Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[N:21]1[C:30]2[C:25](=[C:26]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:38])[CH:27]=[C:28]([OH:31])[CH:29]=2)[CH2:24][NH:23][C:22]1=[O:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:60][CH2:61][N:62]1[CH2:67][CH2:66][CH2:65][CH2:64][CH2:63]1>O1CCCC1>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[N:21]1[C:30]2[C:25](=[C:26]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:38])[CH:27]=[C:28]([O:31][CH2:60][CH2:61][N:62]3[CH2:67][CH2:66][CH2:65][CH2:64][CH2:63]3)[CH:29]=2)[CH2:24][NH:23][C:22]1=[O:39]
Reactant: O=C1NCc2c(-c3ccccc3Cl)cc(O)cc2N1c1c(Cl)cccc1Cl
Reactant: OCCN1CCCCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1NCc2c(-c3ccccc3Cl)cc(OCCN3CCCCC3)cc2N1c1c(Cl)cccc1Cl
Temperature: 25 °C

Procedure:
Diethyl azodicarboxylate (50 μL, 0.32 mmol) was added dropwise to a solution of 1-(2,6dichlorophenyl)-5-(2-chlorophenyl)-7-hydroxy-3,4-dihydro-2(1H)-quinazolinone (30 mg, 0.07 mmol) INTERMEDIATE 49), triphenylphosphine (95 mg, 0.36 mmol) and 1-(2-hydroxyethyl)piperidine (55 mg, 0.43 mmol) in 1 mL tetrahydrofuran at 65° C. under an argon atmosphere. After 1 h the solution was cooled to RT and partitioned between saturated NaHCO3 (5 mL) and EtOAc (15 mL). The organic phase was separated, dried over Na2SO4, filtered and concentrated. The residue was purified by thin layer chromatography using EtOAc followed by CHCl3/MeOH/NH4OH (87/12/1) as the eluent to give 1-(2,6-dichlorophenyl)-5-(2-chlorophenyl)-7-[2-(1-piperidinyl)ethoxy]-3,4-dihydro-2(1H)-quinazolinone. 1H NMR(CDCl3, 500 MHz): δ 1.44 (m, 2H), 1.62 (m, 4H), 2.48 (m, 4H), 2.72 (m, 2H), 4.00 (t, 2H, J=6.0 Hz), 4.18 (d, 1H, J=14.0 Hz), 4.36 (d, 1H, J-14.0 Hz), 5.22 (s, 1H), 5.76 (d, 1H, J=1.8 Hz), 6.45 (d, 1H, J=2.0 Hz), 7.28-7.39 (m, 4H), 7.45-7.53 (m, 3H). MS(ES) 530 (M+H); LC 1: 2.28 min.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]([OH:20])=O)[CH2:14][CH2:13]1)[CH2:8][CH2:9][CH2:10][CH3:11].NC1C=CC([C:28]2[NH:29][C:30]3[CH:36]=[CH:35][C:34](N)=[CH:33][C:31]=3[N:32]=2)=CC=1>CN(C=O)C.N1C=CC=CC=1>[CH2:7]([C@H:12]1[CH2:13][CH2:14][C@H:15]([C:18]([C:28]2[NH:29][C:30]3[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=3[N:32]=2)=[O:20])[CH2:16][CH2:17]1)[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: Nc1ccc(-c2nc3cc(N)ccc3[nH]2)cc1
Reactant: CCCCC[C@H]1CC[C@H](C(=O)O)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCCCC[C@H]1CC[C@H](C(=O)c2nc3ccccc3[nH]2)CC1

Procedure:
Bis-trans-4-pentylcyclohexyl carbonyl benzimidazole was synthesized as follows: oxalyl chloride (1.07 ml, 2 M in CH2Cl2) was added to trans-4-pentylcyclohexyl carboxylic acid (0.424 g, 2.14 mmole) followed by one drop DMF. The mixture was allowed react at RT for 1 hour. To the above solution was added 2-(4-aminophenyl)-6-amino-benzimidazole (0.200 g, 0.89 mmole) in pyridine (2 ml). The
Reaction SMILES: C(O)(C(F)(F)F)=O.O[C:9]([C:12]1[CH:13]=[CH:14][C:15]2[C:19]([CH3:21])([CH3:20])[O:18][B:17]([OH:22])[C:16]=2[CH:23]=1)([CH3:11])[CH3:10].[N-:24]=[N+:25]=[N-:26].[Na+]>C(Cl)(Cl)Cl>[N:24]([C:9]([C:12]1[CH:13]=[CH:14][C:15]2[C:19]([CH3:21])([CH3:20])[O:18][B:17]([OH:22])[C:16]=2[CH:23]=1)([CH3:11])[CH3:10])=[N+:25]=[N-:26]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(O)c1ccc2c(c1)B(O)OC2(C)C
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(N=[N+]=[N-])c1ccc2c(c1)B(O)OC2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 102 %

Procedure:
A solution of TFA (200 μL, 2 mmol) in chloroform (3 mL) was added slowly to a mixture of 6-(2-hydroxypropan-2-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol (88 mg, 0.4 mmol) and sodium azide (80 mg, 1.2 mmol) in chloroform (7 mL) at −5° C. to 0° C. The cooling bath was removed and the mixture was stirred at rt overnight. Concentrated ammonium hydroxide was added until pH was basic (moist PH paper). DCM (50 mL) was added and the organic layer was washed with brine:water (1:1), dried over Na2SO4, filtered and concentrated to give the crude product 6-(2-azidopropan-2-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol (100 mg) as colorless oil. It was used without further purification in the next step.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]([NH:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH2:24][C:25]([O:27]CC)=[O:26])=[C:16]([N+:30]([O-:32])=[O:31])[CH:15]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O.CCO>[CH2:3]([O:10][C:11]([NH:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH2:24][C:25]([OH:27])=[O:26])=[C:16]([N+:30]([O-:32])=[O:31])[CH:15]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)Cc1c([N+](=O)[O-])cc(NC(=O)OCc2ccccc2)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)Cc1c([N+](=O)[O-])cc(NC(=O)OCc2ccccc2)c2ccccc12
Reaction time: 8 h
Yield: 88.5 %

Procedure:
A solution of NaOH (0.17 g, 4.31 mmol) in H2O (20 mL) was added to a suspension of ethyl [4-(N-benzyloxycarbonylamino)-2-nitronaphthalen-1-yl]acetate (0.8 g, 1.96 mmol) in EtOH (20 mL), and the mixture was heated to reflux for 2hr. EtOH was evaporated and washed with Et2O (10 mL). The aqueous layer was acidified (pH 1) with 6 M HCl. The resulting precipitate was filtered and left out overnight to provide [4-(N-benzyloxycarbonylamino)-2-nitronaphthalen-1-yl]acetic acid (0.66 g, 89%) as an orange solid. M.p. 170-172° C. (decomp.); 1H NMR (DMSO-d6, 500 MHz) δ 8.40 (d, 8.5, 1H), 8.13 (d, 9.0, 1H), 7.67 (m, 2H), 7.55 (m, 1H), 7.41 (d, 7.5, 2H), 7.32 (t, 7.0, 2H), 7.22 (t, 8.0, 1H), 6.71 (s, 1H), 4.55 (d, 5.5, 2H), 4.04 (s, 2H); ESMS m/z 337 (M−CO2+H+), 673 ((M−CO2)×2+H+); IR (nujol) 3405, 2652, 1696, 1590, 1515, 1461, 1439, 1377, 1333, 1249, 1120, 929, 832, 792, 752, 699 cm−1. FABMS (NBA) m/z 336 (M−CO2+).
Reaction SMILES: [F:1][C:2]1([F:9])[CH2:5][C:4]([CH2:7][OH:8])([CH3:6])[CH2:3]1.[CH3:10][S:11](Cl)(=[O:13])=[O:12]>C(Cl)Cl>[CH3:10][S:11]([O:8][CH2:7][C:4]1([CH3:6])[CH2:5][C:2]([F:9])([F:1])[CH2:3]1)(=[O:13])=[O:12]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(CO)CC(F)(F)C1
Solvent: ClCCl
Product: CC1(COS(C)(=O)=O)CC(F)(F)C1
Reaction time: 3 h
Yield: 63.5 %

Procedure:
To a solution of Intermediate 229A (100 mg, 0.735 mmol) and TEA (0.102 mL, 0.735 mmol) in DCM was added methanesulfonyl chloride (0.059 mL, 0.735 mmol) dropwise at 5° C. and the reaction mixture was stirred for 3 h. The reaction mass was diluted with DCM, washed with water and brine, dried over Na2SO4, filtered and the filtrate evaporated under reduced pressure. The crude product was purified by silica gel chromatography (12 g REDISEP® column, eluting with 30% EtOAc in petroleum ether). Fractions containing the product were combined and evaporated to afford the Intermediate 229B as a yellow oil (100 mg, 63.5%). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.27 (s, 2H), 3.01 (s, 3H), 2.55-2.69 (m, 2H), 2.06-2.37 (m, 2H), 1.15 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][OH:11])[C@H:6]([OH:12])[CH2:5]1.Cl[C:14]1[C:19]([CH3:20])=[N:18][CH:17]=[CH:16][N:15]=1.[O-2].[Ca+2]>C(Cl)Cl.CO>[CH3:20][C:19]1[C:14]([NH:1][CH2:2][CH2:3][N:4]2[CH2:9][CH2:8][C@H:7]([CH2:10][OH:11])[C@H:6]([OH:12])[CH2:5]2)=[N:15][CH:16]=[CH:17][N:18]=1
Reactant: NCCN1CC[C@H](CO)[C@H](O)C1
Reactant: Cc1nccnc1Cl
Agent: [Ca+2]
Agent: [O-2]
Solvent: CO
Solvent: ClCCl
Product: Cc1nccnc1NCCN1CC[C@H](CO)[C@H](O)C1
Temperature: 120 °C
Reaction time: 5 h
Yield: 23.5 %

Procedure:
A mixture of (±)-cis-1-(2-aminoethyl)-3-hydroxy-4-piperidinemethanol (0.064 mol), 2-chloro-3-methylpyrazine (0.068 mol) and calcium oxide (0.145 mol) was stirred for 5 hours at 120° C. The reaction mixture was cooled. The mixture was dissolved in CH2Cl2 /CH3OH and filtered over dicalite. The filtrate was evaporated and the residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /(CH3OH/NH3) 90/10). The desired fractions were collected and the solvent was evaporated. The oily residue was triturated in CH3CN. The precipitate was filtered off and dried, yielding 4 g (23.5%) of (±)-cis-1-[2-[(3-methyl-2-pyrazinyl)amino]ethyl]-3-hydroxy-4-piperidinemethanol (interm. 5a).
Reaction SMILES: N[C@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].N([O-])=O.[Na+].[BrH:14]>>[Br:14][C@@H:2]([C@@H:3]([CH3:4])[CH2:5][CH3:6])[C:7]([OH:9])=[O:8]
Reactant: Br
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Agent: O=N[O-]
Agent: [Na+]
Product: CC[C@H](C)[C@H](Br)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To a cooled (0° C.) solution of L-Isoleucine (66 g) dissolved in HBr (6N, 500 ml) was added dropwise a solution of sodium nitrite (35 g in 100 ml water). The reaction was stirred overnight at room temperature and then extracted with EtOAc (3×150 ml). The combined organic extracts washed with 10% sodium bisulfit solution, water, saturated brine, dried over MgSO4, filtered and concentrated. The product a yellowish oil (53.9 g) was obtained in 55% yield. (The product can be purified by distillation and crystallization from PE). (see FIG. 6)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([NH2:12])=[C:5]2[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20].[CH2:21](OC(OCC)OCC)C>>[F:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]=[CH:21][N:13]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[F:20])[C:5]=3[C:4]=2[CH:3]=1
Reactant: CCOC(OCC)OCC
Reactant: Nc1cnc2ccc(F)cc2c1Nc1ccccc1F
Product: Fc1ccc2ncc3ncn(-c4ccccc4F)c3c2c1

Procedure:
200 mg (0.74 mmol) 6-fluoro-N4-(2-fluoro-phenyl)-quinoline-3,4-diamine (Example 19e) in 8 ml triethylorthoformate are heated at 160° C. for 3 h. The cold solution is evaporated to dryness, and the residue is dissolved in hot ethyl acetate. By adding hexane to this solution, the title compound precipitates. The compound is filtered off and dried overnight at 60° C. (high vacuum). mp: 162-163° C.; MS: 282 (M*+1); HPLC: tret=7.26 min (Grad 1).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(O)C.[CH2:23]1[CH2:29][S:26](=[O:28])(=[O:27])[O:25][CH2:24]1>C(OCC)C>[CH2:16]([O:15][C:13]([C:12]1[CH:18]=[CH:19][C:9]([CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][N:4]([CH2:24][CH2:23][CH2:29][S:26]([OH:28])(=[O:27])=[O:25])[CH2:3][CH2:2]2)=[CH:10][CH:11]=1)=[O:14])[CH3:17]
Reactant: CCOC(=O)c1ccc(CCN2CCNCC2)cc1
Reactant: O=S1(=O)CCCO1
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)c1ccc(CCN2CCN(CCCS(=O)(=O)O)CC2)cc1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
To a solution of 10.25 g. (39 mmole) ethyl 4-[2-(piperazin-1-yl)-ethyl]-benzoate and 70 ml. anhydrous ethanol, there are added 4.76 g. (39 mmole) 1,3-propanesultone, followed by stirring at 20° C. After standing overnight, the ethanol is stripped off and the residue is treated with diethyl ether and ligroin. After suction filtration, it is recrystallised from ethanol to give 11.2 g. (75% of theory) of the desired compound; m.p. 235°-236° C.
Reaction SMILES: [BH4-].[Li+].C([O:5][C:6]([C:8]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]3[N:33]=[N:34][N:35]([C:37]([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[N:36]=3)=[CH:22][CH:21]=2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1)=O)C.O>O1CCCC1>[OH:5][CH2:6][C:8]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]3[N:33]=[N:34][N:35]([C:37]([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)[N:36]=3)=[CH:24][CH:25]=2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1
Reactant: CCOC(=O)c1cc(OCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c2ccccc2n1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cc(OCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c2ccccc2n1
Reaction time: 18 h
Yield: 65.5 %

Procedure:
Lithium borohydride (11 mg) was added to a solution of 2-ethoxycarbonyl-4-([2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl]methoxy)quinoline (346 mg) in tetrahydrofuran (4 ml) and the mixture stirred for 18 hours. Water (20 ml) was added to the mixture and a white solid precipitated. The solid was collected by filtration, dissolved in ethyl acetate and the solution dried (MgSO4). The solvent was removed by evaporation and the residue crystallised from ethyl acetate/hexane to give 2-hydroxymethy-4-([2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl]methoxy)quinoline (213 mg), as a white crystalline solid, m.p. 183°-185° C. (dec.); NMR: 4.85(s,2H), 5.18(s,2H), 6.70(s,1H), 6.85-6.98(m,6H), 7.15-7.35(m,13H), 7.35-7.58(m,4H), 7.70(dt,1H), 7.95-8.08(m,2H), 8.15(d,1H); microanalysis, found: C,78.7; H,4.7; N,10.7%; C43H 33 N5O2 requires C,79.2; H,5.1; N,10.7%.
Reaction SMILES: [C:1]([O:15]CC)(=O)[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH3:13].O.[NH2:19][NH2:20]>C(O)C>[C:1]([NH:19][NH2:20])(=[O:15])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH3:13]
Reactant: CCOC(=O)COCCOCCOCCOC
Reactant: NN
Solvent: O
Solvent: CCO
Product: COCCOCCOCCOCC(=O)NN
Reaction time: 25 h

Procedure:
A solution of 61 g (0.244 mol) of crude ethyl 3,6,9,12-tetra-oxa-tridecanoate and 25 ml (0.488 mol) of hydrazine hydrate in 600 ml of ethanol is left to stand for 25 hours at 25°. The reaction mixture is evaporated and the crude, oily 3,6,9,12-tetra-oxa-tridecanoic acid hydrazide, which is thus obtained, is further processed direct.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:21][CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[CH:18]1([N:13]2[C:12]([C:34]3[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH2:19][CH2:20][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CCC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Reactant: OB(O)c1ccc(F)cc1
Product: Fc1ccc(-c2c3c(nn2C2CCC2)CCNCC3)cc1
Yield: 94.9 %

Procedure:
The title compound (122 mg) was prepared according to Example 263 using 198 mg of 2-cyclobutyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 276, Step A) and 88 mg of 4-fluorophenylboronic acid. MS (ESI): exact mass calculated for C17H20FN3, 285.16. found, m/z 286.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.35-7.27 (m, 4H), 4.65-4.59 (m, 2H), 3.95-3.3.40 (m, 2H), 3.32-3.05 (m, 3H), 3.00-2.75 (m, 2H), 2.67-2.59 (m, 2H), 2.29-2.23 (m, 2H), 1.84-1.73 (m, 2H).
Reaction SMILES: [CH3:1][S-:2].[Na+].Br[CH2:5][CH2:6][N:7]1[C:20](=[O:21])[C:19]2[C:18](=[O:22])[C:17]3[CH:16]=[CH:15][C:14]([Cl:23])=[CH:13][C:12]=3[NH:11][C:10]=2[C:9]([OH:24])=[N:8]1>CN(C)C=O>[Cl:23][C:14]1[CH:15]=[CH:16][C:17]2[C:18](=[O:22])[C:19]3[C:20](=[O:21])[N:7]([CH2:6][CH2:5][S:2][CH3:1])[N:8]=[C:9]([OH:24])[C:10]=3[NH:11][C:12]=2[CH:13]=1
Reactant: O=c1c2ccc(Cl)cc2[nH]c2c(O)nn(CCBr)c(=O)c12
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCCn1nc(O)c2[nH]c3cc(Cl)ccc3c(=O)c2c1=O
Reaction time: 1 h
Yield: 91 %

Procedure:
To a suspension of sodium thiomethoxide (230 mg, 3.2 mM) in dimethylformamide (20 mL), was added in one portion 2-(2-bromoethyl)-7-chloro-4-hydroxy-1,2,5,10-tetrahydropyridazino-[4,5-b]quinoline-1,10-dione (0.4 g, 1.08 mM, prepared in Example 4a. of docket No. 37811) as a dry powder. This mixture was warmed to gentle reflux for aboutthree hours. At this point the heat was removed and the reaction mixture was poured into ice cold 1.2N HCl (l00 mL) and stirred about one hour. Theresulting precipitate was vacuum filtered and washed with water and ether, then vacuum dried at 50° C. to yield 330 mg (91%) of the title compound as an off white powder. mp=275°-277° C.; MS: 338(M+1).
Reaction SMILES: [N:1]#[C:2][NH2:3].C(N(C(C)C)CC)(C)C.[CH3:13][S:14]([NH:17][C:18]1[N:23]=[CH:22][C:21]([N:24]=[C:25]=[N:26][CH:27]([CH3:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:20][CH:19]=1)(=[O:16])=[O:15]>C(Cl)(Cl)Cl>[CH3:13][S:14]([NH:17][C:18]1[N:23]=[CH:22][C:21]([NH:24][C:25]([NH:26][CH:27]([CH3:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[N:3][C:2]#[N:1])=[CH:20][CH:19]=1)(=[O:15])=[O:16]
Reactant: CC(N=C=Nc1ccc(NS(C)(=O)=O)nc1)C(C)(C)C
Reactant: N#CN
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=NC#N)Nc1ccc(NS(C)(=O)=O)nc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.9 %

Procedure:
Cyanamide (172 mg, 4.1 mmol) and diisopropylethylamine (711 μl, 4.1 mmol) were added to 1 ml of a solution of N-(6-methanesulfonylamino-3-pyridyl)-N'-(1,2,2-trimethylpropyl)carbodiimide (121 mg, 0.41 mmol) in chloroform and the mixture was stirred at room temperature for 16 hours. After an insoluble matter was removed by filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography [eluent: chloroform alone to chloroform:methanol =5:1 (v/v)] and subjected to recrystallization from chloroform-ether to obtain 97 mg of the intended product (yield: 72%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[O:13][C:12]([C:14]([N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[CH3:22][S:23](Cl)(=[O:25])=[O:24].CO>N1C=CC=CC=1>[S:23]([O:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[O:13][C:12]([C:14]([N:16]3[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]3)=[O:15])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1)([CH3:22])(=[O:25])=[O:24]
Reactant: O=C(c1ccc(CN2CCC(O)CC2)o1)N1CCCCC1
Reactant: CS(=O)(=O)Cl
Solvent: CO
Solvent: c1ccncc1
Product: CS(=O)(=O)OC1CCN(Cc2ccc(C(=O)N3CCCCC3)o2)CC1
Temperature: 0 °C
Reaction time: 4.5 h
Yield: 91.8 %

Procedure:
In 70 ml of pyridine was dissolved 3.47 g (11.88 mmol) of Compound t and with ice-cooling, 1.9 ml (23.77 mmol) of methanesulfonyl chloride was added dropwise. The mixture was stirred at 0° C. for 4.5 hours and, after addition of 5 ml of methanol, stirred at room temperature for 30 minutes. The solvent was then distilled off under reduced pressure and the residue was dissolved in 100 ml of methylene chloride. This solution was washed with 3 portions of saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to give 4.04 g (91.8%) of 1-[5-(4-mesyloxypiperidinomethyl)-2-furancarbonyl]piperidine (Compound u) as red-brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][OH:24])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[O:14][C:15]=1[CH3:16].O[C:26]1[C:30]([CH:31]=[O:32])=[CH:29][N:28]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:27]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[O:14][C:15]=1[CH3:16])[CH2:23][O:24][C:26]1[C:30]([CH:31]=[O:32])=[CH:29][N:28]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:27]=1
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Reactant: COc1cc(CO)ccc1OCc1nc(-c2cccnc2)oc1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2cccnc2)oc1C
Reaction time: 15 h
Yield: 47.3 %

Procedure:
To a mixture of {3-methoxy-4-[(5-methyl-2-pyridin-3-yl-1,3-oxazol-4-yl)methoxy]phenyl}methanol (1.00 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (0.58 g), tributylphosphine (0.95 g) and tetrahydrofuran (100 mL) was added 1,1′-(azodicarbonyl)dipiperidine (1.19 g) at room temperature, and the mixture was stirred for 15 hrs. The precipitated crystals were removed by filtration and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give 3-({3-methoxy-4-[(5-methyl-2-pyridin-3-yl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazole-4-carbaldehyde as colorless crystals (0.72 g, 47%) from a fraction eluted with ethyl acetate-hexane (4:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 161-162° C.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([F:10])([F:9])[F:8])[S:4][C:3]=1[CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]2([C:24]3=[CH:25][C:26]4[O:30][CH2:29][O:28][C:27]=4[CH:31]=[C:23]3[O:22][CH2:21]2)[C:13]1=[O:32].[OH-].[Na+].I[CH3:36]>CN(C)C=O>[CH3:36][O:1][C:2]1[CH:6]=[C:5]([C:7]([F:8])([F:9])[F:10])[S:4][C:3]=1[CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]2([C:24]3=[CH:25][C:26]4[O:30][CH2:29][O:28][C:27]=4[CH:31]=[C:23]3[O:22][CH2:21]2)[C:13]1=[O:32]
Reactant: O=C1N(Cc2sc(C(F)(F)F)cc2O)c2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1cc(C(F)(F)F)sc1CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.9 %

Procedure:
A mixture of 1′-{[3-hydroxy-5-(trifluoromethyl)-2-thienyl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.18 g, 0.39 mmol), NaOH (0.08 g, 1.96 mmol) and iodomethane (0.17 g, 1.18 mmol) in anhydrous N,N-dimethylformamide (2.00 mL) was stirred at ambient temperature for 16 h. The reaction was quenched by addition of saturated ammonium chloride (10.0 mL) and extracted with ethyl acetate (3×50.0 mL). The combined organic layers was washed with water (3×20.0 mL), brine (20.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The colorless solid was triturated with ether to give the title compound (0.15 g, 81%): mp 178-180° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.71 (s, 1H), 7.30 (dt, 1H), 7.15 (d, 1H), 7.07-7.02 (m, 2H), 6.68 (s, 1H), 6.08 (s, 1H), 5.89 (d, 2H), 4.95 (ABq, 2H), 4.70 (ABq, 2H), 3.90 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 177.0, 155.8, 154.9, 148.9, 142.2, 141.8, 132.1, 129.4, 125.7, 124.3, 123.8, 120.4, 120.3, 120.0, 119.5, 109.4, 103.2, 102.0, 93.9, 80.1, 59.9, 57.9, 34.9; MS (ES+) m/z 476.3 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]3[CH:14]=[CH:15][C:16]([O:18][CH2:19][O:20][CH3:21])=[CH:17][C:12]=3[O:11][CH2:10][C:9]2([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][O:31][CH3:32])=[CH:25][CH:24]=2)[CH3:22])[CH:5]=[CH:6][CH:7]=1.Br[CH2:34][CH2:35][CH2:36][CH2:37][Cl:38].[OH-].[Na+].O>CC(C)=O>[Cl:38][CH2:37][CH2:36][CH2:35][CH2:34][O:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]3[CH:14]=[CH:15][C:16]([O:18][CH2:19][O:20][CH3:21])=[CH:17][C:12]=3[O:11][CH2:10][C:9]2([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH2:30][O:31][CH3:32])=[CH:27][CH:28]=2)[CH3:22])[CH:5]=[CH:6][CH:7]=1
Reactant: ClCCCCBr
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2c2cccc(O)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2c2cccc(OCCCCCl)c2)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 96.5 %

Procedure:
(3RS,4RS)-4-(3-Hydroxyphenyl)-7-methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-3-methyl-2,3-dihydro-4H-benzopyran (260 mg, 0.59 mmol), 1-bromo-4-chlorobutane (0.8 ml, 2.98 mmol) and aqueous 2N-NaOH solution (0.8 ml) were dissolved in acetone (10 ml) and then stirred for 4 hours at 50° C. The reaction mixture was cooled to room temperature and then water was added thereto. The reaction solution was extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to remove the organic solvent. The concentrate was separated by column chromatography (n-hexane:ethyl acetate=4:1) to obtain 300 mg (yield: 96%) of the title compound as a colorless oil.