Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([CH2:25][O:26][CH2:27][CH3:28])[N:14]([CH2:15][CH2:16][N:17]3[C:21]([CH3:23])([CH3:22])[O:20][N:19]=[C:18]3[CH3:24])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:29]>CO>[CH2:27]([O:26][CH2:25][C:13]1[N:14]([CH2:15][CH2:16][N:17]2[C:21]([CH3:23])([CH3:22])[O:20][N:19]=[C:18]2[CH3:24])[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:29])[C:11]=2[N:12]=1)[CH3:28]
Reactant: N
Reactant: CCOCc1nc2c(Cl)nc3ccccc3c2n1CCN1C(C)=NOC1(C)C
Solvent: CO
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCN1C(C)=NOC1(C)C
Temperature: 150 °C
Reaction time: 15 h

Procedure:
A slurry of 4-chloro-2-ethoxymethyl-1-[2-(3,5,5-trimethyl-1,2,4-oxadiazol-4(5H)-yl)ethyl]-1H-imidazo[4,5-c]quinoline (670 mg, 1.67 mmol) in a solution of 7 M ammonia in methanol (20 mL) was sealed in a pressure vessel and heated to 150° C. After 15 hours, the volatiles were removed under reduced pressure and the residue was partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The aqueous layer was extracted with two additional portions of dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, gradient elution from 97:3 to 95:5 dichloromethane/methanol) to afford 2-ethoxymethyl-1-[2-(3,5,5-trimethyl-1,2,4-oxadiazol-4(5H)-yl)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine (350 mg) as a white solid that was recrystallized from acetonitrile to give white needles, mp 204-205° C.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:12]([OH:14])=[O:13])[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li][CH2:16][CH2:17]CC.IC>C1COCC1>[CH2:16]([C:11]1[S:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:17]
Reactant: [Li]CCCC
Reactant: O=C(O)c1cc(-c2ccccc2)cs1
Solvent: CI
Solvent: C1CCOC1
Product: CCc1sc(C(=O)O)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
At −78° C., a solution of 4-phenylthiophene-2-carboxylic acid (800 mg, 3.92 mmol) in THF (10 mL) is treated with tert.-BuLi (8 mL, 1.6 M in pentane). The mixture is stirred at −70° C. for 40 min before iodomethane (1 mL) is added. Stirring is continued for 5 h at −78° C., then the reaction mixture is allowed to warm to rt overnight. The reaction is quenched with sat. aq. NH4Cl and extracted with EA. The organic extract is dried over MgSO4, the solvent is removed and the crude product is purified by CC on silica gel eluting with DCM containing 3% of methanol to give 5-ethyl-4-phenyl-thiophene-2-carboxylic acid (340 mg) as a red solid; LC-MS: tR=0.95 min, [M+1+MeCN]+=274.15; 1H NMR (CDCl3): δ 7.79 (s, 1H), 7.46-7.31 (m, 5), 2.92 (q, J=7.6 Hz, 2H), 1.30 (t, J=7.6 Hz, 3H).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[CH:21]=[N:20][C:19](/[CH:22]=[CH:23]/[C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[CH:18][N:17]=2)=[N:13][C:12]=1[CH3:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.C(O)C.[OH-].[OH-].[Pd+2]>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[CH:21]=[N:20][C:19]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[CH:18][N:17]=2)=[N:13][C:12]=1[CH3:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(-c2cnc(/C=C/c3ccc(F)cc3)cn2)sc1C(=O)NCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1nc(-c2cnc(CCc3ccc(F)cc3)cn2)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.1 %

Procedure:
Part B. To a solution of 2-{5-[(E)-2-(4-fluoro-phenyl)-vinyl]-pyrazin-2-yl}-4-methyl-thiazole-5-carboxylic acid benzylamide (20 mg, 0.05 mmol, 1.0 equiv) in ethyl acetate/ethanol (1:1) was added Pd(OH)2 (10 mg, 20%). The flask was first purged with nitrogen, then with hydrogen. The reaction mixture was stirred at ambient temperature for 3 hr and monitored by LCMS. Upon completion, the reaction mixture was diluted with ethyl acetate, filtered through Celite and concentrated in vacuo. The crude product was purified by preparative HPLC (acetonitrile/water, 0.1% trifluoroacetic acid) to afford 2-{5-[2-(4-fluoro-phenyl)-ethyl]-pyrazin-2-yl}-4-methyl-thiazole-5-carboxylic acid benzylamide (13 mg, 65%). 1H NMR (400 MHz, CD2Cl2) δ 9.27 (s, 1H), 8.27 (s, 1H), 7.27-7.35 (m, 5H), 7.12-7.15 (m, 2H), 6.92-6.96 (m, 2H), 6.19 (bs, 1H), 4.58 (d, J=4.0 Hz, 2H), 3.05-3.16 (m, 4H), 2.72 (s, 3H); HRMS (M+H)+=433.15.
Reaction SMILES: [CH3:1][N:2]([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[C:3](=[O:6])[CH:4]=[CH2:5].[CH3:15][C:16]([C:19]1[CH:24]=[C:23]([SH:25])[CH:22]=[C:21]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]=1[OH:30])([CH3:18])[CH3:17].C(N(CC)CC)C>CO>[CH3:29][C:26]([C:21]1[CH:22]=[C:23]([S:25][CH2:5][CH2:4][C:3]([N:2]([CH3:1])[CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[O:6])[CH:24]=[C:19]([C:16]([CH3:18])([CH3:17])[CH3:15])[C:20]=1[OH:30])([CH3:27])[CH3:28]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: C=CC(=O)N(C)CCc1ccccn1
Solvent: CO
Solvent: CCN(CC)CC
Product: CN(CCc1ccccn1)C(=O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-methyl-N-[2-(2-pyridinyl)ethyl]-2-propenamide (0.95 g, 0.005 mole) was dissolved in methanol (200 ml) containing 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (1.19 g, 0.005 mole). After addition of triethylamine (0.5 ml), the solution was stirred at room temperature overnight. The solvent was removed by a nitrogen stream to give a residue which was purified by chromatography on silica to give the title compound, m.p. ca . 82°-84° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]2[C:25](=[O:26])[NH:24][N:23]=[CH:22][C:11]3=[C:12]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[NH:13][C:14]([CH:15]=1)=[C:10]23>C(Cl)Cl.N1C=CC=CC=1>[O:26]=[C:25]1[C:9]2[C:10]3[C:11](=[C:12]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[NH:13][C:14]=3[CH:15]=[C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:8]=2)[CH:22]=[N:23][NH:24]1
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Temperature: 22 °C
Reaction time: 24 h
Yield: 26.7 %

Procedure:
Methanesulfonyl Chloride (1.5 eq, 0.003 g) was added to a solution of the title compound of Example 7 (0.005 g, 0.018 mmol) in CH2Cl2 (0.045 M, 0.4 mL) and pyridine (0.045 M, 0.4 mL). The mixture was stirred at 22° C. for 24 hours and concentrated under reduced pressure. Silica gel chromatography (triethylamine/methanol/CH2Cl2; 1:5:94) afforded the title compound (1.7 mg) in 30% yield.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[Se:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[B:19](OC)([O:22]C)[O:20]C.Cl>CCOCC>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[Se:6][C:5]=2[C:4]([B:19]([OH:22])[OH:20])=[CH:3][CH:2]=1
Reactant: COB(OC)OC
Reactant: c1ccc2c(c1)[se]c1ccccc12
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: OB(O)c1cccc2c1[se]c1ccccc12
Temperature: -78 °C
Reaction time: 8 h

Procedure:
4.0 g (17.3 mmol) of dibenzoselenophene and 150 mL of dry ether were added in a 250 mL three necked flask under nitrogen. To the mixture, 11.5 mL of BuLi (1.6 M in hexane) was added slowly at room temperature. The reaction mixture was then heated to reflux for 5 hours. The reaction mixture was cooled to −78° C. and 5 mL of trimethyl borate was added. It was then left to stir at room temperature for overnight. About 50 mL of 1 M HCl was added to the reaction mixture. The organic phase was extracted with ethyl acetate and dried with sodium sulfate. The combined organic phase was evaporated to dryness and 100 mL of 30% ethyl acetate in hexane was added to the solid with stirring at room temperature for 8 hours. The suspension was filtered, the solids were washed with hexane and dried, yielding 2 of white solids as the product which was confirmed by NMR
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:8][O:9][C:10]=2[C:11]([F:14])([F:13])[F:12])[N:3]=[CH:2]1.F[C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1>>[C:15]1([C:7]2[C:6]([C:4]3[N:3]=[CH:2][N:1]([C:22]4[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=4)[CH:5]=3)=[C:10]([C:11]([F:14])([F:12])[F:13])[O:9][N:8]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: FC(F)(F)c1onc(-c2ccccc2)c1-c1c[nH]cn1
Product: N#Cc1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)cc1
Yield: 49 %

Procedure:
As described for Example 4, 4-(1H-imidazol-4-yl)-3-phenyl-5-trifluoromethyl-isoxazole (90 mg, 0.32 mmol) was converted, using 4-fluorobenzonitrile instead of 4-fluorobenzotrifluoride, to the title compound (60 mg, 49%) which was obtained as a white solid. MS: m/e=381.2 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]2[O:26][C:13]3([CH2:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:14]3)[NH:12][C:11](=[O:27])[C:10]=2[CH:28]=1.[OH-].[Na+]>O.O1CCOCC1>[CH2:19]([N:15]1[CH2:16][CH2:17][CH2:18][C:13]2([NH:12][C:11](=[O:27])[C:10]3[CH:28]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:29])=[O:2])[CH:7]=[CH:8][C:9]=3[O:26]2)[CH2:14]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)NC1(CCCN(Cc3ccccc3)C1)O2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)/C=C/c1ccc2c(c1)C(=O)NC1(CCCN(Cc3ccccc3)C1)O2
Yield: 104 %

Procedure:
A solution of (±)-(E)-3-{1′-benzyl-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-acrylic acid methyl ester (240 mg, 0.61 mmol) in water (5 ml) and dioxane (10 ml) was treated with 1 M NaOH (0.80 ml) as described in Example 30, Step A, to give (±)-(E)-3-{1′-benzyl-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-acrylic acid (hydrochloride salt, 240 mg) as a brown oil.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]#[C:18][CH2:19]O)[N:12]=[CH:11][N:10]=1.[F:21]C1(F)N(C)CCN1C.O>C(#N)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]#[C:18][CH2:19][F:21])[N:12]=[CH:11][N:10]=1
Reactant: CN1CCN(C)C1(F)F
Reactant: OCC#CCOc1cc(-c2cccc(F)c2F)ncn1
Solvent: O
Solvent: CC#N
Product: FCC#CCOc1cc(-c2cccc(F)c2F)ncn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 16.7 %

Procedure:
In 6 ml of acetonitrile was dissolved 255 mg of 4-(2,3-difluorophenyl)-6-(4-hydroxy-2-butynyloxy)pyrimidine, to which 148 mg of 2,2-difluoro-1,3-dimethylimidazolidine was added, followed by stirring at room temperature for 24 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 43 mg of 4-(2,3-difluorophenyl)-6-(4-fluoro-2-butynyloxy)pyrimidine (the present compound (135)).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:23]3[CH:24]=[CH:25][C:26]4[C:30]([CH:31]=3)=[N:29][N:28]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:27]=4)[CH:9]=[C:10]([CH:11]3[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:32]([N:28]1[CH:27]=[C:26]2[C:30]([CH:31]=[C:23]([C:8]3[CH:9]=[C:10]([CH:11]4[CH2:15][CH2:14][NH:13][CH2:12]4)[N:6]4[C:7]=3[C:2]([NH2:1])=[N:3][CH:4]=[N:5]4)[CH:24]=[CH:25]2)=[N:29]1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncnn2c(C3CCNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reaction time: 1.5 h
Yield: 94.8 %

Procedure:
To a dry flask was added tert-butyl 3-[4-amino-5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]pyrrolidine-1-carboxylate (420 mg, 0.824 mmol) followed by a solution of 1:1 trifluoroacetic acid in dichloromethane (3 mL). The mixture was stirred under N2 atmosphere for 1.5 h. The reaction was then partitioned between dichloromethane (150 mL) and 10% aqueous potassium carbonate. The aqueous layer was back extracted with dichloromethane (2×25 mL). The combined organic layer was washed with brine (50 mL) then dried with sodium sulfate. The solvent was evaporated under reduced pressure to yield 320 mg (95%) of the desired product as a tan solid. 1H NMR (300 MHz, DMSO-d6) δ 8.53 (s, 1 H), 7.89 (s, 1 H), 7.78 (d, 1 H), 7.58 (s, 1 H), 7.50-7.30 (m, 4H), 7.14 (d, 1 H), 6.58 (s, 1 H), 5.64 (s, 2 H), 3.98 (m, 1 H), 3.35-3.25 (m, 3 H), 2.10 (m, 1 H), 1.92 (m, 1 H); ES-MS m/z 410.4 [M+H]+, HPLC RT (min) 2.00.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[N:21]=[N:20][C:19]([C:22](O)=[O:23])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:56][CH:57]1[CH2:62][CH2:61][O:60][CH2:59][CH2:58]1>CN(C=O)C>[O:60]1[CH2:61][CH2:62][CH:57]([NH:56][C:22]([C:19]2[N:20]=[N:21][C:16]([O:15][CH2:14][C:9]3[N:10]([CH3:13])[N:11]=[N:12][C:8]=3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:17][CH:18]=2)=[O:23])[CH2:58][CH2:59]1
Reactant: Cn1nnc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)nn1
Reactant: NC1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nnc(-c2ccc(F)cc2)c1COc1ccc(C(=O)NC2CCOCC2)nn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.2 %

Procedure:
To a solution of 6-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-pyridazine-3-carboxylic acid (67 mg, 0.20 mmol) and TBTU (72 mg, 0.22 mmol) in DMF (2 mL) was added DIPEA (175 μL, 1.0 mmol). Then 4-aminotetrahydropyran (23 mg, 0.22 mmol) was added and the mixture was stirred at room temperature under Ar for 16 h. The mixture was then evaporated and purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) afforded the title compound (62 mg, 73%) as an off white solid. MS: m/e=413.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([C:26](O)=[O:27])=[CH:21][CH:20]=[CH:19]2.[NH2:29][CH2:30][C:31]1[CH:46]=[CH:45][C:34]([C:35]([NH:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[NH2:44])=[O:36])=[CH:33][CH:32]=1>>[NH2:44][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=1[NH:37][C:35]([C:34]1[CH:33]=[CH:32][C:31]([CH2:30][NH:29][C:26]([C:22]2[C:23]3[C:18](=[CH:17][C:16]([O:15][C:6]4[C:5]5[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=5)[N:9]=[CH:8][CH:7]=4)=[CH:25][CH:24]=3)[CH:19]=[CH:20][CH:21]=2)=[O:27])=[CH:46][CH:45]=1)=[O:36]
Reactant: NCc1ccc(C(=O)Nc2ccccc2N)cc1
Reactant: COc1cc2nccc(Oc3ccc4c(C(=O)O)cccc4c3)c2cc1OC
Product: COc1cc2nccc(Oc3ccc4c(C(=O)NCc5ccc(C(=O)Nc6ccccc6N)cc5)cccc4c3)c2cc1OC
Yield: 81.9 %

Procedure:
The title compound (49.0 mg, 82% yield) was prepared as a brown solid from 6-(6,7-dimethoxyquinolin-4-yloxy)-1-naphthoic acid (37.5 mg, 0.1 mmol) and 4-(aminomethyl)-N-(2-aminophenyl)benzamide (28.9 mg, 0.12 mmol) by an analogous procedure to that described in example 16. 1H NMR (DMSO-d6) δ 3.93 (s, 3H, —OCH3), 3.95 (s, 3H, —OCH3), 4.63 (d, J=5.6 Hz, 2H, —CH2), 4.90 (s, 2H, benzene-NH2), 6.56-6.59 (m, 2H, Ar—H), 6.78 (d, J=7.6 Hz, 1H, Ar—H), 6.96 (t, J=8.1 Hz, 1H, Ar—H), 7.17 (d, J=7.6 Hz, 1H, Ar—H), 7.42 (s, 1H, Ar—H), 7.53-7.55 (m, 4H, Ar—H), 7.62 (t, J=8.0 Hz, 1H, Ar—H), 7.71 (d, J=6.8 Hz, 1H, Ar—H), 7.87 (s, 1H, Ar—H), 7.98-8.06 (m, 3H, Ar—H), 8.39 (d, J=9.2 Hz, 1H, Ar—H), 8.49 (d, J=5.2 Hz, 1H, Ar—H), 9.26 (t, J=6.0 Hz, 1H, —CONH), 9.66 (s, 1H, benzene-NH). LC-MS (m/z) 599 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[CH:4]([C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[N:12]=[C:11]([C:25]2[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=2)[CH:10]=1)[CH2:5][C:6]([CH3:8])=[CH2:7]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:39])[CH:4]([C:9]1[CH:14]=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=2)[N:12]=[C:11]([C:25]2[CH:26]=[C:27]([C:35]([F:38])([F:36])[F:37])[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=2)[CH:10]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: C=C(C)CC(C(=O)OC)c1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 101.4 %

Procedure:
A solution of 2-[2-(3,5-Bis-trifluoromethyl-phenyl)-6-(4-trifluoromethyl-phenyl)-pyridin-4-yl]-4-methyl-pent-4-enoic acid methyl ester (80 mg, 0.14 mmol), Pd/C (10%, 10 mg) in methanol (10 mL) was hydrogenated for 4 h. The mixture was filtered through Celite, washed with methanol, evaporated. The residue was dissolved in CH2Cl2, filtered and evaporated to give the product as a colorless oil (80 mg, 100%). 1H NMR (300 MHz, CDCl3) δ 8.56 (s, 2H), 8.24 (d, J=7.91 Hz, 2H), 7.96 (s, 1H), 7.70-7.85 (m, 4H), 3.80-3.92 (m, 1H), 3.73 (s, 3H), 2.14 (ddd, J=6.97, 8.48, 13.56 Hz, 1H), 1.76 (dt, J=7.06, 13.75 Hz, 1H), 1.50-1.65 (m, 1H), 0.98 (d, J=6.78 Hz, 6H). MS m/e 564.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:19]([O:20][CH3:21])=[N:18][C:5]2[CH2:6][CH2:7][N:8](C(=O)C(F)(F)F)[CH2:9][CH:10]([CH3:11])[C:4]=2[C:3]=1[Cl:22].C([O-])([O-])=O.[K+].[K+].CO>O>[Cl:1][C:2]1[C:19]([O:20][CH3:21])=[N:18][C:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH:10]([CH3:11])[C:4]=2[C:3]=1[Cl:22]
Reactant: COc1nc2c(c(Cl)c1Cl)C(C)CN(C(=O)C(F)(F)F)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1nc2c(c(Cl)c1Cl)C(C)CNCC2
Temperature: 57.5 °C
Yield: 90.1 %

Procedure:
To a solution of CuCl2 (87 mg, 0.65 mmol) and nBuNO2 (950 μl, 0.81 mmol) in MeCN (18 ml) was added a solution of 4-chloro-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine (182 mg, 0.54 mmol) in MeCN (9 ml) at room temperature. After heating the mixture at 50° C. for 4 h, it was quenched with sat. aq. NaHCO3 and extracted with EtOAc The organic layer was dried over Na2SO4, concentrated in vacuo and purified by column chromatography to provide 62 mg (32%) of 3,4-dichloro-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. 1H-NMR (CDCl3) δ 4.30 (0.5H), 4.00 (0.5H), 3.92 (3H), 3.83 (1H), 3.74 (1H), 3.38 (1H), 3.25 (2H), 3.10 (1H), 1.16 (3H) ppm. A mixture of 3,4-dichloro-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (61 mg, 0.17 mmol), K2CO3 (70 mg, 0.51 mmol), MeOH (2.4 ml) and H2O (0.5 ml) was heated at 55-60° C. for 30 minutes. After removal of solvent under reduced pressure, the mixture was taken into aq. NaHCO3 and extracted with DCM. The organic layer was dried and concentrated in vacuo to give 40 mg (90%) of 3,4-dichloro-2-methoxy-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. 1H-NMR (CDCl3) δ 3.91 (s, 3H), 3.55 (m, 1H), 3.20 (m, 2H), 3.10 (dd, 1H), 2.93 (m, 2H), 2.71 (dd, 1H), 1.25 (d, 3H) ppm.
Reaction SMILES: [CH3:1][Mg]Br.[Br:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[CH:8]=[O:9]>C1COCC1>[Br:4][C:5]1[CH:6]=[C:7]([CH:8]([OH:9])[CH3:1])[CH:10]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:12]=1
Reactant: O=Cc1cc(Br)cc(C(F)(F)F)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)c1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a stirred solution at −10° C. of methyl magnesium bromide (38.00 mL, 3.0 M in ethyl ether, 114.0 mmol) in THF (200.0 mL) was added dropwise a solution of 3-bromo-5-(trifluoromethyl)benzaldehyde (Reference Example 39, 22.01 g, 86.98 mmol) in THF (100 mL) and after the addition was complete, the reaction mixture was held at −10° C. for 2 h. After this time, the reaction was quenched with saturated ammonium hydrochloride (300.0 mL) and warmed to room temperature. The reaction mixture was diluted with ethyl acetate, washed with water, and saturated sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure to provide 1-(3-bromo-5-(trifluoromethyl)phenyl)ethanol (21.30 g, 91%) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Br.[Br:6][CH:7]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9][C:8]1=O>C(O)C>[BrH:6].[S:3]1[C:7]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9][C:8]=2[N:1]=[C:2]1[NH2:4]
Reactant: NC(N)=S
Reactant: O=C1CCNCCC1Br
Agent: Br
Solvent: CCO
Product: Nc1nc2c(s1)CCNCC2
Temperature: 80 °C
Reaction time: 3 h
Yield: 103.7 %

Procedure:
1.44 g thiourea was added to 4 g 5-bromo-azepan-4-one hydrobromide in 50 mL ethanol and stirred 3 h at 80° C. and over the weekend at RT. The precipitate was filtered and dried to yield 3.8 g of the product.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[F:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=2)[NH2:7])=[CH:15][CH:14]=1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(Oc2ccc(F)cc2)ccc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 24 h
Yield: 102.7 %

Procedure:
A mixture of 5-chloro-2-nitroaniline (345 mg, 2.00 mmol), 4-fluorophenol (224 mg, 2 mmol), potassium carbonate (549 mg, 4 mmol) and DMF (8 mL) was stirred at 120° C. for 1 day. The mixture was cooled and then water (10 mL) was added. The mixture was extracted with ethyl acetate (4×2 mL). The combined extract was dried over magnesium sulfate and concentrated. Product was purified from the residue by silica gel column chromatography (eluted with a 6:1 mixture of hexane/EtOAc) to give 5-(4-fluorophenoxy)-2-nitroaniline (510 mg, quant) as a yellow powder.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].CS(O)(=O)=O.[H][H]>[Pt]>[F:1][C:2]([F:11])([F:12])[CH:3]([OH:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: [H][H]
Agent: [Pt]
Agent: CS(=O)(=O)O
Product: CCOC(=O)CC(O)C(F)(F)F
Temperature: 40 °C
Reaction time: 6 h
Yield: 50.1 %

Procedure:
Ethyl 4,4,4-trifluoroacetoacetate (50 g), under a blanket of nitrogen gas, is heated to 40° C. and treated with platinum (0.1 g of 5% Pt/C, 0.01% load) and methanesulfonic acid (1.5 g, 2.9% load). Hydrogen is charged to a pressure of 5 bars, and the mixture agitated at 40° C. for 6h. After filtration to remove the catalyst, 25.3 g (50% yield) of ethyl 4,4,4-trifluoro-3-hydroxybutyrate is obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]([F:16])([F:15])[F:14])=[C:11]([CH3:17])[C:10]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:9]1[C:25]([N:27]1[CH2:32][CH2:31][S:30][CH2:29][CH2:28]1)=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:33]OS([O-])=O.[K+]>CO.O>[CH2:1]([N:8]1[C:12]([C:13]([F:15])([F:16])[F:14])=[C:11]([CH3:17])[C:10]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[C:9]1[C:25]([N:27]1[CH2:28][CH2:29][S:30](=[O:33])[CH2:31][CH2:32]1)=[O:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S([O-])OO
Reactant: Cc1c(-c2ccc(Cl)cc2)c(C(=O)N2CCSCC2)n(Cc2ccccc2)c1C(F)(F)F
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1c(-c2ccc(Cl)cc2)c(C(=O)N2CCS(=O)CC2)n(Cc2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of (1-benzyl-3-(4-chlorophenyl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl)(thiomorpholino)methanone [for synthesis see SC-26] (131 mg, 0.28 mmol) in MeOH (4 mL) and H2O (1 mL) was added oxone (85 mg, 0.138 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with H2O and extracted with DCM (60 mL). The organic layer was washed with brine, dried (Na2SO4) and purified by flash column chromatography (silica, heptane/EtOAc, 1:1→0:1) to give SC-19 (48 mg, 35%) as a white foam.