Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]2[CH2:20][CH2:19][C:18]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:11][C:10]=3[CH2:9]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C(Cl)(Cl)Cl>[CH2:9]1[C:10]2[NH:11][C:12]3[C:17]([C:18]=2[CH2:19][CH2:20][N:8]1[CH2:7][CH:4]1[CH2:5][CH2:6][N:1]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:2][CH2:3]1)=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: CCOC(=O)Cl
Reactant: c1ccc2c3c([nH]c2c1)CN(CC1CCNCC1)CC3
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCC(CN2CCc3c([nH]c4ccccc34)C2)CC1

Procedure:
7.06 g (26.2 mmol) of 2-[(4-piperidyl)methyl]-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole, 70 ml of chloroform and 4 ml (26.2 mmol) of triethylamine are introduced under an argon atmosphere into a Keller flask, and 2.8 ml (26.2 mmol) of ethyl chloroformate are added.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]5[C:28](=[CH:29][CH:30]=4)[N:27]=[C:26]([C:31]([O:33]C)=[O:32])[CH:25]=[CH:24]5)=[CH:17][CH:16]=3)=[C:11]([CH:35]([CH3:37])[CH3:36])[O:10][N:9]=2)=[C:6]([Cl:38])[CH:5]=[CH:4][N:3]=1.[OH-].[Na+].Cl>C1COCC1>[Cl:1][C:2]1[C:7]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]4[CH:22]=[C:23]5[C:28](=[CH:29][CH:30]=4)[N:27]=[C:26]([C:31]([OH:33])=[O:32])[CH:25]=[CH:24]5)=[CH:19][CH:20]=3)=[C:11]([CH:35]([CH3:36])[CH3:37])[O:10][N:9]=2)=[C:6]([Cl:38])[CH:5]=[CH:4][N:3]=1
Reactant: COC(=O)c1ccc2cc(-c3ccc(OCc4c(-c5c(Cl)ccnc5Cl)noc4C(C)C)cc3)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)c1onc(-c2c(Cl)ccnc2Cl)c1COc1ccc(-c2ccc3nc(C(=O)O)ccc3c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of methyl 6-[4-({[3-(2,4-dichloro-3-pyridinyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (85 mg, 0.16 mmol) (from multiple batches) in THF (1.6 mL) was stirred as a 1 N aqueous sodium hydroxide solution (0.24 mL, 0.24 mmol) was added. The solution was allowed to stir at room temperature overnight. The solution was neutralized with 1 N HCl and concentrated. The residue was partitioned between ethyl acetate and brine. The organic layer was dried with MgSO4. The MgSO4 was slurried in dichloromethane, filtered and the combined filtrates were concentrated to yield 6-[4-({[3-(2,4-dichloro-3-pyridinyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylic acid as a bright yellow foam (66 mg, 76% 0.12 ethyl acetate). 1H NMR (400 MHz, DMSO-d6): δ 13.37 (s, 1H), 8.54-8.51 (m, 2H), 8.28 (d, J=1 Hz, 1H), 8.17-8.08 (m, 3H), 7.80 (d, J=5 Hz, 1H), 7.74 (d, J=9 Hz, 2H), 6.92 (d, J=9 Hz, 2H), 4.96 (s, 2H), 3.49 (septet, J=7 Hz, 1H), 1.34 (d, J=7 Hz, 6H). HRMS C28H21N3O4Cl2 m/z 534.0982, (M+H)+Cal; 534.0980 (M+H)+Obs.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[CH:8]1[C:16]2[NH:15][C:14]3[C:17]4[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=4[S:19][C:13]=3[C:12]=2[CH:11]=[CH:10][CH:9]=1>C(Cl)Cl.CCCCCC>[CH3:5][N:15]1[C:16]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[C:13]2[S:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[C:14]1=2
Reactant: c1ccc2c(c1)[nH]c1c3ccccc3sc21
Reactant: COS(=O)(=O)OC
Solvent: ClCCl
Solvent: CCCCCC
Product: Cn1c2ccccc2c2sc3ccccc3c21
Yield: 91.9 %

Procedure:
Using the procedure outlined in Example 34A except that dimethyl sulfate was used as the alkylating agent, 10H-[1]benzothieno[3,2-b]indole (prepared by the method of K. E. Chippendale and B. Iddon, JCS Perkin Trans. I, 2023 (1972)) gave a 91.9% yield of 10-methyl-10H-[1]benzothieno[3,2-b]indole, mp 175°-176°, (CH2Cl2 /hexane), (C,H,N,S).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:8][CH2:7][N:6]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:4].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.CCCCCC.[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:8][CH2:7][N:6]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:4]
Reactant: COC(=O)C1CCN1C(=O)OC(C)(C)C
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)C1(Cc2ccccc2)CCN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of azetidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (1 eq.) in dry THF under Argon at −78° C. was added a solution of LiHMDS 1M in hexane (1.3 eq.). The mixture was stirred at −78° C. for 1 h, then benzyl bromide (1.3 eq.) was added. The reaction was stirred at −78° C. for 30 min, then at 0° C. for 2 h, then at 20° C. for 1 h. The crude was diluted with EtOAc, carefully hydrolyzed with a saturated aqueous solution of NH4Cl. The organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with heptane/EtOAc: 98/2 to 80/20) to afford 2-benzyl-azetidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](F)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][NH:29][CH2:28][CH2:27][NH:26]2)[CH:20]=1.N1C=CC=CC=1>CCOCC>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10]([N:29]3[CH2:28][CH2:27][NH:26][CH:25]([C:21]4[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=4)[CH2:30]3)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2]
Reactant: c1cncc(C2CNCCN2)c1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(c4cccnc4)C3)cc21
Temperature: 25 °C
Yield: 39.7 %

Procedure:
A mixture of 177 mg of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 342 mg of 2-(3-pyridinyl)piperazine and 5 ml of pyridine was heated at 90°-95° C. in a pressure bottle for 5 hours, then cooled at room temperature, then at 0° C. Ether was added to triturate the mixture, then the solid was collected and washed with methanol and ether. This solid was redissolved in a hot mixture of chloroform and methanol, filtered and triturated with ether. The precipitate was collected and dried in vacuo, giving 110 mg of the desired product.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[C:14]1(=[CH:18][C:19]([OH:21])=[O:20])[CH2:17][CH2:16][CH2:15]1>C1COCC1.CN(C=O)C>[C:1]1([S:7][C:14]2([CH2:18][C:19]([OH:21])=[O:20])[CH2:17][CH2:16][CH2:15]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: O=C(O)C=C1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(O)CC1(Sc2ccccc2)CCC1

Procedure:
A solution of thiophenol (70 mmol) in THF (10 ml) was refluxed for 1 h in the presence of K2CO3 (70 mmol) as a base. A solution of Cyclobutylidene acetic acid (intermediate 1) (35 mmol) in DMF (1.0 ml) was added to the above reaction. The reaction was monitored by TLC for completion. After 3 days the reaction was cooled and filtered. It was then neutralized with ethyl acetate saturated with hydrochloric acid and the compound was extracted with ethyl acetate. Organic layer was then separated, dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was column purified to give the compound as a yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12](=S)[NH:13][NH2:14])[CH3:2].[Cl:16][CH:17]([C:23]([CH3:25])=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19].Cl>C(O)C>[ClH:16].[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12]1[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:23]([CH3:25])[NH:14][N:13]=1)[CH3:2]
Reactant: CCc1cccc(CC)c1NC(=S)NN
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(Nc2c(CC)cccc2CC)n[nH]c1C
Temperature: 25 °C
Yield: 91.8 %

Procedure:
A stirred slurry of 9.4 g (0.05 mole) of 4-(2,6-diethylphenyl)-3-thiosemicarbazide in 75 mL of absolute ethanol was treated with 8.25 g (0.05 mole) of ethyl 2-chloroacetoacetate. The reaction mixture was stirred at ambient temperature as the color changed from white to yellow then to a greenish-white. The reaction mixture was treated with 40 mL of 2N ethanolic hydrogen chloride, heated at reflux for 1 hr then filtered hot. The filtrate upon cooling yielded a pale yellow solid, 16 g. Recrystallization from benzene/ligroin gave 15.5 g of white granular solid which was dried at 82+ C. under high vacuum for 3 hr, mp 167°-170° C. Elemental analysis and its 1H NMR spectrum indicated the product was a hydrochloride salt.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:11](O)=O)[CH3:10])=O)(C)(C)C.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C@@H:22]([NH2:24])[CH3:23]>>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C@@H:22]([NH:24][CH2:10][C@@H:9]([NH2:8])[CH3:11])[CH3:23]
Reactant: COc1ccccc1[C@H](C)N
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: COc1ccccc1[C@H](C)NC[C@H](C)N
Yield: 12.2 %

Procedure:
By using N-t-butoxycarbonyl-(L)-alanine (431 mg), and (1S)-1-(2-methoxyphenyl)ethanamine (200 mg) obtained by the method described in the publication (Japanese Patent Unexamined Publication No. 54/154724) as starting materials, the title compound (33.6 mg) was obtained in the same manners as those of Reference Example 10, (1), (2), and Reference Example 3, (2).
Reaction SMILES: [H-].[Na+].[C:3]([O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH2:55][CH2:56][O:57][CH2:58][CH2:59][O:60][CH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1>C1COCC1>[CH2:61]([O:60][CH2:59][CH2:58][O:57][CH2:56][CH2:55][O:54][CH2:53][CH2:52][O:51][CH2:50][CH2:49][O:48][CH2:47][CH2:46][O:44][C:41]1[CH:42]=[CH:43][C:38]([O:37][CH2:36][CH2:35][O:34][CH2:33][CH2:32][O:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23][O:22][C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:39][CH:40]=1)[C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=1
Reactant: BrCCOCCOCCOCCOCCOCc1ccccc1
Reactant: Oc1ccc(OCCOCCOCCOCCOCCOC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc(COCCOCCOCCOCCOCCOc2ccc(OCCOCCOCCOCCOCCOC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 84.1 %

Procedure:
To an ice-cooled suspension of sodium hydride (800 mg, 20 mmol; 60% in mineral oil) in THF (15 ml), a solution of Compound 22 (1.2 g, 2.1 mmol) in THF (20 ml) was gradually added; this was followed by stirring for 20 minutes. A solution of Compound 20 (1.7 g, 4.3 mmol) in THF (12 ml) was added thereto, and this was followed by stirring for 20 minutes. After the ice bath was removed, stirring was further conducted at room temperature for 2 hours. Water was carefully added to stop the reaction, and this was followed by concentration under reduced pressure. Extraction from methylene chloride was conducted, and the combined organic phases were washed with saturated brine and dried with anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue obtained was purified by silica gel column chromatography (Yamazen YFLC Gel, eluent (n-hexane:ethyl acetate 2:1-1:1)) to yield Compound 23 (light-yellow oil 1.56 g, 84%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:32]([O:33][CH3:34])=[CH:31][C:6]2[CH2:7][C:8](=[O:30])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:29])[CH2:16][CH2:17][CH2:18][S:19][C:20]3[CH:25]=[C:24]([Br:26])[C:23]([NH2:27])=[C:22]([Br:28])[CH:21]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[OH:35]O>C(O)(=O)C>[CH3:1][O:2][C:3]1[C:32]([O:33][CH3:34])=[CH:31][C:6]2[CH2:7][C:8](=[O:30])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:29])[CH2:16][CH2:17][CH2:18][S:19]([C:20]3[CH:25]=[C:24]([Br:26])[C:23]([NH2:27])=[C:22]([Br:28])[CH:21]=3)=[O:35])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: OO
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCCSc1cc(Br)c(N)c(Br)c1)CC2
Solvent: CC(=O)O
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCCS(=O)c1cc(Br)c(N)c(Br)c1)CC2

Procedure:
The title compound is prepared from N-[3-(7,8-dimethoxy-1,3,4,5-tetra-hydro-2H-3-benzazepin-2-on-3-yl)-propyl-N-[3-(4-amino-3,5-dibromophenylthio)-propyl]-methylamine and hydrogen peroxide in glacial acetic acid analogously to Example 4.
Reaction SMILES: [K].[CH3:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:5]([C:6]([OH:8])=[O:7])[C:4]=1[NH2:12].[N+]([C:16]1[C:24](C)=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19])([O-])=O>[Pd].CO.O>[CH3:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:5]([C:6]([OH:8])=[O:7])[C:4]=1[NH:12][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19]
Reactant: Cc1cccc(C(=O)O)c1[N+](=O)[O-]
Reactant: Cc1cccc(C(=O)O)c1N
Agent: [Pd]
Agent: [K]
Solvent: CO
Solvent: O
Product: Cc1cccc(C(=O)O)c1Nc1ccccc1C(=O)O
Temperature: 150 °C
Reaction time: 2 h

Procedure:
The potassium salt of 3-methylanthranilic acid was generated by hydrogenation (Palladium-charcoal catalyst) of a solution of the potassium salt of 2-nitro-3-methylbenzoic acid (37.4 gm) in methanol-H2O (1:4 v/v) with following clarification and evaporation to dryness. To this potassium salt were added 2-chlorobenzoic acid (34.5 gm), K2CO3 (34.5 gm), catalytic Cu powder (0.3 gm), CuBr (0.3 gm), N-methyl-2-pyrrolidone (45 ml) and 2-ethoxyethanol (45 ml) and the mixture was heated in an oil bath at 150° C. with stirring for 21/2 hr. Water (1.5 L) was added to the cooled mixture and the whole warmed until the salts had dissolved and crude product was precipitated from the clarified solution by acidiciation with excess HOAc. The product was washed well with boiling water, then dissolved in 5% aqueous Na2CO3 (500 ml) and decolourising charcoal (5 gm) stirred in. To the boiling clarified solution EtOH (500 ml) was added and the mixture acidified by the slow addition of HOAc. The crystalline diacid which separated from the hot solution was collected, washed with boiling water and dried (48.9 gm). Crystallisation from EtOH--H2O provided homogeneous material as colourless needles of mp 258°-259° C.
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1>>[CH:11]1[C:12]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=5)([OH:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:5]4[C:14]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Reactant: Brc1ccccn1
Product: OC1(c2ccccn2)CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Yield: 66 %

Procedure:
Using a procedure similar to that described in example 1 except starting with 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (described in example 5d) and 2-bromopyridine, the title compound was formed in 66% yield as a white solid, mp 194°-196° C. free base: 1H NMR (CDCl3, 250 MHz) 8.53 (d, J=5.0 Hz, 1H), 7.70 (ddd, J=1.5, 7.7, 7.7 Hz, 1H), 7.39 (d, J=7.8 Hz, 1H), 7.22 (m, 5H), 6.94 (m, 4H), 5.23 (s, 1H), 4.30 (s, 1H), 3.52 (s, 2H), 2.99 (m, 2H), 2.81 (dt, J=2.0, 12.0 Hz, 2H), 2.65 (d, J=2.0 Hz, 2H), 2.07 (dt, J=5.0, 13.0 Hz, 2H), 1.60 (m, 2H) MS (CI, CH4) m/z 383 (M+1,100), 411 (M+29,20), 365 (18), 364 (17) hydrochloride salt:
Reaction SMILES: COC1C=CC(C2N(C)C3C(C=2)=CC=C(OC)C=3)=C(N)C=1.Cl.FC1C=C(C=CC=1OCCN1CCCCC1)C(O)=O.[F:42][C:43]1[CH:44]=[C:45]([CH:68]=[CH:69][C:70]=1[O:71][CH2:72][CH2:73][N:74]1[CH2:79][CH2:78][CH2:77][CH2:76][CH2:75]1)[CH2:46][NH:47][C:48]1[CH:53]=[C:52]([O:54]C)[CH:51]=[CH:50][C:49]=1[C:56]1[N:57]([CH3:67])[C:58]2[C:63]([CH:64]=1)=[CH:62][CH:61]=[C:60]([O:65]C)[CH:59]=2>>[F:42][C:43]1[CH:44]=[C:45]([CH:68]=[CH:69][C:70]=1[O:71][CH2:72][CH2:73][N:74]1[CH2:75][CH2:76][CH2:77][CH2:78][CH2:79]1)[CH2:46][NH:47][C:48]1[CH:53]=[C:52]([OH:54])[CH:51]=[CH:50][C:49]=1[C:56]1[N:57]([CH3:67])[C:58]2[C:63]([CH:64]=1)=[CH:62][CH:61]=[C:60]([OH:65])[CH:59]=2
Reactant: COc1ccc(-c2cc3ccc(OC)cc3n2C)c(NCc2ccc(OCCN3CCCCC3)c(F)c2)c1
Agent: COc1ccc(-c2cc3ccc(OC)cc3n2C)c(N)c1
Agent: Cl
Agent: O=C(O)c1ccc(OCCN2CCCCC2)c(F)c1
Product: Cn1c(-c2ccc(O)cc2NCc2ccc(OCCN3CCCCC3)c(F)c2)cc2ccc(O)cc21
Yield: 20.1 %

Procedure:
Synthesized from 5-methoxy-2-(6-methoxy-1-methyl-1H-indol-2-yl)phenylamine (500 mg) and 3-fluoro-4-(2-piperidin-1-ylethoxy)benzoic acid hydrochloride (920 mg) according to an analogous synthetic method to Example 114, [3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl][5-methoxy-2-(6-methoxy-1-methyl-1H-indol-2-yl)phenyl]amine (210 mg) was used according to an analogous synthetic method to Example 364 described below to provide the title compound (40 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH2:9][S:10]C)=[CH:4][N:3]=1.[N:12]#[C:13][NH2:14].IC1C=CC=C(CC([O-])=O)C=1CC([O-])=O.S(=O)(O)[O-].[Na+]>O>[Cl:8][C:7]1[CH:6]=[C:5]([CH2:9][SH:10]=[N:14][C:13]#[N:12])[CH:4]=[N:3][C:2]=1[Cl:1]
Reactant: N#CN
Reactant: CSCc1cnc(Cl)c(Cl)c1
Agent: O=C([O-])Cc1cccc(I)c1CC(=O)[O-]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: N#CN=[SH]Cc1cnc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2,3-dichloro-5-methylthiomethylpyridine (3.5 g, 16.8 mmol) and cyanamide (1.43 g, 34 mmol) cooled in an ice-water bath was added iodobenzenediacetate (6.76 g, 21 mmol) in one portion. The resulting mixture was stirred at 0° C. for 30 min and then continued at room temperature for 1 h. A solution of sodium bisulfite (2 g) in water (50 mL) was added and the organic phase separated. The aqueous phase was extracted with dichloromethane (2×50 mL). The combined organic phase was dried over MgSO4 and the solvent evaporated to give a dark red oily residue which was triturated with boiling ether (2×40 mL) with the ether being discarded each time. After standing at room temperature overnight, the residue solidified, which was triturated with hot ethyl acetate (25 mL). Upon cooling down, the off-white solid product was collected by filtration and dried. Concentration of the filtrate and repeating the trituration process gave additional product. The total yield for the product [1-(5,6-dichloropyridin-3-yl)methyl]-λ4-sulfanylidenecyanamide was 2.45 g (58.8%). LC-MS: calcd for C8H7Cl2N3S [M]+ 247. Found 247.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH3:12][O:13][C:14]([C:16]1[S:17][C:18]([CH2:21][CH2:22][CH2:23][C@@H:24]2[C@@H:28]([C:29]3[CH:34]=[CH:33][C:32]([CH:35]([O:41][CH2:42][C:43]4[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=4)[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:31][CH:30]=3)[C:27](=[O:51])[CH:26]([O:52][C:53](=[O:55])[CH3:54])[CH:25]2OC(=O)C)=[CH:19][CH:20]=1)=[O:15].Cl>CCOCC>[CH3:12][O:13][C:14]([C:16]1[S:17][C:18]([CH2:21][CH2:22][CH2:23][C@@H:24]2[C@@H:28]([C:29]3[CH:34]=[CH:33][C:32]([CH:35]([O:41][CH2:42][C:43]4[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=4)[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:31][CH:30]=3)[C:27](=[O:51])[C:26]([O:52][C:53](=[O:55])[CH3:54])=[CH:25]2)=[CH:19][CH:20]=1)=[O:15]
Reactant: CCCCCC(OCc1ccc(OC)cc1)c1ccc([C@H]2C(=O)C(OC(C)=O)C(OC(C)=O)[C@@H]2CCCc2ccc(C(=O)OC)s2)cc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOCC
Product: CCCCCC(OCc1ccc(OC)cc1)c1ccc([C@H]2C(=O)C(OC(C)=O)=C[C@@H]2CCCc2ccc(C(=O)OC)s2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.7 %

Procedure:
DBU (15 μL, 0.10 mmol) was added to an ice-cold solution of diacetate 28 (32 mg, 0.048 mmol) in ether (0.5 mL). The solution was stirred at 0° C. for 30 min. and then was allowed to warm to room temperature. After stirring overnight, 1 M HCl was added and the resulting mixture was extracted with ethyl acetate (3×25 mL). The combined organic solution was washed with brine and then was dried (Na2SO4), filtered and evaporated. Purification by flash chromatography on silica gel (0%→100% ethyl acetate/hexanes) provided the title compound (21 mg, 71%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[ClH:15].N1C=CC([C:21]([NH2:23])=[NH:22])=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[ClH:15].[NH2:23][C:21]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)=[NH:22]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: N=C(N)c1cc[nH]n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(NC(=N)N)CC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a mixture of tert-butyl 4-aminopiperidine-1-carboxylate (8.93 g, 44.6 mmol) and pyrazole carbox-amidine hydrochloride (6.536 g, 44.6 mmol) was added Hunig's base (7.77 ml, 44.6 mmol) and DMF (25 ml). The reaction was heated at 60° C. for 15 hours. The reaction was then cooled to room temperature and quenched by adding 400 ml of diethyl ether and stirring at room temperature for 2 hours. Product separated out as a white solid, which was filtered, washed and dried (10.9 g, 88%). M.p.=169-172° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.09 (d, J=8.8 HZ, 1H), 6.9-7.9 (br. s, 3H), 3.83 (d, J=13.6 Hz, 2H), 3.63 (m, 1H), 2.88 (m, 2H), 1.80 (m, 2H), 1.40 (s, 9H), 1.25 (m, 2H); LCMS: 243 [M+H]; calc. for C11H22N4O2.1.06HCl.0.2H2O: C, 46.39; H, 8.31; N, 19.68. Found C, 46.43; H, 8.31; N, 20.68.
Reaction SMILES: OCCCN1C=C(C2C=CC(NC3C(C(F)(F)F)=CN=C(NC4C=CC(CP(=O)(OCC)OCC)=CC=4OC)N=3)=C3C=2CN(C)C3=O)C=N1.[NH2:50][C:51]1[C:52]([C:66]([NH:68][CH3:69])=[O:67])=[N:53][C:54]([C:57]2[CH:58]=[N:59][N:60]([CH2:62][CH2:63][CH2:64][OH:65])[CH:61]=2)=[CH:55][CH:56]=1.C(OP1(=O)CC2C=CC(=CC=2)NC2=NC(=C(C(F)(F)F)C=N2)NC2C=CC(=NC=2C(NC)=O)C2=CN(N=C2)CCCCO1)C.Cl[C:115]1[C:120]([C:121]([F:124])([F:123])[F:122])=[CH:119][N:118]=[C:117]([NH:125][C:126]2[CH:140]=[CH:139][C:129]([CH2:130][P:131](=[O:138])([O:135][CH2:136][CH3:137])[O:132][CH2:133][CH3:134])=[CH:128][C:127]=2[CH3:141])[N:116]=1>>[OH:65][CH2:64][CH2:63][CH2:62][N:60]1[CH:61]=[C:57]([C:54]2[N:53]=[C:52]([C:66](=[O:67])[NH:68][CH3:69])[C:51]([NH:50][C:119]3[C:120]([C:121]([F:124])([F:122])[F:123])=[CH:115][N:116]=[C:117]([NH:125][C:126]4[CH:140]=[CH:139][C:129]([CH2:130][P:131](=[O:138])([O:135][CH2:136][CH3:137])[O:132][CH2:133][CH3:134])=[CH:128][C:127]=4[CH3:141])[N:118]=3)=[CH:56][CH:55]=2)[CH:58]=[N:59]1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(C)c1)OCC
Reactant: CNC(=O)c1nc(-c2cnn(CCCO)c2)ccc1N
Agent: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Agent: CCOP1(=O)Cc2ccc(cc2)Nc2ncc(C(F)(F)F)c(n2)Nc2ccc(nc2C(=O)NC)-c2cnn(c2)CCCCO1
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)nc3C(=O)NC)n2)c(C)c1)OCC
Yield: 66 %

Procedure:
Prepared analogously to Compound 1B replacing Compound 1C with Compound 6C and Compound 1 E with diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methylbenzyl)phosphonate (Compound 33C, 339 mg, 774 μmol) to afford 345 mg of the title compound (66%). 1H NMR (400 MHz, CD3OD) δ 8.90 (br. s., 1H), 8.49 (s, 1H), 8.31 (d, J=10.1 Hz, 2H), 7.63 (d, J=9.1 Hz, 1H), 7.35-7.39 (m, 1H), 7.33 (s, 1H), 7.24-7.31 (m, 1H), 4.32 (t, J=7.0 Hz, 2H), 4.11 (quin, J=7.3 Hz, 4H), 3.56-3.61 (m, 2H), 3.33 (d, J=21.0 Hz, 2H), 3.00 (s, 3H), 2.28 (s, 3H), 2.12 (quin, J=6.5 Hz, 2H), 1.24-1.30 (m, 6H). MS (ESI): m/z=677.21 [M+H]+. UPLC: tR=1.42 min (UPLC-TOF: polar—3 min).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1.C(Cl)(=O)C(Cl)=O.CS(C)=O.C(N(CC)CC)C>ClCCl>[F:1][C:2]([F:12])([F:13])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1
Reactant: OCc1ccc(OC(F)(F)F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=Cc1ccc(OC(F)(F)F)cc1

Procedure:
The above alcohol was oxidised using the conditions of Swern (oxalyl chloride, 2.05 ml; dimethyl sulphoxide, 3.33 ml and triethylamine, 14.8 ml) in dichloromethane to give 4-trifluoromethoxy benzaldehyde (4 g). NMR 1H: 10.04(2H,s), 7.98(2H,d), 7.35(2H,d).