Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:4]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][C:8]2([CH3:18])[CH3:17])[CH3:3].[ClH:19].C[CH:21]([NH2:36])[C:22]1C=[CH:26][C:25](CCC2C=CC=CC=2)=[CH:24][CH:23]=1>>[ClH:19].[C:13]([C:11]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2([CH3:17])[CH3:18])=[C:4]([CH:2]([N:1]=[C:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:36]2)[CH3:3])[CH:12]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(N)c1ccc(CCc2ccccc2)cc1
Reactant: CC(N)c1cc(C(C)(C)C)cc2c1CCC2(C)C
Agent: Cl
Product: CC(N=C1CCCCCN1)c1cc(C(C)(C)C)cc2c1CCC2(C)C

Procedure:
Following essentially the same procedure described in Example IV above and substituting 4-(α-aminoethyl)1,1-dimethyl-6-tert.-butylindane for the α-methyl-ρ-phenethylbenzylamine hydrochloride above, results in the formation of 2-[1-(6-tert.-butyl-1,1-dimethyl-4-indanyl)ethylimino]hexahydro-1H-azepine hydrochloride, having a M.P. of 257°-8° C. (dec.)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:4]=1)#[N:2].[C:16](OC)(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[SH:19].C(N(CC)CC)C>C1(C)C=CC=CC=1>[N:11]1[CH:12]=[CH:13][CH:14]=[N:15][C:10]=1[S:9][C:5]1[N:4]=[C:3]([C:1]2[S:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[C:16](=[O:24])[N:2]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: N#Cc1cccc(Sc2ncccn2)n1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1nc(-c2cccc(Sc3ncccn3)n2)sc2ccccc12
Yield: 5.2 %

Procedure:
2-Cyano-6-(2-pyrimidinyl)thiopyridine (1.30 g, 6.07 mmol) and methyl thiosalicylate (1.53 g, 9.10 mmol) were dissolved in toluene (100 ml), and triethylamine (1.70 ml, 12.1 mmol) was added thereto. The mixture was refluxed for 18 hrs. The solvent was evaporated, and the residue was recrystallized from ethanol to give the titled compound (0.11 g, 5%) as pale yellow crystals.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:7])[CH2:3][CH2:2]1.[C:15](O)(=[O:20])[CH2:16][C:17](O)=[O:18].C(O[C:26](=[O:28])[CH3:27])(=O)C>>[C:9]1([N:8]2[C:15](=[O:20])[CH:16]([C:26](=[O:28])[CH3:27])[C:17](=[O:18])[N:5]([CH2:4][CH:1]3[CH2:3][CH2:2]3)[C:6]2=[O:7])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(NCC1CC1)Nc1ccccc1
Reactant: O=C(O)CC(=O)O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)C1C(=O)N(CC2CC2)C(=O)N(c2ccccc2)C1=O

Procedure:
A quantity of 4.75 g of 1-cyclopropylmethyl-3-phenyl urea and 2.60 g of malonic acid are heated in 30 ml of acetic acid anhydride at 75° C. for 4 hours. After cooling slowly, the acetic acid anhydride is evaporated in vacuo. The residue is boiled in ethanol, cooled and filtered. The resulting crystalline product is the title compound (5) and melts at 91°-95° C.; yield 5.21 g.
Reaction SMILES: [CH3:1][N:2]([CH3:50])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:48][CH3:49])=[C:12]([NH:15][C:16]3[N:17]=[C:18]([NH:35][C:36]4[C:41]([C:42]([NH:44][CH3:45])=[O:43])=[C:40]([F:46])[C:39]([F:47])=[CH:38][CH:37]=4)[C:19]4[CH:24]=[CH:23][N:22](S(C5C=CC(C)=CC=5)(=O)=O)[C:20]=4[N:21]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5].O.[OH-].[Na+]>O1CCOCC1.C(OCC)(=O)C>[CH3:50][N:2]([CH3:1])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:48][CH3:49])=[C:12]([NH:15][C:16]3[NH:21][C:20]4=[N:22][CH:23]=[CH:24][C:19]4=[C:18]([NH:35][C:36]4[C:41]([C:42]([NH:44][CH3:45])=[O:43])=[C:40]([F:46])[C:39]([F:47])=[CH:38][CH:37]=4)[N:17]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: CNC(=O)c1c(Nc2nc(Nc3cc4c(cc3OC)CCN4C(=O)CN(C)C)nc3c2ccn3S(=O)(=O)c2ccc(C)cc2)ccc(F)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CNC(=O)c1c(Nc2nc(Nc3cc4c(cc3OC)CCN4C(=O)CN(C)C)[nH]c3nccc2-3)ccc(F)c1F
Temperature: 120 °C
Yield: 80.3 %

Procedure:
6-({2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-2,3-difluoro-N-methylbenzamide (143 mg, 0.203 mmol) was dissolved in 1,4-dioxane (10 mL) and transferred to a 20 ml microwave vessel. Water (3 mL) and a solution of 6M NaOH (3 ml) and was added and reaction heated in microwave at 120° C. for 10 minutes. Resulting brown solution was diluted with ethyl acetate and washed with a saturated sodium bicarbonate solution, water and a saturated brine solution. Organics were dried over sodium sulfate and solvents removed under reduced pressure to afford a brown solid that was purified via chromatography on SiO2 to afford 6-[(2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-2,3-difluoro-N-methylbenzamide (90 mg, 0.163 mmol) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.19-2.31 (m, 6 H), 2.77 (br. s., 3H), 3.04-3.23 (m, 4 H), 3.74-3.84 (m, 3 H), 4.17 (d, J=6.59 Hz, 2 H), 6.23-6.37 (m, 1 H), 6.86-7.02 (m, 2 H), 7.29-7.45 (m, 1 H), 7.50 (d, J=3.85 Hz, 1 H), 8.02-8.15 (m, 1 H), 8.65 (d, J=3.11 Hz, 2 H), 9.64 (d, J=3.94 Hz, 1 H), 11.23 (d, J=1.46 Hz, 1H). (ESIMS (M+H)+=551)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19]C)[CH:15]=2)[C:10]=1[C:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:25][CH:24]=1)=[O:22].B(Br)(Br)Br.C(Cl)(Cl)Cl.C(O)(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=2)[C:10]=1[C:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]2[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]2)=[CH:25][CH:24]=1)=[O:22]
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3c(F)cccc3F)ccc2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CC(C)O
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2c(F)cccc2F)ccc2cc(O)ccc12
Reaction time: 1 h

Procedure:
Dissolve [2-(2,6-difluorophenyl)-6-methoxy-naphthalen-1-yl]-[4-(2-piperidin-1-ylethoxy)-phenyl]-methanone (1.5 gm., 3.0 mmoles) in 500 ml methylene chloride and chill in ice. To this solution add boron tribromide (6.0 ml, 63 mmoles) in portions with swirling between additions. Allow to come to room temp. and stir for one hour. Pour into a two-phase system consisting of an organic layer of 3/1 chloroform/isopropanol and an aqueous layer of saturated sodium bicarbonate. Separate the phases and dry the organic layer using 3A molecular sieves. Purify on a silica column eluting with a 0-10% methanol/methylene chloride gradient. The yield of pure product is 600 mg (44%): 1H-NMR (CD3OD, 400 MHz) δ7.87 (d, J=8.0 Hz, 1H); 7.56 (d, J=8.4 Hz, 2H); 7.49 (d, J=9.2 Hz, 1H); 7.33 (d, j=8.8 Hz, 1H); 7.27-7.25 (m, 1H); 7.23-7.21 (m, 1H); 7.06 (dd, J=8.8, 2.4 Hz, 1H); 6.86-6.79 (m, 4H); 4.14 (t, J=5.6 Hz, 2H); 2.76 (t, J=5.6 Hz, 2H); 2.53-2.53 (m, 4H); 1.65-1.59 (m, 4H); 1.50-1.46 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]([CH:13]([CH3:15])[CH3:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(#N)C>[CH2:22]([O:12][C:10]1[C:9]([CH:13]([CH3:15])[CH3:14])=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([OH:1])[CH:11]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1cc(C(C)C)c(O)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(C(C)C)c(OCc2ccccc2)cc1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.2 %

Procedure:
A mixture of methyl 2,4-dihydroxy-5-isopropylbenzoate (1.05 g, 5.0 mmol) and anhydrous potassium carbonate (828 mg, 6.0 mmol) in acetonitrile (25 ml) was treated with benzyl bromide (0.655 ml, 5.5 mmol) and the mixture was stirred at room temperature for 24 hours. The solvent was removed in vacuo and the residue was treated with water (50 ml). The solid material was collected by suction filtration, rinsed with water (2×50 ml) and sucked dry under reduced pressure to afford methyl 4-benzyloxy-2-hydroxy-5-isopropylbenzoate (1.25 g, 83%) as colourless needles. 1H NMR (DMSO-d6) 10.68 (1H, br s), 7.57 (1H, s), 7.48-7.40 (4H, m), 7.34 (1H, m), 6.64 (1H, s), 5.20 (2H, s), 3.87 (3H, s), 3.18 (1H, m), 1.17 (6H, d). MS: [M+H]+ 301.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[CH2:10][CH2:11][CH2:12][CH:3]([C:4]=23)[C:2]1=[O:13].[H-].[Na+].[C:16]([O:19][CH2:20][CH3:21])(=[O:18])[CH3:17].[CH:22](OC(C)C)(C)C>CN(C=O)C.O>[CH2:20]([O:19][C:16]([CH2:17][CH2:22][C:3]12[CH2:12][CH2:11][CH2:10][C:5]3[C:4]1=[C:9]([CH:8]=[CH:7][CH:6]=3)[NH:1][C:2]2=[O:13])=[O:18])[CH3:21]
Reactant: CCOC(C)=O
Reactant: O=C1Nc2cccc3c2C1CCC3
Reactant: CC(C)OC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCC12CCCc3cccc(c31)NC2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
(RS)-2a,3,4,5-tetrahydro-1H-benz[cd]indol-2-one(3.46 g, 20 mmol) was dissolved in anhydrous N,N,-dimethylformamide (20 ml). Then, 60% sodium hydride (0.8 g, 20 mmol) was added thereto and the resulting mixture was stirred at room temperature for 1 hour. Successively the reaction mixture obtained was cooled to −20° C., and ethyl 3-bromo propionate (2.55 ml, 20 mmol) was added thereto. The resulting mixture was stirred at room temperature for further 1 hour. Ethyl acetate and water were added thereto to extract a reaction product. The ethyl acetate solution was washed with saturated saline solution and then dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure to obtain a reaction product. Thereafter, diisopropyl ether was added to the resulting reaction product to crystallized the same. Thus, the above-described object compound was obtained in an amount of 3.80 g (yield 70%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2].[C:16]([C:18]([C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([C:29]([CH3:33])([C:31]#[N:32])[CH3:30])[CH:28]=1)[CH2:24]Br)([CH3:20])[CH3:19])#[N:17]>>[C:31]([C:29]([C:27]1[CH:26]=[C:23]([CH:22]=[C:21]([C:18]([CH3:20])([C:16]#[N:17])[CH3:19])[CH:28]=1)[CH2:24][N:9]([C:10]1[CH:15]=[N:14][CH:13]=[N:12][CH:11]=1)[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)([CH3:30])[CH3:33])#[N:32]
Reactant: N#Cc1ccc(Nc2cncnc2)cc1
Reactant: CC(C)(C#N)c1cc(CBr)cc(C(C)(C)C#N)c1
Product: CC(C)(C#N)c1cc(CN(c2ccc(C#N)cc2)c2cncnc2)cc(C(C)(C)C#N)c1

Procedure:
Starting compounds: 5-[N-(4-cyanophenyl)amino]pyrimidine and 3,5-bis(1-cyano-1-methylethyl)benzyl bromide
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[CH3:21][C@H:22]1[NH:27][C@@H:26]([CH3:28])[CH2:25][N:24]([C:29]([C:31]2[C:32]([CH3:38])=[C:33]([CH:36]=O)[NH:34][CH:35]=2)=[O:30])[CH2:23]1>C(O)C.N1CCCCC1>[CH3:28][C@H:26]1[NH:27][C@@H:22]([CH3:21])[CH2:23][N:24]([C:29]([C:31]2[C:32]([CH3:38])=[C:33]([CH:36]=[C:11]3[C:10]4[C:14](=[CH:15][CH:16]=[CH:17][C:9]=4[C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:19])[F:20])[CH:4]=4)[NH:13][C:12]3=[O:18])[NH:34][CH:35]=2)=[O:30])[CH2:25]1
Reactant: Cc1c(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c[nH]c1C=O
Reactant: O=C1Cc2c(cccc2-c2cccc(C(F)(F)F)c2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c[nH]c1C=C1C(=O)Nc2cccc(-c3cccc(C(F)(F)F)c3)c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 27 %

Procedure:
To a solution of 4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (69.3 mg, 0.25 mmol) and 4[(cis)3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-{4((cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene}-4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (34.3 mg, 27%).
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][CH2:3][CH:4]=[CH2:5].C(OC(Cl)=O)C.C(N(CC)CC)C.Cl.[CH2:22]([O:29][NH2:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)(Cl)Cl>[CH2:22]([O:29][NH:30][C:1](=[O:7])[CH2:2][CH2:3][CH:4]=[CH2:5])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NOCc1ccccc1
Reactant: C=CCCC(=O)O
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=CCCC(=O)NOCc1ccccc1

Procedure:
This compound was prepared in several steps. 4-pentenoic acid (1.2.6.4) was reacted with ethylchloroformate to obtain the active mixed anhydride. To a solution of the mixed anhydride in chloroform was added triethylamine and O-benzylhydroxylamine hydrochloride to obtain O-benzyl-4-pentenohydroxamic acid (1.2.6.5). The double bond was oxidized using osmium tetroxide/N-methylmorpholine oxide to give the diol (1.2.6.6). The terminal hydroxyl group was then protected with t-butyldimethylsilylchloride in the usual way to yield (1.2.6.7). The secondary hydroxyl group was tosylated using pyridine/p-toluenesulfonyl chloride. Cyclization of (1.2.6.8) to the corresponding pyrrolidone (1.2.6.9) was effected by using sodium carbonate in methanol. The protecting silyl group was removed by treatment with tetraethylammonium fluoride. The title compound (1.2.6.3) was prepared by reacting the latter compound (1.2.6.10) with pyridine/p-toluenesulfonyl chloride. 1.2.6.11 5-Bromo-1-benzyloxy-2-pyrrolidone.
Reaction SMILES: N[C:2](N)=[O:3].S(=NC(N)=O)(=O)=O.[NH2:12][C:13]1[N:18]=[CH:17][C:16]([N:19]2[C:24](=[O:25])[C:23]3[CH:26]=[C:27]([F:32])[C:28]([NH:30][CH3:31])=[CH:29][C:22]=3[O:21][CH2:20]2)=[CH:15][CH:14]=1.CO[C:35]1[CH:39]=[C:38](C)[S:37][C:36]=1[S:41]([NH:44][C:45](=[O:47])[O-])(=[O:43])=[O:42]>>[F:32][C:27]1[C:28]([NH:30][CH3:31])=[CH:29][C:22]2[O:21][CH2:20][N:19]([C:16]3[CH:15]=[CH:14][C:13]([NH:12][C:45]([NH:44][S:41]([C:36]4[S:37][C:38]([O:3][CH3:2])=[CH:39][CH:35]=4)(=[O:42])=[O:43])=[O:47])=[N:18][CH:17]=3)[C:24](=[O:25])[C:23]=2[CH:26]=1
Reactant: NC(N)=O
Reactant: CNc1cc2c(cc1F)C(=O)N(c1ccc(N)nc1)CO2
Reactant: COc1cc(C)sc1S(=O)(=O)NC(=O)[O-]
Agent: NC(=O)N=S(=O)=O
Product: CNc1cc2c(cc1F)C(=O)N(c1ccc(NC(=O)NS(=O)(=O)c3ccc(OC)s3)nc1)CO2

Procedure:
Analogous to the sulfonylurea urea coupling method described in Ex 5, 3-(6-aminopyridin-3-yl)-6-fluoro-7-(methylamino)-2,3-dihydrobenzo[e][1,3]oxazin-4-one was coupled with 3-methoxy-5-methylthiophen-2-ylsulfonylcarbamate to yield 1-(5-(6-fluoro-7-(methylamino)-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)pyridin-2-yl)-3-(5-methoxythiophen-2-ylsulfonyl)urea. RP-HPLC: 2.7 min; ES-MS (M+H)+=508; 1H-NMR (DMSO-d6) δ (ppm): 2.8 (s, 3), 3.9 (s, 3), 5.6 (s, 2), 6.2 (d, 1), 6.5 (d, 1), 6.7 (d, 1), 7.4 (d, 1), 7.6 (d, 1), 7.8 (d, 1), 8.2 (s, 1), 9.4 (bs, 1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([OH:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2].Br[CH2:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:19].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:17][C:18](=[O:19])[N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(O)ccc2[nH]1
Reactant: O=C(CBr)N1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(OCC(=O)N3CCCC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 25.3 %

Procedure:
A mixture of 5-hydroxy-1H-indole-2-carboxylic acid ethyl ester (2 g, 10 mmol), 2-bromo-1-pyrrolidin-1-yl-ethanone (3 g, 20 mmol) and cesium carbonate (19.5 g, 60 mmol) in dimethylformamide (16 mL) was stirred at room temperature for 24 hours. The reaction was diluted with ethyl acetate (150 mL), washed with water (5×50 mL) and brine, dried and concentrated. The residue was recrystallized from ethyl acetate and hexane to give 0.8 g (25%) 5-(2-oxo-2-pyrrolidin-1-yl-ethoxy)-1H-indole-2-carboxylic acid ethyl ester as a brown solid.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]([CH2:11][NH:12][C:13]([C:15]([O:17][Li])=O)=[O:14])[CH2:8][C:7]=2[CH:19]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[NH2:51][CH2:52][CH2:53][O:54][CH:55]1[CH2:60][CH2:59][CH:58]([NH:61][C:62]2[CH:67]=[CH:66][C:65]([N+:68]([O-:70])=[O:69])=[C:64]([C:71]([F:74])([F:73])[F:72])[CH:63]=2)[CH2:57][CH2:56]1>CN(C)C=O.O>[N+:68]([C:65]1[CH:66]=[CH:67][C:62]([NH:61][CH:58]2[CH2:57][CH2:56][CH:55]([O:54][CH2:53][CH2:52][NH:51][C:15](=[O:17])[C:13]([NH:12][CH2:11][CH:9]3[CH2:8][C:7]4[CH:19]=[C:3]([C:2]([F:1])([F:21])[F:20])[CH:4]=[CH:5][C:6]=4[O:10]3)=[O:14])[CH2:60][CH2:59]2)=[CH:63][C:64]=1[C:71]([F:72])([F:73])[F:74])([O-:70])=[O:69]
Reactant: NCCOC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reactant: [Li]OC(=O)C(=O)NCC1Cc2cc(C(F)(F)F)ccc2O1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(NCCOC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)C(=O)NCC1Cc2cc(C(F)(F)F)ccc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29 %

Procedure:
The mixture of lithio ([[5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl]carbamoyl)formate (170 mg, 0.58 mmol), EDAC.HCl (166 mg, 0.87 mmol), HOBt (58.3 mg, 0.43 mmol) and triethylamine (87.3 mg, 0.86 mmol) in N,N-dimethylformamide (10 ml) was stirred for 1 hour before the addition of N-[4-(2-aminoethoxy)cyclohexyl]-4-nitro-3-(trifluoromethyl)aniline (100 mg, 0.29 mmol). The resulting solution was stirred overnight at room temperature, diluted with water (100 ml), and extracted with dichloromethane (3×50 ml). The organic fractions were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by HPLC to afford N1-[2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]ethyl]-N2-[[5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl]ethanediamide as a yellow solid (52 mg, 29%). (ES, m/z): [M+H]+ 619.10; 1H NMR (300 MHz, CDCl3): δ 8.02 (d, J=9.3 Hz, 1H), 7.80 (br s, 1H), 7.72 (br s, 1H), 7.41 (m, 2H), 6.84 (m, 2H), 6.63 (dd, J=9.0, 2.4 Hz, 1H), 5.00 (m, 1H), 3.78 (m, 1H), 3.60-3.55 (m, 3H), 3.53-3.50 (m, 2H), 3.35 (br m, 3H), 2.98 (dd, J=16.2, 7.2 Hz, 1H), 2.12 (m, 4H), 1.46-1.34 (m, 2H), 1.29-1.22 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:15]2[C:6]([CH3:21])([C:7]3[C:8](=[O:20])[CH:9]=[C:10]([CH:17]([CH3:19])[CH3:18])[C:11](=[O:16])[C:12]=3[CH2:13][CH2:14]2)[CH2:5][CH2:4][C:3]=1[C:22]([OH:24])=[O:23].[CH3:25]COCC>>[CH3:1][C:2]1[CH:15]2[C:6]([CH3:21])([C:7]3[C:8](=[O:20])[CH:9]=[C:10]([CH:17]([CH3:19])[CH3:18])[C:11](=[O:16])[C:12]=3[CH2:13][CH2:14]2)[CH2:5][CH2:4][C:3]=1[C:22]([O:24][CH3:25])=[O:23]
Reactant: CC1=C(C(=O)O)CCC2(C)C3=C(CCC12)C(=O)C(C(C)C)=CC3=O
Reactant: CCOCC
Product: COC(=O)C1=C(C)C2CCC3=C(C(=O)C=C(C(C)C)C3=O)C2(C)CC1
Reaction time: 0.5 h

Procedure:
63 Milligrams of the 3,4,4a,5,8,9,10,10a-octahydro-1,4a-dimethyl-7-(1-methylethyl)-5,8-dioxo-2-phenanthrenecarboxylic acid obtained in Example 1 was dissolved in 8 ml of ether, then under ice-cooling condition, a diazomethane-ether solution was added thereto and the mixture was stirred for 30 minutes. Ether was removed by distillation. The resulting crude product was purified by a silica gel column chromatography (eluant: ether/n-hexane=1/2) to obtain 8.8 mg of methyl 3,4,4a, 5,8,9,10,10a-octahydro-1,4a-dimethyl-7-(1-methylethyl)-5,8-dioxo-2-phenanthrenecarboxylate.
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20](=O)[C:21]([O:23][CH3:24])=[O:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CCCCCC.[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.O1CCCC1>[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1/[C:20](=[CH:1]\[CH3:2])/[C:21]([O:23][CH3:24])=[O:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: [Li]CCCC
Reactant: COC(=O)C(=O)c1ccccc1OCc1ccccc1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C/C=C(/C(=O)OC)c1ccccc1OCc1ccccc1
Reaction time: 0.5 h
Yield: 57 %

Procedure:
At 0° C. and under nitrogen, 32 ml (50 mmol) of a 1.6 molar solution of n-butyllithium in hexane is slowly added to 18.5 g (50 mmol) of ethyltriphenylphosphonium bromide in 100 ml of absolute tetrahydrofuran. After the mixture has been stirred for 30 minutes, 13.5 g (50 mmol) of methyl 2-(benzyloxy)-phenylglyoxylate in 25 ml of absolute tetrahydrofuran is dripped in at 0° C. The mixture is stirred for 16 hours at room temperature. After concentration, the residue is taken up in dichloromethane and washed several times with water. After drying over Na2SO4 the solvent is evaporated off. The crude product obtained is purified by chromatography (a 9:1 mixture of cyclohexane and ethyl acetate). There is obtained 8.0 g (57%) of the methyl crotonate (trans:cis ratio=9:1) as an oil.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O)CO.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[CH:19]1([C:22]2[N:33]=[C:25]3[C:26]([O:31][CH3:32])=[CH:27][CH:28]=[C:29](I)[N:24]3[N:23]=2)[CH2:21][CH2:20]1>[Cu](I)I.CC(O)C>[CH:19]1([C:22]2[N:33]=[C:25]3[C:26]([O:31][CH3:32])=[CH:27][CH:28]=[C:29]([N:13]4[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]4)[N:24]3[N:23]=2)[CH2:21][CH2:20]1
Reactant: C1CCNCC1
Reactant: COc1ccc(I)n2nc(C3CC3)nc12
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: COc1ccc(N2CCCCC2)n2nc(C3CC3)nc12
Temperature: 80 °C

Procedure:
Copper iodide (1.0 mg, 0.005 mmol) and potassium phosphate (42.5 mg, 0.200 mmol), kept under argon, was added 2-propanol (200 μL), ethylene glycol (12.4 mg, 0.200 mmol), piperidine (10.1 mg, 0.12 mmol) and 2-cyclopropyl-5-iodo-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine (31.5 mg, 0.100 mmol). The resulting suspension was heated to 80° C. for 4 days. The mixture was allowed to reach room temperature before it was extracted with dichloromethane (3 mL). The organic phase was washed with brine, dried (Na2SO4) and filtered before it was concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 20% EtOAc in toluene to 40% EtOAc in toluene) to give 2-cyclopropyl-8-methoxy-5-piperidin-1-yl-[1,2,4]triazolo[1,5-a]pyridine (2.2 mg.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.Cl.[CH3:10][C:11]1[C:15]([CH2:16][N:17]2[CH:21]=[C:20]([NH2:22])[CH:19]=[N:18]2)=[C:14]([CH3:23])[O:13][N:12]=1>>[CH3:10][C:11]1[C:15]([CH2:16][N:17]2[CH:21]=[C:20]([NH:22][C:6]([C:2]3[NH:1][CH:5]=[CH:4][CH:3]=3)=[O:8])[CH:19]=[N:18]2)=[C:14]([CH3:23])[O:13][N:12]=1
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Reactant: O=C(O)c1ccc[nH]1
Agent: Cl
Product: Cc1noc(C)c1Cn1cc(NC(=O)c2ccc[nH]2)cn1
Yield: 18 %

Procedure:
Prepared as in Example 4-8 from 1H-pyrrole-2-carboxylic acid and 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (Example 4-1a). Yield 18%. MS M+H calculated 286.6, found 286.3.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([NH2:11])[N:8]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([O:19][CH3:20])[C:13]=2[F:21])[N:6]=1)=[O:4].[B-](F)(F)(F)[F:23].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[C:10]([F:23])=[C:9]([NH2:11])[N:8]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([O:19][CH3:20])[C:13]=2[F:21])[N:6]=1)=[O:4]
Reactant: F[B-](F)(F)F
Reactant: COC(=O)c1cc(N)nc(-c2ccc(Cl)c(OC)c2F)n1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(N)c1F
Temperature: 25 °C
Yield: 3.2 %

Procedure:
6-Amino-2-(4-chloro-2-fluoro-3-methoxy-phenyl)-pyrimidine-4-carboxylic acid methyl ester (778 mg, 2.5 mmol) and F-TEDA (974 mg, 2.75 mmol) were combined in acetonitrile and heated at reflux for 4 hours (reaction made little progress after 1 hour). The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated, purified by column chromatography, and then purified a second time by preparative HPLC to yield 6-amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoropyrimidine-4-carboxylic acid methyl ester (26 mg, 3.2% yield): mp 200-202° C.: 1H NMR (CDCl3): δ 7.62 (dd, 1H), 7.21 (dd, 1H), 5.40 (br s, 2H), 4.02 (s, 3H), 4.0 (d, 3H)