:23][C:21]([C@H:19]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][C@@H:11]([C:9]([OH:10])=[O:8])[CH2:20]1)=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(OCc1ccccc1)[C@H]1C[C@@H](C(=O)OCc2ccccc2)c2c(Cl)cc(Cl)cc2N1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)[C@H]1C[C@@H](C(=O)OCc2ccccc2)c2ccccc2N1
Temperature: 25 °C
Reaction time: 14 h
Yield: 17.7 %

Procedure:
Cis-2,4-dibenzyloxycarbonyl-5,7-dichloro-1,2,3,4-tetrahydroquinoline (0.23 g) was dissolved in 50% aqueous methanol (30 ml) and 1N sodium hydroxide (0.54 ml, 1.1 molar equivalents) was added and the reaction mixture was stirred for 14 h at room temperature. The solvents were removed in vacuo to give a residue which was dissolved in water (30 ml) and washed with diethyl ether (2×30 ml). The aqueous layer was acidified to pH 1 with dilute hydrochloric acid and extracted into diethyl ether (2×30 ml) then dried (Na2SO4), filtered and concentrated in vacuo to leave a residue which was purified by chromatography on silica gel with 2.5% methanol, 0.5% acetic acid and 97% dichloromethane as eluent. The solid obtained on evaporation was recrystallised from diethyl ether/hexane to give, as a colourless solid, cis-4-benzyloxycarbonyl-2-carboxy-1,2,3,4-tetrahydroquinoline (0.027 g, m.p. 144° C. dec). δ (360 MHz, CDCl3) 2.35 (1H, m, CHACHBHCCHD), 2.81 (1H, dm, J=13.9 Hz, CHACHBHCCHD), 4.03 (2H, m, CHACHBHCCHD), 5.07 (2H, s, PhCH2), 6.57 (1H, d, J=1.5 Hz, 6-H or 8-H), 6.77 (1H, d, J=1.5 Hz, 6-H or 8-H), 7.32 (5H, m, Ph); m/e 379 (M+), 198 (100%); Found: C, 56.53; H, 4.00; N, 3.65 . C18H15Cl2NO4 requires C, 56.86; H, 3.98; N, 3.68%.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])[N:5]=1)([O-])=O.CO.[H][H]>C(OCC)(=O)C.[Pd]>[CH2:9]([N:6]1[CH:7]=[CH:8][C:4]([NH2:1])=[N:5]1)[CH2:10][CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)CCn1ccc([N+](=O)[O-])n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)CCn1ccc(N)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.2 %

Procedure:
3-Nitro-1-iso-pentyl-1H-pyrazole (115 mg, 0.63 mmol) was dissolved in ethyl acetate (3 mL) and methanol (3 mL) was added. Palladium, 10 wt. % on activated carbon, wet (˜50 mg) was added to the reaction. The vial was charged with hydrogen gas (via balloon) and the reaction stirred for 16 h at 25° C. The reaction was passed through a plug of celite and concentrated in vacuo to afford 1-iso-pentyl-1H-pyrazol-3-ylamine (89 mg, 93%) as golden oil: ESI-LRMS m/e calcd for C8H15N3 [M+] 153.1, found 154.3 [M+H+].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[C:16]([F:22])[C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:23])[CH:6]=1)[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].S([C:45]#[N:46])(C1C=CC(C)=CC=1)(=O)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[C:16]([F:22])[C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:45]#[N:46])[C:13]=2[CH3:23])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)c1
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(Sc2c(C)n(C#N)c3c(F)c(Cl)ccc23)c1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 3-(6-chloro-7-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid ethyl ester (0.50 g, 1.37 mmol) in THF (10 mL) at RT was added sodium bis(trimethylsilyl)amide (0.76 mL of a 2.0M solution in THF, 1.51 mmol). After 30 minutes, tosyl cyanide (0.279 g, 1.54 mmol) was added, and the reaction was stirred for 2 hrs, then subjected to standard aqueous workup. The crude residue was purified on silica gel (0-30% EtOAc in hexanes) to afford the title compound.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[C:5]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)=[N:4]1)[CH3:2].Br[C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH:29]=[C:30]([C:45]1[CH:52]=[CH:51][C:48]([CH:49]=[O:50])=[CH:47][CH:46]=1)[N:31]2[S:36]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)(=[O:38])=[O:37]>>[CH2:1]([N:3]1[CH:7]=[C:6]([C:27]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:28]=2[CH:29]=[C:30]([C:45]2[CH:46]=[CH:47][C:48]([CH:49]=[O:50])=[CH:51][CH:52]=2)[N:31]3[S:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)(=[O:38])=[O:37])[C:5]([C:17]2[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=2)=[N:4]1)[CH3:2]
Reactant: O=Cc1ccc(-c2cc3c(Br)cccc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)c(-c2ccc([N+](=O)[O-])cc2)n1
Product: CCn1cc(-c2cccc3c2cc(-c2ccc(C=O)cc2)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1

Procedure:
Following the procedure described for Intermediate 100 using 1-ethyl-3-(4-nitrophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 4-[4-bromo-1-(phenylsulfonyl)-1H-indol-2-yl]benzaldehyde provided the title compound. ESMS [M+H]+:
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]([CH2:11][CH3:12])[C:9]#[N:10])[CH:3]=1.I[CH2:14][CH3:15].NC1N=CC(C2C=CN=C(C3(C#N)CCOCC3)C=2)=NC=1C1ON=C(C2C=CC(CNC)=CC=2)C=1>C1(C)C=CC=CC=1.O>[CH2:11]([C:8]([C:4]1[CH:3]=[C:2]([I:1])[CH:7]=[CH:6][N:5]=1)([CH2:14][CH3:15])[C:9]#[N:10])[CH3:12]
Reactant: CCI
Reactant: CCC(C#N)c1cc(I)ccn1
Agent: CNCc1ccc(-c2cc(-c3nc(-c4ccnc(C5(C#N)CCOCC5)c4)cnc3N)on2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(C#N)(CC)c1cc(I)ccn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
Crude 2-(4-iodo-2-pyridyl)butanenitrile (270 mg, 0.9923 mmol) was added to a solution of iodoethane (309.6 mg, 158.8 μL, 1.985 mmol) and bis(trimethylsilyl)azanide (sodium ion (1)) (992.3 μL of 1 M, 0.9923 mmol) in toluene (2 mL) at 0° C. The solution was stirred at 0° C. for 10 minutes. Reaction mixture was diluted with water and the product extracted with dichloromethane (×3). Organic extracts were combined, dried over MgSO4, filtered and concentrated in vacuo. (297.8 mg, assumed 100% yield). LC/MS m/z 301.02 [M+H]+
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][N:28]([C:31](=[O:34])[CH2:32][CH3:33])[CH2:27][CH2:26]2)=[C:21]([C:35]([F:38])([F:37])[F:36])[CH:20]=1.[OH-].[Na+]>O1CCOCC1.CCOC(C)=O>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:2]2[NH:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][N:28]([C:31](=[O:34])[CH2:32][CH3:33])[CH2:27][CH2:26]2)=[C:21]([C:35]([F:38])([F:37])[F:36])[CH:20]=1
Reactant: CCC(=O)N1CCN(c2ccc(N)cc2C(F)(F)F)CC1
Reactant: CCOC(=O)c1cnc2ccc(Cl)cc2c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc2ccc(Cl)cc2c1Nc1ccc(N2CCN(C(=O)CC)CC2)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 93.5 %

Procedure:
To a solution of 5.0 ethyl 4,6-dichloroquinoline-3-carboxylate (1.08 g, 4 mmol, 1 equiv.) in 1,4-dioxane (10 mL) at room temperature was added compound 5.1 1-(4-(4-amino-2-(trifluoromethyl)phenyl)piperazin-1-yl)propan-1-one (1.2 g, 4 mmol, 1 equiv.). The resulting solution was heated to 80° C. and stirred 4 h before cooling to room temperature. NaOH ON aqueous solution, 3 mL) was added. The solution was diluted with EtOAc (30 mL) and washed with water (30 mL×2) and brine (30 mL). The organic phase was dried over Na2SO4. After removal of solvents, the residue was purified via flash chromatography (CH2Cl2: MeOH=20:1) to afford the desired product 5.2 ethyl 6-chloro-4-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenylamino)quinoline-3-carboxylate (2 g; 93%). LC-MS: (M+H): 622.20
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([NH:12]C(=O)OC)=[CH:8][CH:7]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2].NC1C=CC=CC=1.C[O-].[Na+]>CO>[C:1]([C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[CH:10][CH:11]=1)([CH2:4][CH3:5])([CH3:2])[CH3:3]
Reactant: CCC(C)(C)c1ccc(NC(=O)OC)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Nc1ccccc1
Product: CCC(C)(C)c1ccc(N)cc1
Temperature: 200 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
A mixture of 110 parts of methyl N-(4-tert.-pentyl-phenyl)-carbamate, 400 parts of aniline, 400 parts of methanol and 0.2 part of sodium methylate is heated to 200° C. in an autoclave and kept at this temperature for 4 hours. The mixture is then subjected to fractional distillation under reduced pressure. 67 parts (83% of theory) of 4-tert.-pentylaniline, of boiling point 140°-142° C./16 mbar, are obtained.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.Cl[C:9]1[C:13]2[CH:14]=[C:15]([CH:27]=[O:28])[C:16]([N:19]3[CH2:24][C@@H:23]([CH3:25])[O:22][C@H:21]([CH3:26])[CH2:20]3)=[C:17]([F:18])[C:12]=2[O:11][N:10]=1>CN(C=O)C.C(Cl)Cl>[CH3:26][C@@H:21]1[CH2:20][N:19]([C:16]2[C:15]([CH:27]=[O:28])=[CH:14][C:13]3[C:9]([N:3]4[CH:7]=[N:6][CH:5]=[N:4]4)=[N:10][O:11][C:12]=3[C:17]=2[F:18])[CH2:24][C@@H:23]([CH3:25])[O:22]1
Reactant: c1nc[nH]n1
Reactant: C[C@@H]1CN(c2c(C=O)cc3c(Cl)noc3c2F)C[C@@H](C)O1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@@H]1CN(c2c(C=O)cc3c(-n4cncn4)noc3c2F)C[C@@H](C)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride (60% dispersion) (0.288 g, 7.19 mmol) was added to a solution of 1H-1,2,4-triazole (0.530 g, 7.67 mmol) and 3-chloro-6-((2R,6R)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-5-carbaldehyde (Intermediate 535, 1.5 g, 4.80 mmol) in DMF (10 ml), and the mixture was stirred at room temperature overnight. The mixture was quenched with aqueous NH4Cl and diluted with water before being extracted with CH2Cl2 5 times. The combined extracts were dried (MgSO4) and concentrated to give a solid that was taken up in CH2Cl2. Insoluble solids were filtered off and rinsed with additional CH2Cl2. The solids were dried in vacuo and were consistent with desired product. The filtrate was concentrated and chromatographed on silica gel (100% CH2Cl2 followed by gradient elution to 50% EtOAc in CH2Cl2) to give additional desired product. Total of 866 mg.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.N1C=CC=CC=1.[C:30](Cl)(=[O:32])[CH3:31]>ClCCl>[F:23][C:2]([F:1])([F:22])[O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:21]=[CH:20][C:18]([NH:19][C:30](=[O:32])[CH3:31])=[CH:17][CH:16]=3)=[N:11]2)=[CH:8][CH:9]=1
Reactant: CC(=O)Cl
Reactant: Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
To a stirred solution containing 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)aniline (WO 2009/102736) (0.272 g, 0.849 mmol) and pyridine (0.137 mL, 1.90 mmol) dissolved in dichloromethane (2.1 mL) at 0° C. was added acetyl chloride (0.079 mL, 1.10 mmol) dropwise. The reaction was warmed to room temperature and stirred for 1 hour. The solution was diluted with dichloromethane (20 mL) and washed successively with hydrogen chloride (1 N, 1×15 mL), saturated aqueous sodium bicarbonate (1×15 mL) and saturated sodium chloride solution (15 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated to afford the title compound (0.291 g, 95%): mp 169-171° C.; 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 8.15 (d, J=8.7 Hz, 2H), 7.80 (d, J=9.1 Hz, 2H), 7.63 (d, J=8.6 Hz, 2H), 7.39 (d, J=9.0 Hz, 2H), 7.28 (s, 1H), 2.22 (s, 3H). ESIMS m/z 362 ([M+H]+).
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:10]([C:11](O)=[O:12])=[CH:9][N:8]=[C:7]([S:14][CH3:15])[N:6]=1)([CH3:3])[CH3:2].C[N:17](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.N.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:1]([NH:4][C:5]1[C:10]([C:11]([NH2:17])=[O:12])=[CH:9][N:8]=[C:7]([S:14][CH3:15])[N:6]=1)([CH3:3])[CH3:2]
Reactant: CSc1ncc(C(=O)O)c(NC(C)C)n1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncc(C(N)=O)c(NC(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
4-(Isopropylamino)-2-(methylthio)pyrimidine-5-carboxylic acid (8.38 g, 36.9 mmol) and HATU (21.03 g, 55.3 mmol) were combined in a 250 mL round-bottomed flask followed by the addition of DMF (92 mL). After that ammonia hydrochloride (9.86 g, 184 mmol) and DIEA (32 mL, 184 mmol) were added and the mixture was stirred at room temperature overnight. The solvent was concentrated under reduced pressure and water (150 mL) was added. The resulting suspension was filtered, washed with water and dried under high vacuum overnight to afford 4-(isopropylamino)-2-(methylthio)pyrimidine-5-carboxamide (8 g, 35.4 mmol, 96% yield); MS (ESI) m/z 227.4 [M+1]+.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[K+].[K+].[Cl:10][C:11]1[C:20]([CH:21]=[CH:22][C:23](=O)[CH3:24])=[C:19]([Cl:26])[CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14]>C(O)C.O>[Cl:10][C:11]1[C:20]([CH:21]=[CH:22][C:23](=[N:2][OH:3])[CH3:24])=[C:19]([Cl:26])[CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1ccc(Cl)c(C=CC(C)=O)c1Cl
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccc(Cl)c(C=CC(C)=NO)c1Cl

Procedure:
1.8 g (25.9 mmol) of hydroxylamine hydrochloride and 1.5 g (11.0 mmol) of potassium carbonate were added to 5.0 g (18.3 mmol) of methyl 2,4-dichloro-3-(2-oxobut-3-en-4-yl)benzoate in 160 ml of ethanol, and the reaction mixture was admixed with water until a clear solution was obtained. The mixture was heated under reflux for 3 hours and then cooled and the reaction mixture was taken up in 400 ml of water and extracted with ethyl acetate. The combined organic phases were dried and the solvent was removed. Methyl 2,4-dichloro-(2-hydroxyiminobut-3-en-4-yl)benzoate was obtained in quantitative yield.
Reaction SMILES: [CH3:1][C@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][C:23]=1[C:31]([F:34])([F:33])[F:32].Cl>CN(C)C1C=CN=CC=1.ClCCl>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:30])=[CH:24][C:23]=1[C:31]([F:32])([F:33])[F:34]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC1(C)C2CC[C@@]1(C)C(=O)CC2=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C2CC[C@@]1(C)C(=O)C(C(=O)Nc1ccc(Cl)c(C(F)(F)F)c1)C2=O
Temperature: 30 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
To an ice-cooled solution of (1R)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.36 g, 2.0 mmole), triethylamine (0.20 g, 2.0 mmole) and 4-(dimethylamino)pyridine (0.24 g, 2.0 mmole) in dry dichloromethane (25 mL) was added a solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (0.44 g, 2.0 mmole) in dry dichloromethane (5 mL). The resulting mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature, and then was heated at 30° C. for 7 hours. The reaction mixture was treated with 2N aqueous HCl and the layers separated. The acidic aqueous layer was extracted with two additional portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give a yellow oil, which was purified by chromatography on silica gel (10% ethyl acetate/hexane) to yield a yellow oil, which was crystallized from 95% ethanol to yield the title compound as a tan solid (0.36 g, 44% yield), mp=117–119° C.; MS (+) ESI m/z=402 (M+H)+, [α]D25=+22.3° (c=1, EtOH).