Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([NH:15][CH:16]=[O:17])=[CH:10][C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([O:28][CH2:29][CH2:30]OS(C2C=CC(C)=CC=2)(=O)=O)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([O:28][CH2:29][CH2:30][O:1][C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[C:11](=[CH:10][C:9]([NH:15][CH:16]=[O:17])=[CH:8][CH:7]=4)[NH:12][C:13]=3[CH:14]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: O=CNc1ccc2c(c1)[nH]c1cc(O)ccc12
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc3c(c2)[nH]c2cc(NC=O)ccc23)cc1

Procedure:
Compound 2-(7-formamido-9H-carbazol-2-yloxy)ethyl 4-methylbenzenesulfonate (AD-CB-012P-WZ02039) was prepared using the same procedure for the preparation of AD-CB-012S-WZ01185) from N-(7-hydroxy-9H-carbazol-2-yl)formamide (100 mg) and ethane-1,2-diyl bis(4-methylbenzenesulfonate) (325 mg). (white solid, 22 mg, 12%). For the major rotomer: 1H NMR (400 MHz, acetone-d6) δ 10.19 (s, 1H), 9.31 (s, 1H), 8.38 (d, J=1.6 Hz, 1H), 8.11 (d, J=2.0 Hz, 1H), 7.90-7.81 (m, 4H), 7.45 (d, J=8.4 Hz, 2H), 7.19 (dd, J=8.4, 2.0 Hz, 1H), 6.95 (d, J=2.0 Hz, 1H), 6.69 (dd, J=8.4, 2.0 Hz, 1H), 4.43-4.41 (m, 2H), 4.29-4.27 (m, 2H); MS (ESI) m/z 425 (M+H+).
Reaction SMILES: [N:1]1([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]3[CH:18]=[N:19][C:20]([C:21]([OH:23])=[O:22])=[C:10]3[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:24]1(O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(P(=O)(OCC)OCC)#N.C(=O)(O)[O-].[Na+]>ClCCl.C(N(CC)CC)C>[N:1]1([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]3[CH:18]=[N:19][C:20]([C:21]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:22])=[C:10]3[CH2:9]2)=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1ncn2c1CN(C(=O)N1CCCC1)c1ccccc1-2
Reactant: Oc1ccccc1
Agent: CCOP(=O)(C#N)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Oc1ccccc1)c1ncn2c1CN(C(=O)N1CCCC1)c1ccccc1-2

Procedure:
To a mixture of 4,5-dihydro-5-[(pyrrolidino)carbonyl]imidizo[1,5-a]quinoxaline-3-carboxylic acid (I, EXAMPLE 323, 0.543 g), 0.245 g of phenol, 0.48 ml of triethylamine, and 6 ml of dichloromethane are added 0.42 ml of diethyl cyanophosphonate. After stirring for 1 hr an additional 0.11 g of phenol are added. When the reaction had stirred another 2.5 hr an additional 0.11 g of phenol and 0.26 ml of diethyl cyanophosphonate are added. The reaction is stored ovemight in the refrigerator and then stirred with 1 ml of aqueous sodium bicarbonate for about 30 min. The mixture is then partitioned between dichloromethane and aqueous sodium bicarbonate. The organic layers are dried over sodium sulfate, concentrated, and the residue chromatographed on silica gel (300 ml) eluting with methanol/methylene chloride (2/98), the appropriate fractions are pooled and concentrated to give the title compound, which is crystallized from dichloromethane/hexane, mp 196.5°-199°; MS (m/z) at 388; IR (mineral oil) 1648, 1199, 1723, 1502, 1410 cm-1 ; 1H NMR (CDCl3) 1.81, 3.31, 5.09, 7.15-7.33, 7.42, 7.55, 8.11 δ.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([NH:13][CH:14]2[CH2:17]C[CH2:15]2)[C:5]([C:6](OCC)=[O:7])=[CH:4][N:3]=1.O.[NH2:19][NH2:20]>C(O)C>[Cl:1][C:2]1[CH:12]=[C:11]([NH:13][CH:14]([CH3:17])[CH3:15])[C:5]([C:6]([NH:19][NH2:20])=[O:7])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cnc(Cl)cc1NC1CCC1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)Nc1cc(Cl)ncc1C(=O)NN
Temperature: 80 °C

Procedure:
To a stirred solution of ethyl 6-chloro-4-(isopropylamino)nicotinate (2) (3 g, 12.39 mmol) in ethanol (10 mL), hydrazine hydrate (3 mL) was added and refluxed at 80° C. for 3 h. The reaction mixture was cooled and concentrated to obtain crude compound. The residue obtained was triturated with diethyl ether and hexane and filtered to get solid, 6-chloro-4-(isopropylamino)nicotinohydrazide (10). LC/MS: Acquity BEH C18 2.1×50 mm, 1.8 micron; Solvent A=0.1% TFA in water; Solvent B=0.1% TFA in ACN; gradient 0-100% B over 2 min; retention time: 0.58 min; LCMS (ES-API), m/z 229.6 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH2:10][O:11][CH2:12][CH2:13]O)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[NH:33]1[CH2:38][CH2:37][CH2:36][C@@H:35]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:34]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O>[CH2:42]([O:41][C:39]([C@@H:35]1[CH2:36][CH2:37][CH2:38][N:33]([CH2:13][CH2:12][O:11][CH2:10][CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:34]1)=[O:40])[CH3:43]
Reactant: CCOC(=O)[C@@H]1CCCNC1
Reactant: OCCOCC=C(c1ccccc1)c1cccc(Cl)c1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1CCCN(CCOCC=C(c2ccccc2)c2cccc(Cl)c2)C1
Temperature: 5 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
A mixture of 2-(3-(3-chlorophenyl)-3-phenyl-2-propen-1-yloxy)ethanol (52.2 g, 0.18 mol) and triethylamine (45.7 g, 0.45 mol) in dry toluene (200 ml) kept under a nitrogen atmosphere was cooled to 5° C. and a solution of methanesulphonyl chloride (41.4 g, 0.36 mol) in dry toluene (200 ml) was added dropwise keeping the temperature below 10° C. When addition was complete the reaction mixture was stirred for 1 h at 5° C. Water was added (250 ml) and the mixture was stirred at room temperature for 10 minutes. The phases were separated and the aqueous phase was extracted with a small portion of toluene. The combined organic extracts were washed with brine and dried over sodium sulphate. The mixture was filtered and the filtrate was reduced in vacuo to approximately 500 ml. Ethyl (R)-3-piperidinecarboxylate (56.8 g, 0.36 mol) and potassium carbonate (49.9 g, 0.36 mol) were added and the mixture was heated at reflux temperature for 7 days. The cooled reaction mixture was poured into water (200 ml) and extracted with ethyl acetate (2×200 ml). The combined organic extracts were washed with a sodium citrate buffer solution (pH 5) and then extracted with a 34% aqueous tartaric acid solution (3×100 ml). The combined acidic aqueous extracts were poured into a mixture of ice water (3 1) and ethyl acetate (400 ml). Sodium hydroxide pellets (27.2 g) was added until pH was measured at ca. 4 and the phases were separated. The organic phase was washed with a 5% sodium bicarbonate solution (3×150 ml) and dried over sodium sulphate. The solvent was evaporated in vacuo to give 57.5 g (74%) of (R)-N-(2-(3-(3-chlorophenyl)-3-phenyl-2-propen-1-yloxy)ethyl)-3-piperidinecarboxylic acid ethyl ester as an oil. TLC: rf=0.45 (SiO2 ; dichloromethane/methanol/acetic acid=20:2:1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][C:22]1[CH:37]=[CH:36][C:25]([C:26](OCC2C=CC=CC=2)=[O:27])=[CH:24][CH:23]=1)[C@H:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[NH:39][C:40](=[NH:52])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51]>>[F:19][C:17]([F:18])([F:20])[C:14]1[CH:15]=[CH:16][C:11]([C@@H:9]([N:8]([CH2:21][C:22]2[CH:37]=[CH:36][C:25]([C:26]3[O:27][N:52]=[C:40]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[N:39]=3)=[CH:24][CH:23]=2)[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH3:10])=[CH:12][CH:13]=1
Reactant: C[C@@H](c1ccc(C(F)(F)F)cc1)N(Cc1ccc(C(=O)OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Reactant: CCCCCCCCCCCC(=N)NO
Product: CCCCCCCCCCCc1noc(-c2ccc(CN(C(=O)OC(C)(C)C)[C@@H](C)c3ccc(C(F)(F)F)cc3)cc2)n1
Yield: 85 %

Procedure:
The same procedure as employed in the preparation of Example 258 (step a and b) but using benzyl 4-[((tert-butoxycarbonyl){(1S)-1-[4-(trifluoromethyl)phenyl]ethyl}amino)methyl]benzoate and N-hydroxydodecanimidamide gave the title compound as a colorless oil (85%). 1H NMR (CDCl3, 300 MHz) δ 8.02 (d, J=8.1 Hz, 2H), 7.53 (d, J=8.1 Hz, 2H), 7.34-7.17 (m, 4H), 4.47 (br s, 1H), 4.35 (br s, 1H), 2.75 (t, J=7.5 Hz, 2H), 1.83-1.69 (m, 2H), 1.60-1.14 (m, 29H), 0.90 (t, J=7.0 Hz, 311). HPLC (Condition A), Rt: 8.02 min (HPLC purity: 95.7%).
Reaction SMILES: [NH:1]1[CH:5]([C:6]([O:8][CH:9]([CH3:11])[CH3:10])=[O:7])[CH2:4][CH2:3][C:2]1=[O:12].[C:13](Cl)(=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:13]([N:1]1[CH:5]([C:6]([O:8][CH:9]([CH3:10])[CH3:11])=[O:7])[CH2:4][CH2:3][C:2]1=[O:12])(=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: CC(C)OC(=O)C1CCC(=O)N1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCC(=O)N1C(=O)CCC1C(=O)OC(C)C
Yield: 17.9 %

Procedure:
10.0 g of isopropyl 2-pyrrolidone-5-carboxylate was dissolved in 58.4 g of toluene, and 13.04 g of lauroyl chloride was added thereto. Further, 6.03 g of triethylamine was dropwise added, and reacted under reflux for 2 hours. Toluene was concentrated under reduced pressure, then the reaction mixture was purified through silica gel column chromatography (hexane/ethyl acetate=5/1 to 3/1) to obtain 3.69 g of isopropyl N-lauroyl-2-pyrrolidone-5-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1.ClS([N:16]=[C:17]=O)(=O)=O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:17]#[N:16])=[CH:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2cc[nH]c2c1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CN(C)C=O
Product: COc1ccc2c(C#N)c[nH]c2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
A solution of 6-methoxy-1H-indole (100.0 g, 679.0 mmol) in DMF (560 mL) was cooled to −78° C. and treated with chlorosulfonyl isocyanate (71 mL, 815 mmol). After the addition the reaction mixture was stirred for 1 hour. The dark solution was poured into ice water (2 L) and the light brown solid was collected by filtration, washed with additional water and dried to afford 6-methoxy-1H-indole-3-carbonitrile as a light brown solid (104.8 g, 90%).
Reaction SMILES: ClC1[N:11]2[CH:12]=[N:13][N:14]=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[OH-].[K+].Cl>>[NH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=1[C:10]1[NH:14][N:13]=[CH:12][N:11]=1
Reactant: Clc1nc2ccccc2c2nncn12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: Nc1ccccc1-c1ncn[nH]1

Procedure:
To a flask containing 40 gms. of 5-chloro-1,2,4-triazolo[4,3-c]quinazoline is added 800 ml. of a 10% KOH solution and the resulting mixture heated to reflux. A gentle reflux is maintained overnight after which time the mixture is neutralized to pH 7.0 with cooling and stirring by adding dropwise a 1:1 HCl solution and the resulting precipitate filtered off. The aqueous layer is washed 3 or 4 times with methylene chloride, dried and evaporated in vacuo to dryness. The residue is recrystallized from benzene/ether to obtain 5-(2-aminophenyl)-s-triazole, m.p. 145°-148° C.
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH:4][CH3:5].[C:6]1(=[CH:9][C:10](=[O:12])[CH3:11])[CH2:8][CH2:7]1.[OH-].[Na+]>CCOCC.[Cl-].[Cl-].[Zn+2]>[CH3:5][C@@H:4]1[CH:3]=[CH:2][CH2:1][C:6]2([CH2:8][CH2:7]2)[C@@H:9]1[C:10](=[O:12])[CH3:11]
Reactant: CC(=O)C=C1CC1
Reactant: C=CC=CC
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CC(=O)[C@@H]1[C@H](C)C=CCC12CC2
Reaction time: 24 h
Yield: 37.1 %

Procedure:
At 20° C. under N2, a suspension of anhydrous ZnCl2 (0.31 g, 2.29 mmol) in Et2O (1.5 ml) was treated with 1,3-pentadiene (65% pure, 3.34 ml, 22.9 mmol) then with a solution of 1-cyclopropylidenepropan-2-one (0.44 g, 4.58 mmol) in Et2O (1,5 ml). After 24 h stirring, the resulting mixture treated with 6N aq. NaOH (3.1 ml) and the aqueous phase extracted three time with Et2O. The combined organic phases were washed twice with a saturated aqueous solution of NH4Cl, once with a saturated aqueous solution of NaCl, dried (MgSO4), and concentrated. FC (100 g SiO2, pentane/Et2O 10:0.5) of the crude product (1.12 g) gave rel-(4R,5R)-1-(5-methylspiro[2.5]oct-6-en-4-yl)ethanone (279 mg, 36%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[C:5]2[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[CH2:22]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)[C:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[C:6]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCCCCc1c(-c2ccccc2)[nH]c2ccc(Br)cc12
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Product: CCCCCc1c(-c2ccccc2)n(Cc2ccccc2)c2ccc(Br)cc12

Procedure:
The desired product was prepared using a procedure similar to step 2 of example 3. Thus, 5-bromo-3-pentyl-2-phenyl-1H-indole (1.711 g, 5 mmol) was reacted with k-t-butoxide (0.589 g, 5.25 mmol) and benzyl bromide (0.901 g, 5.25 mmol) in DMF (15 ml) to give the product (1.285 g, 2.972 mmol, 59%) as a white solid, mp 98-101° C. 1H DMSO-d6) δ 0.75 (t, J=7.0 Hz, 3H), 1.11-1.19 (m, 4H), 1.46-1.52 (m, 2H), 2.60 (t, J=7.5 Hz, 2H), 5.25 (s, 2H), 6.77-6.78 (m, 2H), 7.13-7.22 (m, 4H), 7.32 (d, J=8.7 Hz, 1H), 7.34-7.36 (m, 2H), 7.42-7.49 (m, 3H), 7.75 (d, J=1.8 Hz, 1H); [ESI(+)], m/z 432/434 (M+H)+.
Reaction SMILES: [O:1]([CH2:9][C@H:10]1[C:15](=O)[CH2:14][O:13][C@@H:12]([CH3:17])[O:11]1)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[C:18]([CH:23]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:20][CH2:21][CH3:22])=[O:19]>O1CCCC1>[O:1]([CH2:9][C@H:10]1[C:15](=[CH:23][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][O:13][C@@H:12]([CH3:17])[O:11]1)[Si:2]([C:5]([CH3:6])([CH3:7])[CH3:8])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[C@@H]1OCC(=O)[C@H](CO[Si](C)(C)C(C)(C)C)O1
Solvent: C1CCOC1
Product: CCOC(=O)C=C1CO[C@@H](C)O[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 65.9 %

Procedure:
A mixture of (2R,4S)-4-t-butyldimethylsiloxymethyl -2-methyl-1,3-dioxan-5-one (2.50 g) and carboethoxymethylenetriphenylphosphorane (4.00 g) in tetrahydrofuran (25 ml) was stirred at room temperature for 24 hours and the solvent was evaporated in vacuo. The residue was chromatographed on a silica gel column (50 g) with a mixture of n-hexane and ethyl acetate (10:1) as an eluent to give (2R,4R)-4-t-butyldimethylsiloxymethyl-5-ethoxycarbonylmethylene-2-methyl-1,3-dioxane (2.09 g) as an oil.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Br:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH2:33][CH2:34][CH2:35][O:36][CH3:37])[CH:28]=[C:27]2[CH2:38][NH:39][CH:40]1[CH2:42][CH2:41]1.[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][O:53][C@@H:52]([C:56](O)=[O:57])[CH2:51]1)=[O:49])([CH3:46])([CH3:45])[CH3:44]>CN(C)C=O.C(OCC)(=O)C>[Br:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH2:33][CH2:34][CH2:35][O:36][CH3:37])[CH:28]=[C:27]2[CH2:38][N:39]([CH:40]1[CH2:42][CH2:41]1)[C:56]([C@@H:52]1[O:53][CH2:54][CH2:55][N:50]([C:48]([O:47][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:49])[CH2:51]1)=[O:57]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](C(=O)O)C1
Reactant: COCCCn1cc(CNC2CC2)c2cc(Br)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCCn1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CCO2)C2CC2)c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Hydroxybenzotriazole (162 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (288 mg) were added successively to a solution of N-{[5-bromo-1-(3-methoxypropyl)indol-3-yl]methyl}cyclopropanamine (a compound of Reference Example 127(2), 405 mg) and (2R)-4-(tert-butoxycarbonyl)morpholin-2-carboxylic acid (231 mg) in N,N-dimethylformamide (12.5 ml) and the mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with water, a saturated aqueous solution of sodium bicarbonate and saturated brine successively and dried over magnesium sulfate. The solvent was evaporated in vacuo and the resulted residue was purified with a silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=50/50 to 10/90) to give tert-butyl(2R)-2-{[{[5-bromo-1-(3-methoxypropyl)indol-3-yl]methyl}(cyclopropyl)amino]carbonyl}morpholin-4-carboxylate (581 mg) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1.[CH3:11][C:12]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:15]2[CH2:16][CH2:17][C:12]([CH3:11])([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:13][CH2:14]2)=[S:10])=[CH:4][CH:3]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: CCOC(=O)C1(C)CCNCC1
Solvent: ClCCl
Product: CCOC(=O)C1(C)CCN(C(=S)Nc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-chlorophenyl isothiocyanate (2.36 g, 13.98 mmol), and ethyl 4-methylpiperidine-4-carboxylate (U.S. 2002/0086887, example 532C) (2.17 g, 12.71 mmol) in dichloromethane (50 mL) was stirred at room temperature for 30 minutes. The mixture was partitioned between dichloromethane and brine, and the layers were separated. The organic phase was dried over MgSO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane:ethyl acetate (100:0 to 90:10) to provide the title compound as a white solid, 3.46 g.
Reaction SMILES: [C:1]([C:4]1[N:8]([CH3:9])[N:7]=[C:6]([O:10][CH2:11][C:12]([O:14]CC)=[O:13])[CH:5]=1)(O)=O.CCN=C=NCCCN(C)C.[CH2:28]([N:31]1[C:38]([NH2:39])=[C:37]([NH2:40])[C:35](=[O:36])[N:34]([CH2:41][CH2:42][CH3:43])[C:32]1=[O:33])[CH2:29][CH3:30]>CO>[CH2:41]([N:34]1[C:35](=[O:36])[C:37]2[NH:40][C:1]([C:4]3[N:8]([CH3:9])[N:7]=[C:6]([O:10][CH2:11][C:12]([OH:14])=[O:13])[CH:5]=3)=[N:39][C:38]=2[N:31]([CH2:28][CH2:29][CH3:30])[C:32]1=[O:33])[CH2:42][CH3:43]
Reactant: CCOC(=O)COc1cc(C(=O)O)n(C)n1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Agent: CCN=C=NCCCN(C)C
Solvent: CO
Product: CCCn1c(=O)c2[nH]c(-c3cc(OCC(=O)O)nn3C)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl (5-carboxy-1-methypyrazol-3-yl)oxyacetate (0.5 mmol) and EDCI (0.5 mmol) in methanol (20 mL) was added a solution of 1,3-dipropyl-5,6-diaminouracil (0.5 mmol), dissolved in methanol (20 mL). The mixture was stirred at room temperature for two hours, the solvent was then removed in vacuo, water added, and the solid that formed was collected by filtration and washed with additional cold water. The intermediate amide was heated in 20 mL of 2.5 N NaOH at 70° C. for 30 minutes to afford the desired 2-[5-(1,3-dipropyl-xanthin-8-yl)-1-methylpyrazol-3-vloxy]acetic acid.
Reaction SMILES: CC[O:3][C:4]([C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:10]=1[C:17]([NH2:19])=[O:18])=[O:7])=O.[NH3:20]>C(O)C>[C:17]([C:10]1[C:11]([O:15][CH3:16])=[CH:12][CH:13]=[CH:14][C:9]=1[NH:8][C:6]([C:4]([NH2:20])=[O:3])=[O:7])(=[O:18])[NH2:19]
Reactant: CCOC(=O)C(=O)Nc1cccc(OC)c1C(N)=O
Reactant: N
Solvent: CCO
Product: COc1cccc(NC(=O)C(N)=O)c1C(N)=O
Reaction time: 2 h

Procedure:
2'-Carbamoyl-3'-methoxyoxanilic acid ethyl ester (5.0 g, 0.0188 mole) is added to 50 ml of ethanol saturated with ammonia at 0°-5° C., and the mixture is stirred in an ice-bath for 2 hours, then filtered. The cake is washed with ethanol, giving 1.41 g of the title compound, m.p. 252°-255° C., after crystallization from water.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][C:6]=1[CH2:14][O:15][CH3:16])([CH3:3])[CH3:2].[NH2:17][C:18](=[N:37]O)[C:19]1[CH:20]=[CH:21][C:22]([F:36])=[C:23]([CH:35]=1)[CH2:24][N:25]([CH3:34])[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]>>[F:36][C:22]1[CH:21]=[CH:20][C:19]([C:18]2[N:17]=[C:9]([C:8]3[CH:12]=[CH:13][C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[C:6]([CH2:14][O:15][CH3:16])[CH:7]=3)[O:11][N:37]=2)=[CH:35][C:23]=1[CH2:24][N:25]([CH3:34])[CH2:26][C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28]
Reactant: CN(CC(=O)OC(C)(C)C)Cc1cc(C(N)=NO)ccc1F
Reactant: COCc1cc(C(=O)O)ccc1OC(C)C
Product: COCc1cc(-c2nc(-c3ccc(F)c(CN(C)CC(=O)OC(C)(C)C)c3)no2)ccc1OC(C)C

Procedure:
The title compound was prepared following procedure described for example 141, step 1, but starting from Intermediate 56 (134.55 mg; 0.60 mmol) and Intermediate 60 (177.47 mg; 0.57 mmol), the crude mixture was purified by flash chromatography (c-hex/(DCM/EtOAc 1:1) gradient from 1:0 to 1:1) to afford the title compound as a colorless oil. 1H NMR (CDCl3) δ 8.24-8.20 (m, 2H), 8.11-8.04 (m, 2H), 7.17 (t, J=9.0 Hz, 1H), 6.98 (d, J=8.8 Hz, 1H), 4.70 (quint., J=6.1 Hz, 1H), 4.54 (s, 2H), 3.89 (s, 2H), 3.50 (s, 3H), 3.27 (s, 2H), 2.46 (s, 3H), 1.51 (s, 9H), 1.40 (d, J=6.0 Hz, 6H). LC/MS (Method B): 500.4 (M+H)+. HPLC (Method A) Rt 4.44 min (Purity: 97.6%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[C:11]1(=O)[O:16][C:14](=[O:15])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:8]2[C:14](=[O:15])[C:13]3[C:12](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:11]2=[O:16])=[CH:5][CH:4]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(CN2C(=O)c3ccccc3C2=O)cc1

Procedure:
4-Methoxybenzylamine (4.9 g, 36 mmol) was added to phthalic anhydride (4.5 g, 30 mmol) in 15 mL glacial acetic acid. The reaction was stirred at 100° C. for 4 h as water was collected with a Dean-Stark trap. Solvent was evaporated and the product was obtained by crystallization from ethanol (7 g, 87%).
Reaction SMILES: C(N(CC)CC)C.CI.C1O[C:13]2([CH2:22][CH2:21][C@H:20]3[C@:15]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=4)([CH2:16][CH2:17][N:18]([CH3:23])[CH2:19]3)[CH2:14]2)[O:12]C1.O1CCOCC1>CO>[CH3:31][O:30][C:26]1[CH:25]=[C:24]([C@@:15]23[CH2:14][C:13](=[O:12])[CH2:22][CH2:21][C@@H:20]2[CH2:19][N:18]([CH3:23])[CH2:17][CH2:16]3)[CH:29]=[CH:28][CH:27]=1
Reactant: COc1cccc([C@]23CCN(C)C[C@H]2CCC2(C3)OCCO2)c1
Solvent: CCN(CC)CC
Solvent: CI
Solvent: CO
Product: COc1cccc([C@]23CCN(C)C[C@H]2CCC(=O)C3)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
25.93 g (0.1 mol) of octahydro-4a-(3-methoxyphenyl)-cis-6(2H)-isoquinolinone (see Example 1), 100 ml of benzene, 11.2 ml (0.2 mol) of ethylene glycol and 8.1 ml (125 mmol) of methanesulphonic acid are boiled for 3 hours in a water separator. The mixture is cooled, made basic with aqueous ammonia and extracted with methylene chloride. The organic phase is evaporated to dryness to yield octahydro-4a-(3-methoxyphenyl)-cis-6(2H)-isoquinolinone ethylene ketal. The ketal is dissolved in 50 ml of absolute methanol, cooled to 0° C., and 13.91 ml (0.1 mol) of triethylamine and 7.46 ml (0.12 mol) of methyl iodide are added thereto. The mixture is kept at 22° for 1 hour. The mixture, containing octahydro-4a-(3-methoxyphenyl)-2-methyl-cis-6(2H)-isoquinolinone ethylene ketal, is mixed with 20 ml of dioxane and concentrated by evaporation. 100 ml of dioxane and 100 ml of 2 N aqueous hydrochloric acid are added to the residual oil. The resultant mixture is stirred for 2 hours at 40°, made basic with aqueous ammonia, and extracted with toluene. The extracts are concentrated by evaporation to yield the title compound as an oil, which is crystallized as the hydrogen fumarate from ethanol.