Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[C:12]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH2:27][CH2:28][CH2:29][N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][CH:15]=2)=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([NH2:36])=[CH:8]2.CCN(CC)CC.[CH2:44]([N:46]=[C:47]=[O:48])[CH3:45]>>[CH2:44]([NH:46][C:47]([NH:36][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:12]([O:13][C:14]3[C:23]4[C:18](=[CH:19][C:20]([O:26][CH2:27][CH2:28][CH2:29][N:30]5[CH2:31][CH2:32][O:33][CH2:34][CH2:35]5)=[C:21]([O:24][CH3:25])[CH:22]=4)[N:17]=[CH:16][CH:15]=3)[C:3]=2[F:2])[CH:8]=1)=[O:48])[CH3:45]
Reactant: CCN=C=O
Reactant: COc1cc2c(Oc3ccc4cc(N)ccc4c3F)ccnc2cc1OCCCN1CCOCC1
Agent: Cl
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1ccc2c(F)c(Oc3ccnc4cc(OCCCN5CCOCC5)c(OC)cc34)ccc2c1

Procedure:
5-Fluoro-6-[6-methoxy-7-(3-morpholin-4-ylpropoxy)(4-quinolyloxy)]-2-naphthylamine (Example 9, Step b, 47.7 mg, 0.1 mmol) was reacted with Et3N (55 mg, 0.5 mmol, Aldrich) and ethylisocyanate (35.5 mg, 0.5 mmol, Aldrich) under the conditions of Example 110 to give the title compound as a white solid. M.p. 193.5-196.4° C. MS (ESI, pos. ion) m/z: 549.6 (M+1), 547.4 (M−1). Calc'd for C30H33FN4O5−548.24.
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:11]([NH:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NC1CCc2ccccc21
Reactant: O=C(Cl)c1ccccc1
Product: O=C(NC1CCc2ccccc21)c1ccccc1

Procedure:
The title compound was prepared in 77% from (rac)-1-aminoindan (1.0 g, 7.5 mmole) and benzoyl chloride (2.1 g, 15 mmole), under the Schotten-Bauman conditions, according to J. Chem. Soc. 71, 251 (1897) and J. Org. Chem. 27, 4465 (1962), m.p.: 140-2° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[O:20]=[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]1[C:27]1[O:31][C:30]([C:32](O)=[O:33])=[CH:29][CH:28]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:32]([C:30]1[O:31][C:27]([N:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]2=[O:20])=[CH:28][CH:29]=1)=[O:33]
Reactant: O=C(O)c1ccc(-n2ccccc2=O)o1
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1ccc(-n2ccccc2=O)o1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 5-(2-oxo-2H-pyridin-1-yl)-furan-2-carboxylic acid. MS: 447.2 (M+H).
Reaction SMILES: [I-:1].[Na+].Cl[C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[CH2:10][N:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][C:5]=12>C(#N)C>[I:1][C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[CH2:10][N:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][C:5]=12
Reactant: CCOC(=O)N1Cc2nccc(Cl)c2C1
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)N1Cc2nccc(I)c2C1

Procedure:
Sodium iodide (3.93 g, 26.2 mmol) and Ex 11-Step 1 product, hydrochloride salt (step 1, 2.30 g, 8.74 mmol) in acetonitrile (20 mL) were refluxed for 3 days. The reaction mixture was cooled, concentrated and partitioned between CH2Cl2 and saturated aqueous sodium bicarbonate. The phases were separated and the aqueous phase was re-extracted twice with CH2Cl2 (total volume 750 mL). The solution was passed through a plug of silica gel (0.5″) layered with celite (0.5″) using 1:1 EtOAc/CH2Cl2 for elution to yield 1.98 g (71%) of Ex 11-Step 2 product as a brown solid: 1H NMR shows a ˜1:1 mixture of rotamers (400 MHz, CDCl3) δ 8.08-8.11 (overlapping doublets, 1H total), 7.61 (br d, J=5.3, 1H), 4.89/4.84 (br singlets, 2H total), 4.68/4.64 (br singlets, 2H total), 4.23-4.29 (overlapping quartets, 2H total), 1.32-1.37 (overlapping triplets, 3H total).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[CH:7][CH2:8][C@H:9]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([OH:13])=[O:12])[CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[O:1]1[CH2:2][CH2:3][CH:4]([CH2:7][CH2:8][C@H:9]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([OH:13])=[O:12])[CH2:5][CH2:6]1
Reactant: CC(C)C[C@@H](C(=O)O)[C@H](CC=C1CCOCC1)C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@@H](C(=O)O)[C@H](CCC1CCOCC1)C(=O)OC(C)(C)C
Yield: 82.9 %

Procedure:
A solution of 0.397 g of 4-tert-butyl hydrogen 3(S)-[(tetrahydro-2H-pyran-4-ylidene)ethyl]-2(R)-isobutylsuccinate in 10 ml of methanol was shaken in a hydrogen atmosphere in the presence of 0.196 g of 10% palladium on charcoal catalyst until no further uptake of hydrogen was observed. The catalyst was filtered off and the filtrate was evaporated. There was obtained 0.331 g of 4-tert-butyl hydrogen 3(S)-[(tetrahydro-2H-pyran-4-yl)ethyl]-2(R)-isobutylsuccinate in the form of a colourless gum.
Reaction SMILES: [C:1]([C:3]([CH3:10])([CH2:7][CH2:8][CH3:9])[C:4]([OH:6])=[O:5])#[N:2].P(Cl)(Cl)(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+].[CH2:22](O)[CH3:23]>>[C:1]([C:3]([CH3:10])([CH2:7][CH2:8][CH3:9])[C:4]([O:6][CH2:22][CH3:23])=[O:5])#[N:2]
Reactant: CCO
Reactant: CCCC(C)(C#N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: CCCC(C)(C#N)C(=O)OCC
Yield: 90 %

Procedure:
0.30 g (2.1 mM) of (-)-2-cyano-2-methylpentanoic acid was dissolved in 3 ml of dry ethanol. To the mixture under stirring, 0.49 g (3.2 mM) of phosphorus oxychloride was added dropwise. After the reaction for 3 hours at 80° C., 6 ml of 1N-sodium carbonate aqueous solution was added, followed by extraction with diethyl ether. The resultant ether solution was dried on anhydrous sodium sulfate, followed by distilling-off of the solvent and distillation to obtain 0.32 g (1.9 mM) of (-)-ethyl 2-cyano-2-methylpentanoate. Yield:90%, b.p.:110° C./22 mmHg, [α]D -3.0 degrees, [α]435 -4.5 degrees, (c1, methanol)
Reaction SMILES: [Na].[N:2]#[C:3][NH2:4].[C:5]([NH:7][C:8](=[N:11][CH2:12][CH2:13][S:14][CH2:15][C:16]1[N:17]=[CH:18][NH:19][C:20]=1[CH3:21])SC)#[N:6]>C(O)C>[C:3]([NH:4][C:8]([NH:7][C:5]#[N:6])=[N:11][CH2:12][CH2:13][S:14][CH2:15][C:16]1[N:17]=[CH:18][NH:19][C:20]=1[CH3:21])#[N:2]
Reactant: N#CN
Reactant: CSC(=NCCSCc1nc[nH]c1C)NC#N
Agent: [Na]
Solvent: CCO
Product: Cc1[nH]cnc1CSCCN=C(NC#N)NC#N
Yield: 49.2 %

Procedure:
To a solution of sodium metal (1.01 g) in ethanol (120 ml) were added cyanamide (18.5 g) and N-cyano-S-methyl-N'-[2-(5-methylimidazol-4-ylmethylthio)ethyl]isothiourea (10.76 g). The resulting mixture was heated under reflux for 1.5 hrs. After concentration under a reduced pressure, the residue was added to cold water (50 ml) and acidified (pH 4.5) with 10% HCl and cooled for 1 hr. in an ice bath. The precipitate was filtered, washed with water and dried. The resulting crude product (7.43 g) was recrystallized from C2H5OH-H2O (1:1) to give N,N'-dicyano-N"-[2-(5-methylimidazol-4-ylmethylthio)ethyl]guanidine (5.17 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([CH:11]=1)=[C:9]([CH2:12][CH3:13])[CH:8]=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6]2=[O:19].[CH3:20][CH:21]1[CH2:26][NH:25][CH2:24][CH2:23][NH:22]1>N1C=CC=CC=1>[CH2:12]([C:9]1[CH:8]=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6](=[O:19])[N:5]2[C:10]=1[CH:11]=[C:2]([N:25]1[CH2:24][CH2:23][NH:22][CH:21]([CH3:20])[CH2:26]1)[CH:3]=[CH:4]2)[CH3:13]
Reactant: CC1CNCCN1
Reactant: CCOC(=O)c1cc(CC)c2cc(Cl)ccn2c1=O
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(CC)c2cc(N3CCNC(C)C3)ccn2c1=O
Temperature: 65 °C
Yield: 100.5 %

Procedure:
Ethyl 8-chloro-1-ethyl-4H-quinolizin-4-one-3-carboxylate (558 mg, 2.0 mmol), the product of Step 3 of Example 62, was dissolved in 10 mL of dry pyridine under a nitrogen atmosphere. To the resultant solution was added 600 mg (6.0 mmol) of 2-methylpiperazine and the stirred reaction mixture was heated at 65° C. for 3 hours. The reaction mixture was allowed to cool to ambient temperature and then concentrated in vacuo in order to remove all of the pyridine. The residue was dissolved in 60 mL of methylene chloride and the methylene chloride solution was washed with 60 mL of water. The aqueous layer was extracted with 2×60 mL of methylene chloride and the combined methylene chloride solutions were dried over anhydrous sodium sulfate, filtered and concentrated and dried in vacuo to afford 690 mg of the title compound. The product was carried on to the next step without purification.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH:3]=[C:4]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15])[CH:5]=O.[N+:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])([O-:20])=[O:19]>C(OC(=O)C)(=O)C>[CH3:25][O:24][C:22](=[O:23])[C:21]([N+:18]([O-:20])=[O:19])=[CH:5][C:4]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15])=[CH:3][N:2]([CH3:17])[CH3:1]
Reactant: COC(=O)C[N+](=O)[O-]
Reactant: Cc1ccc(C(C=O)=CN(C)C)c([N+](=O)[O-])c1
Solvent: CC(=O)OC(C)=O
Product: COC(=O)C(=CC(=CN(C)C)c1ccc(C)cc1[N+](=O)[O-])[N+](=O)[O-]
Yield: 77.2 %

Procedure:
A mixture of 67.5 g (0.29 mol) of the compound of Example 15 and 34.3 g (0.29 mol) of methyl nitroacetate in 540 ml of acetic anhydride was heated at 60° for 2 hours. The product was worked up and recrystallized from benzene-DMF (3:1) affording 75.1 g (78%) of product as red orange crystals, m.p. 213°-215°.
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:5][CH:4]=1)=O.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[CH3:25][C:22]1[CH:23]=[CH:24][C:19](/[N:18]=[CH:1]/[C:3]2[CH:17]=[CH:16][C:6]([O:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:5][CH:4]=2)=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(C=O)cc1
Reactant: Cc1ccc(N)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(/N=C/c2ccc(OCC(=O)OC(C)(C)C)cc2)cc1

Procedure:
tert-Butyl (4-formylphenoxy)acetate (5.0 g, 21.2 mmol) was dissolved in dry toluene (100 mL) and p-toluidine (2.27 g, 21.2 mmol) was added. The mixture was refluxed in a Dean-Stark apparatus for 18 hours, cooled and concentrated under reduced pressure. Heptane was added and the mixture was concentrated under reduced pressure. This afforded the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][N:6]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:31])[C@@H:13]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[C:22]([Cl:30])[CH:21]=2)[CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[N:7]1.CN1CC[O:39][CH2:38][CH2:37]1.C(Cl)(=O)C>C(Cl)Cl>[C:38]([NH:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][N:6]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:31])[C@@H:13]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[C:22]([Cl:30])[CH:21]=2)[CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[N:7]1)(=[O:39])[CH3:37]
Reactant: CN1CCOCC1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(Cc3cccc(N)c3)n2)cc1Cl
Solvent: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)Nc1cccc(Cn2ccc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.9 %

Procedure:
N-[1-(3-Amino-benzyl)-1H-pyrazol-3-yl]-2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (prepared in Example 58, 110 mg, 0.22 mmol) was dissolved in methylene chloride (2 mL) and N-methyl-morpholine (26 μL, 0.24 mmol) was added. Acetyl chloride (16 μL, 0.22 mmol) was added and the reaction stirred at 25° C. for 30 min. The reaction was concentrated in vacuo to give a beige foam. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 0% ethyl acetate/methylene chloride to 20% ethyl acetate/methylene chloride) afforded N-[1-(3-acetylamino-benzyl)-1H-pyrazol-3-yl]-2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (68 mg, 57%) as a white powder: ESI-LRMS m/e calcd for C27H31ClN4O4S [M+] 542.18, found 543.17 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.03-1.23 (m, 2H, CH2), 1.41-2.00 (m, 8H, 4×CH2), 2.15 (s, 3H, NCH3), 2.16-2.27 (m, 1H, CH), 3.25 (s, 3H, SO2CH3), 3.55 (t, J=7.5 Hz, 1H, CH), 5.09 (s, 2H, NCH2), 6.69 (d, J=2.3 Hz, 1H, Ar), 6.87 (d, Jo=7.5 Hz, 1H, Ar), 7.21-7.28 (m, 2H, NH and Ar), 7.28-7.33 (m, 2H, Ar), 7.35-7.41 (m, 1H, Ar), 7.44 (dd, Jo=8.1, Jm=1.3 Hz. 1H, Ar), 7.58 (d, Jm=1.3 Hz, 1H, Ar), 7.90-8.20 (m, 2H, Ar and NH).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](Cl)=[O:28]>C(Cl)Cl>[C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:27]([C:23]2[O:22][CH:26]=[CH:25][CH:24]=2)=[O:28])[CH2:9]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(CNc2ccccc2)C1
Reactant: O=C(Cl)c1ccco1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(CN(C(=O)c2ccco2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.9 %

Procedure:
To a stirred suspension of N-(1-Boc-piperidin-3-ylmethyl)-aniline 4 (61.0 mg, 0.21 mmol) and piperidinomethyl polystyrene resin (60 mg) in 0.6 mL of dry CH2Cl2 was added 2-furoyl chloride (95%, 35.1 mg, 1.2 eq.) at room temperature. After being shaken at room temperature for 4 hours, the reaction mixture was passed through an aminopropyl NH2 cartridge and washed with CH2Cl2. Removal of CH2Cl2 afforded furan-2-carboxylic acid N-(1-Boc-piperidin-3-ylmethyl)-N-phenyl amide 13 (75 mg, 93%). LRMS 285 (M-100)+.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:11][C:10]2[C:5](=[N:6][C:7]([C:12]3[CH:13]=[N:14][N:15]4[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][C:16]=34)=[N:8][CH:9]=2)[N:4]1[C@H:23]1[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]1.Cl[C:30]([O:32][CH3:33])=[O:31].CCN(C(C)C)C(C)C>CN(C=O)C>[C:21]([C:18]1[CH:19]=[CH:20][N:15]2[N:14]=[CH:13][C:12]([C:7]3[N:6]=[C:5]4[C:10]([NH:11][C:3](=[O:2])[N:4]4[C@H:23]4[CH2:28][CH2:27][CH2:26][N:25]([C:30]([O:32][CH3:33])=[O:31])[CH2:24]4)=[CH:9][N:8]=3)=[C:16]2[CH:17]=1)#[N:22]
Reactant: COC(=O)Cl
Reactant: N#Cc1ccn2ncc(-c3ncc4[nH]c(=O)n([C@H]5CCCNC5)c4n3)c2c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N1CCC[C@H](n2c(=O)[nH]c3cnc(-c4cnn5ccc(C#N)cc45)nc32)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.1 %

Procedure:
To a solution of example 6 (200 mg, 0.26 mmol) in DMF (2.6 mL), methyl chloroformate (27 mg, 0.28 mmol) and DIPEA (0.068 mL, 0.39 mmol) were added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was evaporated under reduced pressure, dissolved in CH2Cl2, and washed thrice with saturated NaHCO3 aqueous solution. The combined organic phases were dried over MgSO4 and concentrated to dryness. The crude residue was chromatographed on a silica gel flash system (ISCO Combiflash) using CH2Cl2/MeOH mixtures of increasing polarity as eluent to afford 36 mg of the desired product (32% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH2:15]([O:17][C:18](=[O:30])[CH2:19][O:20][C:21](OC1C=CC=CC=1)=[O:22])[CH3:16]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:21]([O:20][CH2:19][C:18]([O:17][CH2:15][CH3:16])=[O:30])=[O:22])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)COC(=O)Oc1ccccc1
Reactant: Brc1ccc(OC2CCNCC2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)COC(=O)N1CCC(Oc2ccc(Br)cc2)CC1
Temperature: 50 °C
Yield: 99.1 %

Procedure:
2.7 g (7.58 mmol) of 4-[(4-bromophenyl)-oxy]piperidine, prepared in Step 4.2., and 1.70 g (7.6 mmol) of ethyl{[(phenyloxy)carbonyl]oxy}acetate, prepared in accordance with Example 1.1, are mixed in 40 ml of toluene and the solution is heated at 50° C. for 20 hours. After cooling, it is evaporated to dryness and the product is purified by chromatography on silica gel, eluting with a 40/60 mixture of ethyl acetate and cyclohexane. The eluate is subsequently triturated in diisopropyl ether, to give 2.9 g of product in powder form.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:16](=[O:21])C(F)(F)F)=[CH:7][N:8]2[CH2:11][C:12]([NH:14][CH3:15])=[O:13])=[CH:4][CH:3]=1.C[Si](C)(C)[O-:24].[Na+]>ClCCCl>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:16]([OH:21])=[O:24])=[CH:7][N:8]2[CH2:11][C:12](=[O:13])[NH:14][CH3:15])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)[O-]
Reactant: CNC(=O)Cn1cc(C(=O)C(F)(F)F)c2ccc(Cl)cc21
Agent: [Na+]
Solvent: ClCCCl
Product: CNC(=O)Cn1cc(C(=O)O)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2-[6-Chloro-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-N-methyl-acetamide was suspended in DCE and treated with (2.2 eq.) of sodium trimethylsilanolate. After shaking at room temperature for 20 min, the mixture was concentrated in vacuo and purified by prep. HPLC to give the title compound.
Reaction SMILES: [C:1]([CH2:4][C@H:5]1[CH2:16][CH2:15][C:14]2[S:13][C:12]3[N:11]=[CH:10][N:9]=[C:8]([O:17][CH:18]4[CH2:23][CH2:22][CH:21]([N:24](C)[C:25](=O)OC(C)(C)C)[CH2:20][CH2:19]4)[C:7]=3[C:6]1=2)(=[O:3])[NH2:2].[ClH:33]>C(Cl)Cl>[ClH:33].[CH3:25][NH:24][CH:21]1[CH2:22][CH2:23][CH:18]([O:17][C:8]2[C:7]3[C:6]4[C@@H:5]([CH2:4][C:1]([NH2:2])=[O:3])[CH2:16][CH2:15][C:14]=4[S:13][C:12]=3[N:11]=[CH:10][N:9]=2)[CH2:19][CH2:20]1
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(N)=O)CC4)CC1
Agent: Cl
Solvent: ClCCl
Product: CNC1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(N)=O)CC4)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl N-(4-[[(3R)-3-(carbamoylmethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (524 mg, 1.14 mmol, 1.00 equiv) in DCM (6 mL) was added 6 M aqueous hydrochloric acid (1 mL) at 0° C. and the resulting solution was stirred for 2 h at room temperature. After concentrated under reduced pressure, the desired 2-[(3R)-12-[[4-(methylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]acetamide hydrochloride (451 mg, crude) was obtained as a light yellow solid.
Reaction SMILES: FC1C=CC(CCN2CCC([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=4)[CH:16]=[CH:15]3)CC2)=CC=1.O>FC(F)(F)C(O)=O>[CH3:24][O:23][C:20]1[CH:21]=[C:22]2[C:17]([CH2:16][CH2:15][NH:14]2)=[CH:18][CH:19]=1
Reactant: COc1ccc2ccn(C3CCN(CCc4ccc(F)cc4)CC3)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1ccc2c(c1)NCC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
A 1 M solution (0.18 ml) of a borane/tetrahydrofuran complex was added dropwise at 0° C. into a solution of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-methoxyindole (24 mg) in trifluoroacetic acid (1 ml) over 2 min followed by stirring at 0° C. for 30 min. Af ter the completion of the reaction, water (0.1 ml) was added thereto and the resulting reaction solution was concentrated under reduced pressure. The resulting residue was dissolved in a 2 N aqueous solution of sodium hydroxide and stirred at room temperature for 10 min. The mixture was extracted with methylene chloride. The organic layer was separated and dried over magnesium sulfate. After concentrating the solvent under reduced pressure, the resulting residue was purified by preparative TLC to give 1-[1-(4-fluorophenethyl)piperidin-4-yl)]-6-methoxyindoline (10 mg) (yield: 35%).
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])=[CH:8][CH:7]=1)=O.[OH-].[K+]>CC(O)C>[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])=[CH:10][CH:11]=1
Reactant: O=C(Nc1ccc(C#CCCCCO)cc1)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: Nc1ccc(C#CCCCCO)cc1

Procedure:
A solution of Intermediate 39 (8.5 mmol) in IPA (20 mL) was added to a 100° C. solution of potassium hydroxide (1.4 g, 26 mmol) in IPA (150 mL). The mixture was henceforth heated to reflux for 3.5 hours before being concentrated to drying under reduced pressure. The residue was partitioned between water and dichloromethane. The aqueous phase was extracted three times with dichloromethane. The combined extracts were concentrated to dryness under reduced pressure, and the resulting residue was purified via automated flash silica gel chromatography, using a 25 g Silicycle SiliSep flash column (hexanes/ethyl acetate). Concentration of the desired fractions under reduced pressure provided the title compound as a pale blond oil. ES/MS calcd. for C12H16NO+: 190.1. Found m/z=190.2 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:15][CH2:14][C@H:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([N:11]2[CH2:15][CH2:14][C@H:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])[CH2:12]2)=[CH:3][C:2]=1[Br:1]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccc([N+](=O)[O-])c(Br)c2)C1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccc(N)c(Br)c2)C1
Temperature: 25 °C
Yield: 99.3 %

Procedure:
A solution of (S)-tert-butyl 1-(3-bromo-4-nitrophenyl)pyrrolidin-3-ylcarbamate (2.5 g, 6.5 mmol), ammonium chloride (380 mg, 7.1 mmol), and iron (1.8 g, 32 mmol) in ethanol (20 mL) and water (10 mL) was heated to reflux for 1 h. The reaction mixture was cooled to room temperature and filtered through diatomaceous earth. The filtrate was concentrated to afford the desired product (2.3 g, >99%) as a blue solid: ESI MS m/z 357 [C15H22BrN3O2+H]+.
Reaction SMILES: [OH-].[Na+].[NH:3]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([C:16]([O:18]CC)=[O:17])=[CH:10]2)[C:4]([CH3:6])=[O:5]>CO>[NH:3]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([C:16]([OH:18])=[O:17])=[CH:10]2)[C:4]([CH3:6])=[O:5]
Reactant: CCOC(=O)c1cc2cc(NC(C)=O)ccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)Nc1ccc2[nH]c(C(=O)O)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
3N NaOH (2 mL) was added to a solution of 3 (250 mg, 1.02 mmol) in methanol (7 mL) and the reaction mixture was stirred overnight at room temperature. The reaction mixture was evaporated and water (5 mL) was added. The solution was neutralized to pH 2 using 20% HCl and the precipitate was filtered and washed with water. 4 was obtained as a grey powder (158 mg, 71% yield), mp: 260° C. (dec). 1H NMR (DMSO-d6, ppm): 11.62 (s, 1 H, NH), 9.77 (s, 1 H, NH), 7.98-7.97 (d, 1 H, J=1.4 Hz, Ar--H), 7.36-7.28 (m, 2 H, Ar--H), 7.02 (d, 1 H, J=1.5 Hz, Ar--H), 2.03 (s, 3 H, CH3CO), Anal. (C11H10N2O3 0.6H2O), C, H, N.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:14](=O)[NH:13][CH:12]=[N:11][C:10]=2[CH:9]1[CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:40]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([Cl:40])=[N:13][CH:12]=[N:11][C:10]=2[CH:9]1[CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC1c2nc[nH]c(=O)c2CCN1C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Product: CC1c2ncnc(Cl)c2CCN1C(=O)OC(C)(C)C

Procedure:
A combination of 8-methyl-4-oxo-4,5,6,8-tetrahydro-3H-pyrido[3,4-d]pyrimidine-7-carboxylic acid tert-butyl ester (374 mg, 1.41 mmol), triphenylphosphine (739 mg, 2.82 mmol) and carbon tetrachloride (409 uL, 4.23 mmol) and 1,2-DCE (10 mL) are heated at 70° C. for 6 h. The solution is then concentrated in vacuo and the residue separated via FCC (5-60% EtOAc/heptane). MS (ESI) m/z 284.2 (M+H).