Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5])C.[NH:17]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)[NH2:18].CCCCCCC>C(O)CCC>[O:5]=[C:4]1[C:6]2=[CH:7][NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:15]2=[N:18][N:17]1[C:19]1[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:26][CH:27]=1
Reactant: CCOC(=O)c1cnc2ccccc2c1Cl
Reactant: NNc1ccc(C(=O)O)cc1
Solvent: CCCCCCC
Solvent: CCCCO
Product: O=C(O)c1ccc(-n2nc3c4ccccc4[nH]cc-3c2=O)cc1
Temperature: 60 °C
Yield: 8.5 %

Procedure:
A solution of 4-chloro-quinoline-3-carboxylic acid ethyl ester (11.8 mg, 0.5 mmol) and 4-hydrazino-benzoic acid (7.6 mg, 0.5 mmol) in n-butanol (0.5 mL) was stirred at 115° C. over night in a sealed tube. After cooling to 50-70° C., heptane (1.0 mL) was added and the product was allowed to crystallize upon further cooling to room temperature. The solvent was removed and the product was washed with heptane and dried under vacuum to yield 4-(3-oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl)-benzoic acid (13 mg). 1H NMR (400 MHz, DMSO-d6) δ 12.9 (1H, s), 8.77 (1H, d), 8.38 (2H, d), 8.25 (1H, d), 8.03 (2H, d), 7.65-7.77 (2H, m), 7.58 (1H, t).
Reaction SMILES: Br[CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:3]=O.[NH2:12][C:13]([NH2:15])=[O:14].C1(CCC=O)C=CC=CC=1>C(O)C>[CH2:5]([C:2]1[O:14][C:13]([NH2:15])=[N:12][CH:3]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NC(N)=O
Reactant: O=CC(Br)Cc1ccccc1
Agent: O=CCCc1ccccc1
Solvent: CCO
Product: Nc1ncc(Cc2ccccc2)o1

Procedure:
A mixture of 2-bromo-3-phenylpropionaldehyde (14.2 g, crude from above) and urea (7.2 g, 0.12 mol) were heated to reflux for 15 hours in 200 mL of ethanol. The solvent was evaporated to dryness and the residue was diluted with dichloromethane (250 mL) and then washed with sodium hydroxide (10% aqueous solution, 100 mL) and water (50 mL). The organic layer was extracted three times with hydrochloric acid (5% aqueous solution, 250 mL). The combined aqueous layers were adjusted to between pH 9 to 10 with a 10% aqueous solution of sodium hydroxide and then extracted three times with dichloromethane (300 mL). The organic layer was dried over sodium sulfate, evaporated to dryness, and purified by silica gel column chromatography to give a pale yellow solid. (1.6 g, 9.2 mmol, 9.2% from 3-phenyl-propionaldehyde). ESI-MS m/z calc. 174.1. found 175.1 1H NMR (CDCl3) δ 7.32-7.22 (m, 5H), 6.39 (s, 1H), 4.72 (bs, 2H), 3.84 (s, 2H).
Reaction SMILES: [CH3:1][OH:2].[H-].[Na+].Cl[C:6]1[N:7]([CH2:32][CH2:33][CH3:34])[C:8](=[O:31])[C:9]2[NH:10][C:11]([C:15]3[CH:16]=[N:17][N:18]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[CH:19]=3)=[N:12][C:13]=2[N:14]=1>C(OCC)(=O)C>[CH3:1][O:2][C:6]1[N:7]([CH2:32][CH2:33][CH3:34])[C:8](=[O:31])[C:9]2[NH:10][C:11]([C:15]3[CH:16]=[N:17][N:18]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[CH:19]=3)=[N:12][C:13]=2[N:14]=1
Reactant: CO
Reactant: CCCn1c(Cl)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCCn1c(OC)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Temperature: 80 °C
Yield: 53 %

Procedure:
To the mixture of methanol (2 ml) and NaH (45 mg, 1.1 mmol), 2-Chloro-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one (50 mg, 0.11 mmol) was added and refluxed for 2 hours at 80° C. Reaction mixture was cooled, diluted with ethyl acetate (10 ml) and quenched with saturated NH4Cl solution. The organic layer was separated and washed with brine (2×10 ml), dried over Na2SO4, filtered and evaporated. The residue obtained was purified by preparative HPLC to obtain pure 2-Methoxy-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one (26 mg, 53%) as an off white solid.
Reaction SMILES: [C:1]([NH:22][C@H:23]([C:30]([OH:32])=[O:31])[CH2:24][O:25][P:26]([OH:29])([OH:28])=[O:27])(=[O:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH:8]=[CH:9][CH2:10][CH:11]=[CH:12][CH2:13][CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[C:33](O)(=O)[CH2:34]C/C=C\CC=CCC=CCC=CCC=CCC=CCC>>[C:1]([NH:22][C@H:23]([C:30]([OH:32])=[O:31])[CH2:24][O:25][P:26]([OH:29])([OH:28])=[O:27])(=[O:21])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6][CH:7]=[CH:8][CH2:9][CH:10]=[CH:11][CH2:12][CH:13]=[CH:14][CH2:15][CH:16]=[CH:17][CH2:18][CH:19]=[CH:20][CH2:33][CH3:34]
Reactant: CCC=CCC=CCC=CCC=CCC=CC/C=C\CCC(=O)O
Reactant: CCCCCC=CCC=CCC=CC/C=C\CCCC(=O)N[C@@H](COP(=O)(O)O)C(=O)O
Product: CCC=CCC=CCC=CCC=CCC=CC/C=C\CCC(=O)N[C@@H](COP(=O)(O)O)C(=O)O

Procedure:
This compound was prepared as described above for (6) using 0.5 mmol (164 mg) of cis-4,7,10,13,16,19-docosahexaenoic acid; yield 91 mg (37%); Rhd f 0.05-0.10 (system B); 1H-NMR (CD3SOCD3, 200 MHz) δ0.9-1.0 (t, 3H, ω-CH3); 2.0-2.1 (t, 2H, CH2CO); 2.2-2.4 (m, 4H, 2CH2CH═CH); 2.7-2.9 (br s, 10H, 5HC═CHCH2CH═CH); 3.9-4.0 (br s, 2H, CH2OP); 4.3-4.4 (m, 1H, NHCHCO); 5.2-5.4 (br s, 12H, 6HC═CH); 8.2-8.4 (m, 3H, NH and 2POH)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](O)=[O:11])=[CH:4][CH:3]=1.B.O1CCCC1.CO>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1ccc(Cl)cc1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: OCCCc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 104 %

Procedure:
To a stirred solution of 3-(4-chlorophenyl)-propionic acid (10.0 g, 54.17 mmol) in tetrahydrofuran (100 ml) at −8° C. was added dropwise borane-tetrahydrofuran complex (100 ml, 1M in tetrahydrofuran, 100 mmol). The reaction mixture was cooled to 0° C. and methanol (100 ml) was added dropwise. The reaction mixture was warmed to room temperature, stirred for one hour and then concentrated in vacuo. The residue was treated with methanol (50 ml) and each time concentrated in vacuo twice to yield the title compound as an oil (9.61 g) which was characterized by IR spectral analysis and used without further purification.
Reaction SMILES: [C:1]1([OH:13])[CH:12]=[C:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH:5]=[C:3]([OH:4])[CH:2]=1.[CH3:14][N:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1.[ClH:22]>C(O)(=O)C>[ClH:22].[CH3:14][N:15]1[CH2:16][CH:17]=[C:18]([C:2]2[C:3]([OH:4])=[CH:5][C:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH:12][C:1]=2[OH:13])[CH2:19][CH2:20]1
Reactant: CN1CCC(=O)CC1
Reactant: CCCCCc1cc(O)cc(O)c1
Agent: Cl
Solvent: CC(=O)O
Product: CCCCCc1cc(O)c(C2=CCN(C)CC2)c(O)c1
Yield: 79 %

Procedure:
Olivetol (22.3 g) and N-methyl-4 -piperidone (14 g) were dissolved in 50 ml acetic acid and treated with HCl gas as described in Example VI giving 30.6 g (79%) product, m.p. 179°-180°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1.[ClH:12].Cl.[Cl:14][C:15]1[CH:32]=[CH:31][C:18]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][SH:30])[CH2:23][CH2:22]2)=[CH:17][CH:16]=1.C(N(CC)CC)C>C(Cl)Cl>[ClH:14].[ClH:12].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[SH:30][CH2:29][CH2:28][CH2:27][N:24]2[CH2:25][CH2:26][N:21]([CH2:20][CH2:19][C:18]3[CH:17]=[CH:16][C:15]([Cl:14])=[CH:32][CH:31]=3)[CH2:22][CH2:23]2)[OH:11])=[CH:7][CH:8]=1
Reactant: SCCCN1CCN(CCc2ccc(Cl)cc2)CC1
Reactant: COc1ccc(N=C=O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(NC(O)=[SH]CCCN2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Yield: 49.8 %

Procedure:
The procedure described in Example 2 was followed, using 1.7 g of 4-methoxyphenyl isocyanate, 4.0 g of 3-[4-(4-chlorophenethyl)piperazin-1-yl]propanethiol dihydrochloride, 1.1 g of triethylamine and 50 ml of methylene chloride, to give 1.4 g (25% of theory) of N-(4-methoxyphenyl)-S-{3-[4-(4-chlorophenethyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride as a white crystalline solid, M.p. 236°-238° C.
Reaction SMILES: [NH2:1][C:2]1[CH2:6][CH2:5][C@@H:4]([CH3:7])[C:3]=1[C:8]([O:10]CC)=O.C([O-])=O.[NH4+].[CH:17]([NH2:19])=O>>[CH3:7][C@H:4]1[C:3]2[C:8]([OH:10])=[N:19][CH:17]=[N:1][C:2]=2[CH2:6][CH2:5]1
Reactant: CCOC(=O)C1=C(N)CC[C@H]1C
Reactant: NC=O
Agent: O=C[O-]
Agent: [NH4+]
Product: C[C@@H]1CCc2ncnc(O)c21
Temperature: 150 °C
Reaction time: 17 h
Yield: 65 %

Procedure:
A solution containing (R)-ethyl 2-amino-5-methylcyclopent-1-enecarboxylate (161.61 g, 955.024 mmol) and ammonium formate (90.3298 g, 1432.54 mmol) in formamide (303.456 ml, 7640.19 mmol) was heated to an internal temperature of 150° C. and stirred for 17 hours. The reaction mixture was cooled, and transferred to a 2 L single neck flask. Then excess formamidine was removed by high vacuum distillation. Once formamidine stopped coming over, the remaining oil in the still pot was dissolved in DCM and washed with brine (3×200 mL). The combined aqueous washes were extracted with DCM. The combined organic extracts were dried (Na2SO4), filtered, and concentrated. The resulting brown oil was dissolved in minimal DCM, and this solution was added using a separatory funnel to a stirred solution of ether (ca. 5 vol of ether vs. DCM solution), causing some brown precipitate to form. This brown precipitate was removed by filtration through a medium frit funnel which was rinsed with ether and disposed. The filtrate was concentrated, the trituration from ether repeated two more times and then dried on high vacuum line to give (R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (93.225 g, 65.00% yield) as a brown-yellow pasty solid. LC/MS (APCI−) m/z 149.2.
Reaction SMILES: [OH-].[OH:2][C:3]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5](=[O:19])[C:4]=1[NH+:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1.[CH2:25]([N:27]([CH2:31][CH3:32])[C:28](Cl)=[O:29])[CH3:26].N#N.N12CCCN=C1CCCCC2>N1C=CC=CC=1.C(O)(=O)C.CN(C)C=O.C(N(CC)CC)C>[CH2:25]([N:27]([CH2:31][CH3:32])[C:28]([O:2][C:3]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5](=[O:19])[C:4]=1[N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:29])[CH3:26]
Reactant: CCN(CC)C(=O)Cl
Reactant: O=c1c([NH+]2CCCC2)c(O)c2cccnc2n1-c1ccccc1
Agent: N#N
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)Oc1c(N2CCCC2)c(=O)n(-c2ccccc2)c2ncccc12
Temperature: 80 °C

Procedure:
A mixture of 1-(1,2-dihydro-4-hydroxy-1-phenyl-2-oxo-1,8-naphthyridin-3-yl)-pyrrolidinium hydroxide, inner salt (3 g), triethylamine (1.88 g), and diethylcarbamoyl chloride (1.57 g) in dry pyridine (50 mL) was stirred overnight at room temperature in an N2 atmosphere. Some starting material remained so dimethylformamide (50 mL), 1,8-diazabicyclo[5.4.0]undec7-ene (DBU) (2.83 g), and diethylcarbamoyl chloride (1.57 g) were added and the mixture was heated at 80° C. for 0.5 hour. The reaction mixture was then poured over ice and the pH was adjusted to about 6 with acetic acid. The resulting solution was extracted three times with ethyl acetate. The organic extracts were combined, dried (Na2SO4), filtered and evaporated to a solid which was recrystallized from isopropanol to yield the desired product, 2.03 g (54%), m.p. 158°-160° C.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].C([O:6][C:7]([C:9]1[N:14]2[N:15]=[C:16]([NH:18][C:19]([NH:21][CH2:22][CH3:23])=[O:20])[N:17]=[C:13]2[CH:12]=[C:11]([Br:24])[CH:10]=1)=O)C.NC(N)=S>C(O)C>[CH2:1]([NH:3][C:7]([C:9]1[N:14]2[N:15]=[C:16]([NH:18][C:19]([NH:21][CH2:22][CH3:23])=[O:20])[N:17]=[C:13]2[CH:12]=[C:11]([Br:24])[CH:10]=1)=[O:6])[CH3:2]
Reactant: CCN
Reactant: CCNC(=O)Nc1nc2cc(Br)cc(C(=O)OCC)n2n1
Agent: NC(N)=S
Solvent: CCO
Product: CCNC(=O)Nc1nc2cc(Br)cc(C(=O)NCC)n2n1

Procedure:
Ethylamine (0.300 mL, 70% solution in water) and 7-bromo-2-(3-ethyl-ureido)-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid ethyl ester, prepared as in Example 6 (0.251 g, 0.705 mmol), was suspended in ethanol (3.00 mL) and shaken. After 20 hours the reaction was filtered and the filtrate washed with cold ethanol to afford 7-bromo-2-(3-ethyl-ureido)-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid ethylamide MS (APCI+): m/z 356.0 (M+H).
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7](CC2C=CC(OC)=CC=2)[C:6]2[CH:19]=[CH:20][CH:21]=[CH:22][C:5]=2[N:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:3]1=[O:29].[N+]([O-])([O-])=O.[NH4+]>C(#N)C.O>[NH2:1][CH:2]1[C:3](=[O:29])[N:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:5]2[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=2[NH:7][C:8]1=[O:9]
Reactant: COc1ccc(CN2C(=O)C(N)C(=O)N(c3ccccc3)c3ccccc32)cc1
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: NC1C(=O)Nc2ccccc2N(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a stirred solution of 3-amino-1-(4-methoxybenzyl)-5-phenyl-1,5-dihydrobenzo [b] [1,4] diazepine-2,4-dione (0.50 g) in acetonitrile/H2O (9:1, 12 ml) at ambient temperature was added cerric ammonium nitrate (1.84 g) portionwise over a ten minute period. The solution was stirred overnight at room temperature. The solution was concentrated in vacuo and the resultant solid partitioned between saturated aqueous potassium carbonate (40 ml) and ethanol (60 ml). The phases were separated and the aqueous phase extracted with ethanol (4×50 ml). The ethanol portions were combined, dried over sodium sulfate and concentrated in vacuo to a tan solid. This solid was extracted exhaustively with boiling CH2Cl2 (10×60 ml), the organics combined, dried over sodium sulfate, filtered and concentrated to give the title compound (0.30 g) as a tan solid. 1H (300 MHz, DMSO-d6): d 1.98 (br s, 2H), 4.08 (s, 1H), 6.86 (d, J=8.4 Hz, 1H), 7.11-7.46 (m, 8H), 10.78 (br s, 1H); 13C (75.429 MHz, DMSO-d6): d 56.98, 123.41, 126.22, 126.51, 127.34, 128.30, 128.89, 130.15, 132.29, 134.42, 142.36, 168.13, 169.39. MS (FAB): m/z=268.10 (MH+); TLC (CH2Cl2 /CH3OH,15:1): Rf =0.21
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([C:20]([OH:22])=O)=[CH:18][NH:17][C:14]4=[N:15][CH:16]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[NH2:43][C:44]1([CH3:56])[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45]1>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[CH3:56][C:44]1([NH:43][C:20]([C:19]2[C:13]3[C:14](=[N:15][CH:16]=[C:11]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=5)[NH:8][N:7]=4)[N:12]=3)[NH:17][CH:18]=2)=[O:22])[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45]1
Reactant: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)O)c4n3)n[nH]c2c1
Reactant: CC1(N)CCN(C(=O)OC(C)(C)C)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)NC5(C)CCN(C(=O)OC(C)(C)C)C5)c4n3)n[nH]c2c1
Reaction time: 16 h
Yield: 47 %

Procedure:
To a stirred solution of 2-(6-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.34 mmol), EDCI (123 mg, 0.64 mmol), DMAP (110 mg, 0.90 mmol) and DIEA (131 mg, 1.02 mmol) in 6 mL of DMF was added tert-butyl 3-amino-3-methylpyrrolidine-1-carboxylate (100 mg, 0.54 mmol) in one portion at room temperature, then the mixture was stirred for 16 hours. The reaction mixture was poured into 40 mL of water, extracted with ethyl acetate (150 mL). The organic phase was evaporated at 40° C. under reduced pressure and the residue was triturated with petroleum ether then decanted and dried to give crude tert-butyl 3-methyl-3-(2-(6-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamido)pyrrolidine-1-carboxylate (76 mg, 47.0%) as a yellow solid. MS: (M+H)+=476.2.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:26]=[CH:25][C:8]3[O:9][CH2:10][CH2:11][C:12]4[N:13]([N:14]=[C:15]([C:17]5[N:21]([CH:22]([CH3:24])[CH3:23])[N:20]=[CH:19][N:18]=5)[CH:16]=4)[C:7]=3[CH:6]=2)[CH2:2]1.Br[CH2:28][CH2:29][O:30]C1CCCCO1>>[CH:22]([N:21]1[C:17]([C:15]2[CH:16]=[C:12]3[N:13]([C:7]4[CH:6]=[C:5]([CH:3]5[CH2:2][N:1]([CH2:28][CH2:29][OH:30])[CH2:4]5)[CH:26]=[CH:25][C:8]=4[O:9][CH2:10][CH2:11]3)[N:14]=2)=[N:18][CH:19]=[N:20]1)([CH3:24])[CH3:23]
Reactant: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C3CNC3)ccc1OCC2
Reactant: BrCCOC1CCCCO1
Product: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C3CN(CCO)C3)ccc1OCC2

Procedure:
Following the procedures of Example 142, 9-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene 144 was reacted with 2-(2-bromoethoxy)-tetrahydropyran followed by acidic hydrolysis of the THP group to give 169 as a white solid, as illustrated in FIG. 13. 1H NMR (400 MHz, DMSO-d6): δ 8.03 (s, 1 H); 7.88 (d, J=2.22 Hz, 1 H); 7.42 (dd, J=8.35, 2.22 Hz, 1 H); 7.26 (d, J=8.32 Hz, 1 H); 6.89 (s, 1 H); 5.62-5.54 (m, 1 H); 4.83 (s, 1 H); 4.50 (t, J=6.03 Hz, 2 H); 4.06 (s, 2 H); 3.94 (t, J=8.52 Hz, 1 H); 3.70 (s, 2 H); 3.51 (s, 3 H); 3.18 (t, J=6.05 Hz, 2 H); 2.94 (s, 2 H); 1.49 (d, J=6.58 Hz, 6 H). LCMS: RT=6.01 min, M+H+=395
Reaction SMILES: [CH3:1][N:2]1[C:9](=[O:10])[CH2:8][C:6](=[O:7])[N:5]([CH3:11])[C:3]1=[O:4].[Cl:12][CH:13]([Cl:17])[C:14](O)=[O:15].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:12][CH:13]([Cl:17])[C:14]([CH:8]1[C:9](=[O:10])[N:2]([CH3:1])[C:3](=[O:4])[N:5]([CH3:11])[C:6]1=[O:7])=[O:15]
Reactant: CN1C(=O)CC(=O)N(C)C1=O
Reactant: O=C(O)C(Cl)Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CN1C(=O)C(C(=O)C(Cl)Cl)C(=O)N(C)C1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 63.2 %

Procedure:
A mixture of 1,3-dimethylbarbituric acid (5.00 g, 32.05 mmol), dichloroacetic acid (6.19 g, 48.03 mmol), 4-dimethylaminopyridine (1.95 g, 16.01 mmol) in dry CH2Cl2 (30 ml) was cooled to 0° C. and 1,3-dicyclohexylcarbodiimide (7.26 g, 35.22 mmol) added. The reaction mixture was stirred at room temperature overnight and filtered. The solid was washed with CH2Cl2 (150 ml) and the combined solution was washed with 2 N HCl solution (40 ml). The organic phase was dried over MgSO4 and evaporated. The residue was crystallised from MeOH giving 5-dichloroacetyl-1,3-dimethyl-2,4,6(1H,3H,5H)-pyrimidinetrione 7 (5.41 g, 63%).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[Cl-].[NH4+]>O.CCO.[Fe]>[CH3:1][S:2]([N:5]1[CH2:6][CH2:7][CH:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH2:9][CH2:10]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)N1CCC(Oc2ccc(N)cc2)CC1
Yield: 69.9 %

Procedure:
A mixture of 1-methanesulfonyl-4-(4-nitro-phenoxy)-piperidine (9.07 g, 30.2 mmol), iron powder (˜325 mesh, 5.05 g, 90.6 mmol), ammonium chloride solution (6.46 g, 120.8 mmol) in water (50 mL) and EtOH (IMS grade, 150 mL) was heated at reflux for 2 hours. The cooled mixture was filtered through Celite® washing with DCM and the organic solvent removed under vacuum. The remaining aqueous was diluted with water and extracted into DCM (3×). The combined extracts were dried over Na2SO4 and concentrated under vacuum. Purification by silica gel column chromatography (0-10% EtOAc in DCM) followed by trituration from Et2O afforded the title compound (5.71 g, 70%) as an off white solid. 1H NMR (300 MHz, DMSO) δ 6.70 (d, J=8.5 Hz, 2H), 6.50 (d, J=8.5 Hz, 2H), 4.65 (br s, 2H), 4.22 (m, 1H), 3.32 (m, 2H), 3.07 (m, 2H), 2.88 (s, 3H), 1.90 (m, 2H), 1.67 (m, 2H). LCMS (m/z, Method A) ES+ 271.0 [M+1]+.
Reaction SMILES: CC([N:5]([CH2:9][CH2:10][NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH:29]3[CH2:34][CH2:33][N:32]([C:35]4[O:39][N:38]=[C:37]([CH:40]([CH3:42])[CH3:41])[N:36]=4)[CH2:31][CH2:30]3)=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])C(=O)[O-])(C)C.[C:43]([OH:49])([C:45]([F:48])([F:47])[F:46])=[O:44]>C(Cl)Cl>[C:43]([OH:49])([C:45]([F:48])([F:47])[F:46])=[O:44].[F:46][C:45]([F:48])([F:47])[C:43]([OH:49])=[O:44].[NH2:5][CH2:9][CH2:10][NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH:29]3[CH2:30][CH2:31][N:32]([C:35]4[O:39][N:38]=[C:37]([CH:40]([CH3:42])[CH3:41])[N:36]=4)[CH2:33][CH2:34]3)=[CH:25][CH:26]=2)=[CH:17][CH:16]=1)(=[O:13])=[O:14]
Reactant: CC(C)c1noc(N2CCC(COc3ccc(-c4ccc(S(=O)(=O)NCCN(C(=O)[O-])C(C)(C)C)cc4)cc3)CC2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1noc(N2CCC(COc3ccc(-c4ccc(S(=O)(=O)NCCN)cc4)cc3)CC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
A mixture of 1,1-dimethylethyl{2-[({4′-[({1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl)oxy]-4-biphenylyl}sulfonyl)amino]ethyl}carbamate (Example 108, 160 mg, 0.27 mmol) and TFA (0.3 mL) in CH2Cl2 (3 mL) was stirred at ambient temperature for 1 h. The crude product was concentrated and purified by reverse-phase preparative HPLC using a CH3CN:H2O gradient (0.5:99.5 to 90:10) with 0.05% TFA as a modifier to give 123 mg (91%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.09 (bs, 2H), 7.86 (d, 2H, J=8.2 Hz), 7.60 (d, 2H, J=8.2 Hz), 7.46 (d, 2H, J=8.8 Hz), 7.33 (bs, 1H), 6.92 (d, 2H, J=8.8 Hz), 4.24-4.14 (m, 2H), 3.84 (d, 2H, J=6.2 Hz), 3.27 (bs, 4H), 3.14-3.04 (m, 2H), 2.94-2.81 (m, 1H), 2.10-2.00 (m, 1H), 1.98-1.88 (m, 2H), 1.51-1.37 (m, 2H), 1.27 (d, 6H, J=7.0 Hz); LRMS (ESI), m/z 500 (M+H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH3:15])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.C(Cl)Cl.[C:19](Cl)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl.C(N(CC)CC)C>CO.O.C(N(CC)CC)C>[C:19]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH3:15])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCOC(=O)C(=NOC)c1csc(N)n1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C(=NOC)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1

Procedure:
A mixture of 3.41 kg of the product of Step C., 17 liters of methylene chloride and 2.275 liters of triethylamine was stirred for 15 minutes and then 4.55 kg of trityl chloride were added at 20°-25° C. over one hour with stirring under nitrogen. The mixture was stirred for 20 hours at 20°-25° C. under nitrogen during which triethylamine hydrochloride crystallized and the mixture was washed with 10.2 liters of iced 0.5N hydrochloric acid and twice with 10.2 liters of iced demineralized water and the wash waters were extracted with 1.7 liters of methylene chloride. The combined organic extracts were dried and filtered and the filter was washed with 1.7 liters of methylene chloride. The filtrates were evaporated to dryness under reduced pressure below 50° C. to obtain 8.425 kg of raw product. The latter was dissolved at 20°-25° C. in 8.4 liters of methanol and the solution was stirred for an hour at 20°-25° C. after the addition of 2.8 liters of demineralized water to induce crystallization. The mixture was stirred for another hour and was vacuum filtered. The product was empasted twice with 1.7 liters of methanol containing 25% water and was dried at 40° C. to obtain 7.165 kg of the syn isomer of ethyl 2-(2-tritylamino-4-thiazolyl)-2-methoxyiminoacetate which was identical to the product of Example 3, Step B.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[CH2:5]2.[Se](=O)=[O:15]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[O:15]
Reactant: O=C1Cc2cc(Cl)ccc2C(=O)N1
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: O=C1NC(=O)c2ccc(Cl)cc2C1=O
Temperature: 25 °C
Yield: 26.9 %

Procedure:
Under argon, a mixture of 6-chloroisoquinoline-1,3(2H,4H)-dione (600 mg g, 3.0 mmol) and selenium dioxide (357 mg, 3.2 mmol) in abs. 1,4-dioxane (20 ml) was stirred at a temperature of 100° C. for 3 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Purification of the residue that remained by column chromatography (gradient ethyl acetate/n-heptane) gave 6-chloroisoquinoline-1,3,4(2H)-trione (169 mg, 22% of theory) in the form of a slightly yellowish solid. 1H-NMR (400 MHz, d6-DMSO δ, ppm) 12.02 (br. s, 1H, NH), 8.12 (d, 1H), 8.01-7.95 (m, 2H).