Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH2:25])[CH:20]=4)[CH2:15][CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30].C(N(CC)CC)C.O>ClCCl>[Cl:26][C:27]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:28]=1[C:29]([NH:25][CH2:24][CH2:23][O:22][C:19]1[CH:20]=[C:21]2[C:16]([CH2:15][CH2:14][N:13]=[C:12]2[C:8]2([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:17][CH:18]=1)=[O:30]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 14 h
Yield: 106.7 %

Procedure:
2-(1-(1-(4-chlorophenyl)cyclobutyl)-3,4-dihydroisoquinolin-7-yloxy)ethanamine (80.0 mg, 0.15 mmol), 2,4-dichloro-benzoyl chloride (44.3 mg, 0.21 mmol), and triethyl amine (48.6 mg, 0.48 mmol) were dissolved in dichloromethane (2 ml) and stirred for 14 h at RT. Water was added and the mixture was extracted with ethyl acetate. The organic layers were washed with water and saturated NaCl solution, dried with MgSO4, and the solvent was removed. The residue was purified by flash chromatography on silica gel using methylenchloride/MeOH 98:2→95:5 to give 2,4-dichloro-N-(2-{1-[1-(4-chloro-phenyl)-cyclobutyl]-3,4-dihydro-isoquinolin-7-yloxy}-ethyl)-benzamide as a colourless oil (85.0 mg, 0.16 mmol, 84%).
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CN1CCOCC1.[CH3:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29]Br.C(O)C(N)(CO)CO>CN(C)C=O>[CH3:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:2][CH2:3]1
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Reactant: Cc1ccccc1CBr
Agent: NC(CO)(CO)CO
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1ccccc1CN1CCN(c2cccc3nc(N)nc(N)c23)CC1
Reaction time: 2 h
Yield: 68.7 %

Procedure:
5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) was shaken for 96 hours at 47° C. in the presence of 3-(Morphonlino)propyl polystyrene sulfonamide (PS-NMM) (160 mg; 0.4 mmol) and o-methylbenzyl bromide (68.5 mg; 0.37 mmol) in 4 mL N,N-dimethylformamide. Tris-(2-aminoethyl)aminomethyl polystyrene (PS-Trisamine) (112 mg; 0.4 mmol) was then added to the mixture and continued to shake for an additional 2 hours. Resins were filtered off and rinsed with methanol. Filtrate was concentrated at reduced pressure, and residue was triturated 1N NaOH with ethanol. Solids were collected by filtration to yield 47.9 mg of title compound. (69% yield).
Reaction SMILES: N1(C[C:8]([CH:12]2[CH2:17]O[CH2:15][CH2:14][N:13]2C)=CC#N)CCOCC1.[C:19](Cl)(=O)[CH2:20][CH3:21]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH3:15][CH2:14][N:13]([CH:12]([CH3:17])[CH3:8])[CH:20]([CH3:21])[CH3:19]
Reactant: CCC(=O)Cl
Reactant: CN1CCOCC1C(=CC#N)CN1CCOCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCN(C(C)C)C(C)C
Yield: 78 %

Procedure:
Prepared according to General Procedure A using 4-(-N-morpholinyl)-3(-N methyl-morpholinyl)-but-2-enenitrile (45.0 mg, 0.179 mmol), TiCl4.(THF)2 (120 mg, 0.359 mmol), i-Pr2NEt (125 μL, 0.716 mmol), and propionyl chloride (0.54 mL 1M solution HC2Cl2, 054 mmol) in 1.8 mL of CH2Cl2 at −20° C. to provide the pure product in 78% yield 5.7 mg, 0.139 mmol) as a white solid; mp 92-94 ° C.; 95:5 syn-anti:syn-syn by 1H NMR. Syn-anti isomer: IR (film)2974, 2920, 2858, 1637, 1444, 1359; 1112, 1074, 911, 850, 734 cm−1; 1H NMR (400 MHZ, CDCl3) δ 5.11 (s, 1H, CH2═C), 4.95 (s, 1H, CH2═C) 3.75 (d, J=9.2 Hz, 1H, CHCN) 3.47-3.67 (m, 16H, O(CH2CH2,)2N) 3.10 (dq, J=7.5, 15.3 Hz, 1H, (CHCHCN) 2.92 (m, 1H, (OC)CHCH2), 2.54 (dd, J=8.6, 15.0 Hz, 1H, CH2C═CH2) 2.14 (dd, J=5.6, 15.2 Hz, 1H, CH2C═CH2) 1.30 (d, J=6.8 Hz, 3H, CH3), 1.10 (d, J=6.8 Hz, 3H, CH3), 13C NMR (100 MHZ) δ; 173.7, 171.0, 140.8, 116.1, 112.2, 66.8, 66.7, 66.6, 46.0, 45.9, 42.2, 42.0, 40.5, 37.8, 37.2, 33.6, 17.9, 16.4; LRMS (CI) m/z 363 (M)+; HRMS (CI) exact mass calcd for (C19H29N3O4)+ requires m/z 363.2158, found m/z 363.2162.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S@@:25]([CH:33]2[CH2:35][CH2:34]2)(=[N:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:26])=[CH:21][CH:20]=1>>[CH2:31]([O:30][C:28]([N:27]=[S@@:25]([C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:2]2[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:4][N:3]=2)=[CH:24][CH:23]=1)([CH:33]1[CH2:34][CH2:35]1)=[O:26])=[O:29])[CH3:32]
Reactant: C[C@H](CO)Nc1nc(Cl)ncc1-c1cccs1
Reactant: CCOC(=O)N=[S@@](=O)(c1ccc(N)cc1)C1CC1
Product: CCOC(=O)N=[S@@](=O)(c1ccc(Nc2ncc(-c3cccs3)c(N[C@H](C)CO)n2)cc1)C1CC1
Yield: 50 %

Procedure:
In the reaction of (R)-2-(2-chloro-5-(2-thienyl)pyrimidine-4-ylamino)propan-1-ol (267 mg, 1.0 mmol) with (S)—S-(4-aminophenyl)-N-(ethoxycarbonyl)-S-cyclo-propyl-sulfoximide (241 mg, 0.9 mmol) according to procedure 5c, the desired product is obtained in 50% yield (250 mg) after chromatographic purification (silica gel, dichloromethane/ethanol (0%-20% ethanol)).
Reaction SMILES: C[O:2][P@:3]([CH2:23][N:24]([C:39](=[O:49])[CH2:40][CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C@H:25]([C:30]([N-:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:31])[CH2:26][CH:27]([CH3:29])[CH3:28])([C@@H:5]([NH:7][C:8](=[O:22])[C@H:9]([CH3:21])[NH:10][C:11](=[O:20])[C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17](=[O:19])[CH3:18])[CH3:6])=[O:4].[OH-].[Na+]>CO>[C:33]1([NH:32][C:30](=[O:31])[C@H:25]([CH2:26][CH:27]([CH3:29])[CH3:28])[N:24]([CH2:23][P:3]([OH:4])([C@@H:5]([NH:7][C:8](=[O:22])[C@H:9]([CH3:21])[NH:10][C:11](=[O:20])[C@@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17](=[O:19])[CH3:18])[CH3:6])=[O:2])[C:39](=[O:49])[CH2:40][CH2:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CO[P@](=O)(CN(C(=O)CCCc1ccccc1)[C@@H](CC(C)C)C(=O)[N-]c1ccccc1)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)N[C@@H](C)P(=O)(O)CN(C(=O)CCCc1ccccc1)[C@@H](CC(C)C)C(=O)Nc1ccccc1

Procedure:
A solution of [[(R,S)-Methoxy[1(R)-[N-(N-acetyl-L-prolyl-L-alanyl)-amino]-ethyl]-phosphinyl]methyl]-4-phenylbutanoyl-L-leucyl N-phenylamide (58 mg, 0.096 mmol) in methanol (0.5 mL) was treated with 2N aqueous sodium hydroxide (0.25 mL) for 4 hours at room temperature. The mixture was evaporated, dissolved in water, acidified to pH~1 with 2N hydrochloric acid, and extracted 4 times with ethyl acetate. The combined organic extracts were washed with saturated brine solution, dried (magnesium sulfate), and evaporated.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]([CH:16]=1)[CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].[CH:19]([O-])=[O:20].[Na+]>CN(C)C=O.[C]=O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:19]([C:2]1[CH:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]([CH:16]=1)[CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:20]
Reactant: COc1ccc(Br)cc1CNC(=O)OC(C)(C)C
Reactant: O=C[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [C]=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(C=O)cc1CNC(=O)OC(C)(C)C
Yield: 75.1 %

Procedure:
1.015 g of t-butyl N-(5-bromo-2-methoxybenzyl)carbamate, 45 mg of dichlorobis(triphenylphosphine)palladium (II), 330 mg of sodium formate and 17 mg of triphenylphosphine were dissolved in anhydrous N,N-dimethylformamide, followed by stirring for 2 hours at 110° C. in carbon monoxide atmosphere. The reaction mixture was diluted with ethyl acetate, and washed with water and saturated sodium bicarbonate water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography, and 640 mg of t-butyl N-(5-formyl-2-methoxybenzyl)carbamate was obtained from fractions eluted with hexane-ethyl acetate (3:1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][Si](C(C)C)(C(C)C)C(C)C)[CH:11]=1)[N:8]=[C:7]([CH:23]=[CH:24]OC)[CH:6]=[CH:5]2.BrN1C(=O)CCC1=O.[CH3:35][O:36][CH2:37][CH2:38][O:39][C:40]1[CH:45]=[CH:44][N:43]=[C:42]([NH2:46])[CH:41]=1.C(Cl)(Cl)Cl>C1COCC1.O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([OH:12])[CH:11]=1)[N:8]=[C:7]([C:23]1[N:43]3[CH:44]=[CH:45][C:40]([O:39][CH2:38][CH2:37][O:36][CH3:35])=[CH:41][C:42]3=[N:46][CH:24]=1)[CH:6]=[CH:5]2
Reactant: COC=Cc1ccc2cc(F)cc(O[Si](C(C)C)(C(C)C)C(C)C)c2n1
Reactant: COCCOc1ccnc(N)c1
Agent: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COCCOc1ccn2c(-c3ccc4cc(F)cc(O)c4n3)cnc2c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
6-Fluoro-2-(2-methoxyvinyl)-8-(triisopropylsilyloxy)quinoline (2.5 g, 6.6 mmol) was dissolved in THF (10.3 mL) and water (2.6 mL) and cooled to 0° C. The solution was treated dropwise with a solution of freshly recrystallized N-bromosuccinimide (1.24 g, 6.99 mmol) dissolved in THF (7 mL) and water (1.75 mL). The reaction was stirred at 0° C. for 20 minutes then warmed and stirred at ambient temperature for 2.5 hours. The reaction was treated with 4-(2-methoxyethoxy)pyridin-2-amine (1.12 g, 6.65 mmol) and the mixture was heated to reflux overnight. The mixture was cooled and solids formed in the flask. Chloroform (50 mL), ethyl acetate (300 mL), and water (50 mL) were added to disperse the solids and the undissolved solids were collected by filtration and washed with ethyl acetate and water, then air-dried, (1.2 g). MS APCI (+) m/z 354.1 (M+1) detected.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][CH:9]1[CH2:17][C:18]#[N:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:23]1[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][N:24]=1.Cl>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][C:9]1=[C:17]([C:23]1[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][N:24]=1)[C:18]#[N:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1c2ccccc2NC1CC#N
Reactant: FC(F)(F)c1ccnc(Cl)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C(=C(C#N)c2nccc(C(F)(F)F)n2)Nc2ccccc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 88.1 %

Procedure:
A solution of 2-[1-(tert-butoxycarbonyl)benzimidazol-2(3H)-yl]acetonitrile (6 g, 23 mmol) in THF (50 mL) was added to a suspension of 60% sodium hydride in mineral oil (1.38 g, 35 mmol) in tetrahydrofuran (85 mL) at 0° C. over 10 min. The suspension was stirred at 0° C. for 15 min, and 2-chloro-4-trifluoromethylpyrimidin (2.79 mL, 23 mmol) was added. The mixture was allowed to warm to room temperature and stirred overnight, and water (300 mL) and then 1N hydrochloric acid (40 mL) were added. The crude product was extracted into chloroform and washed twice with water (100 mL each). The organic phase was dried over magnesium sulfate, and the solvent was removed under vacuum to give 2-[1-(tert-butoxycarbonyl)benzimidazol-2(3H)-ylidene]-2-(4-trifluoromethylpyrimidin-2-yl)acetonitrile (8.17 g) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N:19]=C=O)[CH:17]=[CH:18][C:13]=2[N:12]([CH:22]([CH3:24])[CH3:23])[C:11](=[O:25])[C:10]([CH3:27])([CH3:26])[N:9]=1.ClC1C=CC=CC=1C1C2C=C(NC(NCCO)=O)C=CC=2N(C(C)C)C(=O)C(C)(C)N=1>ClCCCl.C(Cl)Cl>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]2[N:12]([CH:22]([CH3:24])[CH3:23])[C:11](=[O:25])[C:10]([CH3:26])([CH3:27])[N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:14]=2[CH:15]=1
Reactant: CC(C)N1C(=O)C(C)(C)N=C(c2ccccc2Cl)c2cc(N=C=O)ccc21
Agent: CC(C)N1C(=O)C(C)(C)N=C(c2ccccc2Cl)c2cc(NC(=O)NCCO)ccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)N1C(=O)C(C)(C)N=C(c2ccccc2Cl)c2cc(N)ccc21

Procedure:
From 4 g (0.011 mol) of 7-amino-5-(o-chlorophenyl)-1,3-dihydro-1-isopropyl-3,3-dimethyl-2H-1,4-benzodiazepin-2-one there is obtained, in analogy to the details in Example 4, via [5-(o-chlorophenyl)-2,3-dihydro-1-isopropyl-3,3-dimethyl-2-oxo-1H-1,4-benzodiazepin-7yl]isocyanate, 1-[5-(o-chlorophenyl)2,3-dihydro-1-isopropyl-3,3-dimethyl-2-oxo-1H-1,4-benzodiazepin-7-yl]-3-(2-hydroxyethyl)urea of melting point 243°-244° (1,2-dichloroethane/methylene chloride).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.N([O-])=O.[Na+].[CH2:13]([CH:15](C(=O)C)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:14].[Cl-].C1(C)C=CC([N+]#N)=CC=1>O.Cl.CCO.[OH-].[Na+]>[CH3:14][C:13]1[C:7]2[C:2](=[CH:3][CH:4]=[C:5]([CH3:8])[CH:6]=2)[NH:1][C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(CC)C(C)=O
Reactant: Cc1ccc(N)cc1
Agent: Cc1ccc([N+]#N)cc1
Agent: Cl
Agent: O=N[O-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1[nH]c2ccc(C)cc2c1C
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
23.57 g of p-toluidine are placed in a mixture of 120 ml of water and 50 ml of concentrated HCl, followed by dropwise addition, at 0° C., of 15.4 g of NaNO2 in 40 ml of water and the mixture is left stirring for 20 minutes at 0° C. A solution of 32 g of ethyl 2-ethyl-3-oxobutyrate in 150 ml of EtOH and 150 ml of 20% NaOH solution are added, at −10° C., to the p-toluenediazonium chloride solution thus formed. After stirring for 30 minutes at −5° C., the mixture is acidified to pH=4 by addition of dilute HCl and one litre of water. On trituration, a red solid forms, which is filtered off and then dried in an oven at 40° C. This solid is taken up in 200 ml of absolute EtOH and 20 ml of concentrated H2SO4 and the mixture is then refluxed for 45 minutes. The reaction medium is poured into an ice/water mixture and filtered, the precipitate is then taken up in EtOAc and this solution is washed with water and dried over MgSO4. The residue is chromatographed on silica, eluting with a DCM/heptane mixture: m.p.=118° C.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[C:21]([C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)[CH:20]=[CH:19][C:3]=1[CH2:4][NH:5][C:6](=[O:18])[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([CH3:15])=[C:9]([O:16][CH3:17])[CH:8]=1.[C:29]([O:33][CH3:34])(=[O:32])[CH:30]=[CH2:31].C(O)(=O)C>>[CH3:34][O:33][C:29](=[O:32])[CH2:30][CH2:31][NH:1][C:2]1[CH:22]=[C:21]([C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)[CH:20]=[CH:19][C:3]=1[CH2:4][NH:5][C:6](=[O:18])[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([CH3:15])=[C:9]([O:16][CH3:17])[CH:8]=1
Reactant: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2N)cc(OC)c1C
Reactant: C=CC(=O)OC
Solvent: CC(=O)O
Product: COC(=O)CCNc1cc(-c2noc(C)n2)ccc1CNC(=O)c1cc(OC)c(C)c(OC)c1
Temperature: 80 °C
Yield: 29.5 %

Procedure:
A suspension of compound 1g (130 mg, 0.34 mmol) in methyl acrylate (1.0 mL, 11.1 mmol), and acetic acid (0.5 mL, 8.7 mmol) was sealed in a pressure tube under argon and heated at 80° C. overnight. The reaction mixture was concentrated on a rotary evaporator and the residue was purified by preparative tlc (silica gel, 40% v/v ethyl acetate/hexane) to give compound 15a (47 mg, 30%). ESI-MS m/e 469.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]([N:22]2[CH2:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:20][NH2:21])=[CH:15][N:14]=1>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:17]=[N:18][C:13]([CH3:12])=[N:14][CH:15]=1)[N:22]1[CH2:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:6]
Reactant: O=C(O)c1cccc(F)c1Cl
Reactant: Cc1ncc(C(CN)N2CCCOCC2)cn1
Product: Cc1ncc(C(CNC(=O)c2cccc(F)c2Cl)N2CCCOCC2)cn1

Procedure:
From 2-chloro-3-fluorobenzoic acid and 2-(2-methylpyrimidin-5-yl)-2-(1,4-oxazepan-4-yl)ethanamine.
Reaction SMILES: Cl[C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[O:7])=[C:4]([CH3:24])[N:3]=1.[CH3:25][N:26]([CH3:31])[CH2:27][CH2:28][NH:29][CH3:30]>C(O)CCC>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([N:29]([CH2:28][CH2:27][N:26]([CH3:31])[CH3:25])[CH3:30])=[N:3][C:4]=2[CH3:24])=[CH:10][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: Cc1nc(Cl)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: CNCCN(C)C
Solvent: CCCCO
Product: Cc1nc(N(C)CCN(C)C)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1

Procedure:
Procedure F was performed using 60 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and 66 μL of N,N,N′-trimethylethylenediamine in 0.5 mL of BuOH. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-((2-(dimethylamino)ethyl)(methyl)amino)-2-methylnicotinamide. MS (Q1) 424.0 (M)+.
Reaction SMILES: [F:1][CH:2]([F:8])[C:3](OCC)=[O:4].C[O-].[Na+].[F:12][C:13]1[CH:14]=[C:15]([C:21](=[O:23])[CH3:22])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20].Cl>C(OC)(C)(C)C>[F:1][CH:2]([F:8])[C:3](=[O:4])[CH2:22][C:21]([C:15]1[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:13]([F:12])[CH:14]=1)=[O:23]
Reactant: CCOC(=O)C(F)F
Reactant: COc1ccc(C(C)=O)cc1F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COC(C)(C)C
Product: COc1ccc(C(=O)CC(=O)C(F)F)cc1F
Reaction time: 16 h

Procedure:
Ethyl difluoroacetate (4.06 g, 32.7 mmol) was placed in a 250 mL Erlenmeyer flask, and dissolved in methyl tert-butyl ether (50 mL). To the stirred solution was added 25% sodium methoxide (7.07 g, 32.7 mmol) followed by 3'-fluoro-4'-methoxyacetophenone from Step 1 (5.0 g, 29.7 mmol). After stirring for 16 hours, 1N HCl (50 mL) was added. The organic layer was collected, washed with water (2×50 mL), dried over anhydrous MgSO4, filtered, and added to hexanes to precipitate a tan solid (7.0 g, 96%): mp 70°-72° C.; 1H NMR (DMSO-d6) 8.0 (m, 3H), 7.3 (t, 1H), 6.9 (s, 1H), 6.5 (t, 1H), 3.9 (s, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C1C=CC(N2[C@@H](C3C=CC=C(OC(F)(F)F)C=3)C=C(N[C@@H](C3C=CC(Cl)=CC=3)C)C2=O)=CC=1.[F:45][C:46]([F:72])([F:71])[O:47][C:48]1[CH:49]=[C:50]([C@@H:54]2[N:58]([C:59]3[CH:64]=[CH:63][C:62]([C:65]([F:68])([F:67])[F:66])=[CH:61][CH:60]=3)[C:57](=[O:69])[C:56](=O)[CH2:55]2)[CH:51]=[CH:52][CH:53]=1.[CH3:73][C:74]([NH2:86])([C:76]1[CH:81]=[CH:80][N:79]=[C:78]([C:82]([F:85])([F:84])[F:83])[N:77]=1)[CH3:75]>C(O)(=O)C.O.C1(C)C=CC=CC=1>[CH3:75][C:74]([NH:86][C:56]1[C:57](=[O:69])[N:58]([C:59]2[CH:64]=[CH:63][C:62]([C:65]([F:66])([F:68])[F:67])=[CH:61][CH:60]=2)[C@@H:54]([C:50]2[CH:51]=[CH:52][CH:53]=[C:48]([O:47][C:46]([F:72])([F:45])[F:71])[CH:49]=2)[CH:55]=1)([C:76]1[CH:81]=[CH:80][N:79]=[C:78]([C:82]([F:83])([F:85])[F:84])[N:77]=1)[CH3:73]
Reactant: O=C1C[C@H](c2cccc(OC(F)(F)F)c2)N(c2ccc(C(F)(F)F)cc2)C1=O
Reactant: CC(C)(N)c1ccnc(C(F)(F)F)n1
Agent: C[C@@H](NC1=C[C@H](c2cccc(OC(F)(F)F)c2)N(c2ccc(C(F)(F)F)cc2)C1=O)c1ccc(Cl)cc1
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)(NC1=C[C@H](c2cccc(OC(F)(F)F)c2)N(c2ccc(C(F)(F)F)cc2)C1=O)c1ccnc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
Add trifluoroacetic acid (7.56 mL, 100 mmol) to a solution of 1-(4-trifluoromethyl-phenyl)-3-[(R)-1-(4-chloro-phenyl)-ethylamino]-5(R)-(3-trifluoromethoxy-phenyl)-1,5-dihydro-pyrrol-2-one (10.8 g, 20.0 mmol) in acetic acid (100 mL) and water (5 mL). Stir at ambient temperature for 60 min. Observe significant formation of (R)-5-(3-trifluoromethoxy-phenyl)-1-(4-trifluoromethyl-phenyl)-pyrrolidine-2,3-dione (LC-MS ESI m/z: 426 (M+Na)+, Tr=2.76 min., method 2). Dilute the reaction with toluene (200 mL) and water (150 mL). Wash the organic layer with water and saturated aqueous sodium bicarbonate solution. Filter the organic layer through sodium sulfate. Add acetic acid (9.17 mL, 160 mmol) and 1-methyl-1-(2-trifluoromethyl-pyrimidin-4-yl)-ethylamine (4.51 g, 22 mmol) to this toluene solution containing (R)-5-(3-trifluoromethoxy-phenyl)-1-(4-trifluoromethyl-phenyl)-pyrrolidine-2,3-dione. Heat to 55° C. for 18 hours. Concentrate reaction mixture under reduced pressure to give a dark purple oil. Purify the residue by silica gel chromatography (25% ethyl acetate-hexane) to obtain (R)-3-[1-methyl-1-(2-trifluoromethyl-pyrimidin-4-yl)-ethylamino]-1-(4-trifluoromethyl-phenyl)-5-(3-trifluoromethoxy-phenyl)-1,5-dihydro-pyrrol-2-one (7.70 g, 65%) as a purple foam. LC-MS ESI m/z: 613 (M+Na)+, Tr=3.35 min., method 2.
Reaction SMILES: Cl.C([O:4][C:5](=O)[CH:6]([C:20]1[CH:25]=[C:24]([C:26]#[N:27])[CH:23]=[CH:22][C:21]=1[N+:28]([O-])=[O:29])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:9][N:8]=1)C.C(=O)([O-])O.[Na+].[NH4+]=S>C1(C)C=CC=CC=1.O>[OH:29][N:28]1[C:21]2[C:20](=[CH:25][C:24]([C:26]#[N:27])=[CH:23][CH:22]=2)[C:6]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:9][N:8]=2)=[C:5]1[OH:4]
Reactant: CCOC(=O)C(c1ccc(CN2CCOCC2)cn1)c1cc(C#N)ccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1ccc2c(c1)c(-c1ccc(CN3CCOCC3)cn1)c(O)n2O
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 76 %

Procedure:
(5-Cyano-2-nitro-phenyl)-(5-morpholin-4-ylmethyl-pyridin-2-yl)-acetic acid ethyl ester HCl (8.0 g, 17.9 mmol was slurried in toluene (80 ml) at room temperature and sodium hydrogen carbonate (7.52 g, 89.5 μmol) dissolved in water (50 ml) was added and the reaction mixture stirred at room temperature for 25 min. The organic phase was separated and washed with water and then concentrated to dryness and then redissolved in ethanol (80 ml) and the solution added to a preheated solution of ammonium sulphide (26 ml, 21 w/w %, 107.4 mmol) in water at 50° C. over 20 mins. The resulting yellow slurry was stirred for 1 hr at 50° C. then cooled in an ice bath. The slurry was filtered and washed with water followed by isopropanol. After drying at 50° C. under vacuum gave a yellow powder, 6.67 g, (purity 94%), 76% yield of 1,2-Dihydroxy-3-(5-morpholin-4-ylmethyl-pyridin-2-yl)-1H-indole-5-carbonitrile. 1H NMR (400 MHz; d6-DMSO,): δ 14.36 (br s, 1H), 10.86 (br s, 1H), 8.12 (s, 1H), 7.96 (s, 1H), 7.88 (br d, 1H), 7.87 (br d, 1H), 7.78 (br dd, 1H), 7.36 (dd, J=1.0, 8.0 Hz, 1H), 7.08 (d, H=8.1 Hz, 1H), 3.56 (t, J=4.0, 8.2 Hz, 4H), 3.37 (s, 2H), 2.27 (br s, 4H); 13C NMR: (100 MHz, d6-DMSO): δ 163.8, 148.8, 142.7, 136.7, 136.1, 123.1, 121.5, 120.4, 119.4, 119.1, 102.0, 81.9, 67.2, 66.6, 58.8, 53.3 ppm; MS (ESI) m/z [M+1]+ 351.