Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][O:15]2)=[CH:4][C:5]2[S:9][C:8]([NH2:10])=[N:7][C:6]=2[CH:11]=1.[CH2:19]([N:21]=[C:22]=[O:23])[CH3:20]>O1CCOCC1>[Br:1][C:2]1[C:3]([O:12][CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][O:15]2)=[CH:4][C:5]2[S:9][C:8]([NH:10][C:22]([NH:21][CH2:19][CH3:20])=[O:23])=[N:7][C:6]=2[CH:11]=1
Reactant: Nc1nc2cc(Br)c(OCC3CCCO3)cc2s1
Reactant: CCN=C=O
Solvent: C1COCCO1
Product: CCNC(=O)Nc1nc2cc(Br)c(OCC3CCCO3)cc2s1
Temperature: 80 °C
Reaction time: 5 h
Yield: 82.4 %

Procedure:
To a solution of iii (1.0 g, 3.03 mmol) in 1,4-dioxane (10 mL) was added ethyl isocynate (1.23 mL, 15.19 mmol) at RT. The mixture was stirred at 80° C. for 5 h. The reaction mixture was evaporated in vacuo, H2O (50 mL) added to and the mixture stirred at 70° C. for 4 h. The residue was filtered and dried under vacuum to obtain iv (1.0 g, 83%). 1HNMR (DMSO-d6, 400 MHz): δ 10.69 (br s, 1H), 7.80 (s, 1H), 7.68 (s, 1H), 6.65 (m, 1H), 4.21 (m, 1H), 4.04 (m, 2H), 3.83 (m, 1H), 3.70 (m, 1H), 3.16 (m, 2H), 2.0 (m, 2H), 1.82 (m, 2H) and 1.09 (t, J=7.20 Hz, 3H). MS: 400 [M+H]+.
Reaction SMILES: [C:1]([OH:12])(=O)[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[NH2:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][NH:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([CH:35]2[C:44]3[C:39](=[C:40]([Cl:46])[CH:41]=[C:42]([Cl:45])[CH:43]=3)[CH2:38][N:37]([CH3:47])[CH2:36]2)=[CH:31][CH:30]=1)(=[O:28])=[O:27]>>[Cl:45][C:42]1[CH:43]=[C:44]2[C:39](=[C:40]([Cl:46])[CH:41]=1)[CH2:38][N:37]([CH3:47])[CH2:36][CH:35]2[C:32]1[CH:31]=[CH:30][C:29]([S:26]([NH:25][CH2:24][CH2:23][O:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][NH:13][C:6](=[O:8])[C:5]2[CH:4]=[CH:3][C:2]([C:1]([NH:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][NH:25][S:26]([C:29]3[CH:30]=[CH:31][C:32]([CH:35]4[C:44]5[C:39](=[C:40]([Cl:46])[CH:41]=[C:42]([Cl:45])[CH:43]=5)[CH2:38][N:37]([CH3:47])[CH2:36]4)=[CH:33][CH:34]=3)(=[O:28])=[O:27])=[O:12])=[CH:10][CH:9]=2)(=[O:28])=[O:27])=[CH:34][CH:33]=1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(S(=O)(=O)NCCOCCOCCOCCN)cc2)C1
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(S(=O)(=O)NCCOCCOCCOCCNC(=O)c3ccc(C(=O)NCCOCCOCCOCCNS(=O)(=O)c4ccc(C5CN(C)Cc6c(Cl)cc(Cl)cc65)cc4)cc3)cc2)C1
Yield: 50.7 %

Procedure:
Compound 233 was prepared following the procedures outlined in Example 215 using terephthalic acid (10.4 mg, 0.0628 mmol) and N-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide (Compound 82, 97.2 mg, 0.1255 mmol). Purification by preparative HPLC gave the title compound (38.9 mg) as a TFA salt. 1H-NMR (400 MHz, CD3OD): δ 7.83 (m, 10H), 7.85 (s, 2H), 7.42 (d, 4H), 6.83 (s, 1H), 3.66-3.55 (m, 28H), 3.46-3.39 (m, 11H), 3.12 (s, 7H), 3.04 (t, 4H). MS (m/z): 1223.14 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14][NH2:15])[CH3:11]>>[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14][N:15]=[CH:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[F:1])[CH3:11]
Reactant: O=Cc1ccccc1F
Reactant: CCOC(CN)OCC
Product: CCOC(CN=Cc1ccccc1F)OCC
Temperature: 100 °C

Procedure:
2-Fluorobenzaldehyde (7.45 g), was added to aminoacetaldehyde diethylacetal (9.16 g) and the reaction heated to 100° C. for 3 h. After cooling, the mixture was transferred to a separating funnel and partitioned between diethyl ether and water. The ether layer was separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure to leave an oil. Distillation at 0.6-0.8 mm collecting the fraction boiling at 102-106° C. afforded the title compound as a colourless oil.
Reaction SMILES: O[C:2]1[C:3]2[S:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.P(Cl)(Cl)(Cl)=O.[NH2:16][CH:17]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18]1>>[CH2:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:25][CH:17]1[NH:16][C:2]1[C:3]2[S:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Oc1ncnc2ccsc12
Reactant: NC1Cc2ccccc2C1
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccc2c(c1)CC(Nc1ncnc3ccsc13)C2
Yield: 28.2 %

Procedure:
Using 4-hydroxythieno[3,2-d]pyrimidine (60 mg, 0.39 mmol), and phosphorus oxychloride (0.6 ml), and then 2-aminoindan (210 mg, 1.56 mmol), a similar procedure to Production Example 194 was carried out. The product obtained was purified by silica gel chromatography (hexane:ethyl acetate=1:2) to obtain the title compound (30 mg, 0.11 mmol) having the following physical properties:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[CH:9][N:10](C)C)=[C:4]([C:13]#[N:14])[CH:3]=1.N[C:16]1[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:17]=1[CH3:23].O>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]=[CH:9][N:10]=[C:13]2[NH:14][C:18]1[CH:19]=[C:20]([OH:22])[CH:21]=[CH:16][C:17]=1[CH3:23]
Reactant: Cc1ccc(O)cc1N
Reactant: CN(C)C=Nc1ccc(Br)cc1C#N
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(O)cc1Nc1ncnc2ccc(Br)cc12
Yield: 101.4 %

Procedure:
6.0 g (23.9 mmol) of N′-(4-bromo-2-cyanophenyl)-N,N-dimethylformamidine and 3.24 g (26.3 mmol) of 2-amino-4-hydroxytoluene are suspended in 40 ml of acetic acid and heated under reflux for 1 h. The resulting mixture is cooled and then added to 100 ml of water and extracted with ethyl acetate. The combined organic phases are washed with water and sat. aqueous sodium chloride solution and dried over sodium sulphate, and the solvent is evaporated. 8.0 g (100%) of the desired product are obtained.
Reaction SMILES: [O:1]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][N+:14]([O-])=[CH:13][CH:12]=1)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].C[Si]([C:22]#[N:23])(C)C.CN(C)C(Cl)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[O:1]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:22]#[N:23])[CH:12]=1)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCCc1cc[n+]([O-])cc1
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCc1ccnc(C#N)c1
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
4-[2-(tert-Butyldimethylsiloxy)ethyl]pyridine-N-oxide (12.5 g, 49.3 mmol) was dissolved in dichloromethane (100 mL), then trimethylsilyl cyanide (5.31 g, 53.5 mmol) was added thereto at room temperature, and dimethylcarbamoyl chloride (5.76 g, 53.5 mmol) was added thereto over 30 minutes. Then, the mixture was stirred for 24 hours. After completion of the reaction was confirmed by thin-layer chromatography, a 10% aqueous potassium carbonate solution (150 mL) was added to the mixture, and the mixture was further stirred for 10 minutes. The reaction mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure to give 4-[2-(tert-butyldimethylsiloxy)ethyl]pyridine-2-carbonitrile (12.5 g, yield 97%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][S:6]([NH:9][C:10]1[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][CH:15]=1)(=[O:8])=[O:7].[Cl:27][C:28]1[N:33]=[C:32](Cl)[C:31]([Cl:35])=[CH:30][N:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:27][C:28]1[N:33]=[C:32]([NH:1][C:2]2[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=2)[CH2:5][S:6]([NH:9][C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][CH:15]=2)(=[O:8])=[O:7])[C:31]([Cl:35])=[CH:30][N:29]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(NS(=O)(=O)Cc2cccc(N)c2)c1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(NS(=O)(=O)Cc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.3 %

Procedure:
To a solution of tert-butyl (3-{[(3-aminobenzyl)sulfonyl]amino}phenyl)carbamate (0.64 g, 1.7 mmol) and 2,4,5-trichloropyrimidine (0.28 g, 1.5 mmol) in DMF (5 mL) was added potassium carbonate (0.26 g, 1.8 mmol). The resulting mixture was stirred overnight at room temperature. The reaction was quenched with sat'd NH4Cl and water. EtOAc was then added and the layers separated. The aqueous phase was extracted with EtOAc. The combined organics were washed with water and brine then dried (MgSO4), filtered, and concentrated to give the desired product (0.75 g, 92%). LCMS for C22H23Cl2N5O4S (M-tBu+H)+: m/z=467.9, 469.9.
Reaction SMILES: CN(C)[CH:3]=[O:4].[Na].[NH2:7][CH:8]1[C:15](=[O:16])[N:14]2[CH:9]1[S:10][CH2:11][C:12]([CH3:20])=[C:13]2[C:17]([OH:19])=[O:18].ClC[CH2:23][C:24]([CH3:29])([CH3:28])[C:25]([O-])=[O:26]>C(OC(=O)C)C>[C:25]([O:4][CH2:3][O:18][C:17]([C:13]1[N:14]2[CH:9]([S:10][CH2:11][C:12]=1[CH3:20])[CH:8]([NH2:7])[C:15]2=[O:16])=[O:19])(=[O:26])[C:24]([CH3:29])([CH3:28])[CH3:23]
Reactant: CC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Reactant: CN(C)C=O
Reactant: CC(C)(CCCl)C(=O)[O-]
Agent: [Na]
Solvent: CCOC(C)=O
Product: CC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(N)C2SC1
Reaction time: 3 h

Procedure:
To 35 ml of dimethylformamide is added 7.5 g of the sodium salt of 7-amino-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and the solution is stirred at room temperature for about 30 minutes after which 8 ml of chloromethylpivalate is added. Stirring is continued at room temperature for about 3 hours. The mixture is diluted with ethylacetate and washed with water. The organic layer is separated, evaporated to dryness, and the residue is recrystallized from ethylacetateto give 7-amino-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid pivalyloxymethyl ester.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@H:11]([NH:27]S(C2C=CC([N+]([O-])=O)=CC=2)(=O)=O)[CH2:12][N:13]([C:21]2[S:22][C:23](Br)=[CH:24][N:25]=2)C(=O)OC(C)(C)C)=[CH:2]1.[O:40]=[C:41]1[NH:45][C:44]2[CH:46]=[CH:47][C:48](B(O)O)=[CH:49][C:43]=2[S:42]1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:27][C@@H:11]([CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)[CH2:12][NH:13][C:21]1[S:22][C:23]([C:48]2[CH:47]=[CH:46][C:44]3[NH:45][C:41](=[O:40])[S:42][C:43]=3[CH:49]=2)=[CH:24][N:25]=1
Reactant: O=c1[nH]c2ccc(B(O)O)cc2s1
Reactant: CC(C)(C)OC(=O)N(C[C@H](Cc1c[nH]c2ccccc12)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1)c1ncc(Br)s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: N[C@H](CNc1ncc(-c2ccc3[nH]c(=O)sc3c2)s1)Cc1c[nH]c2ccccc12

Procedure:
This compound was synthesized using a procedure similar to that shown in Scheme 1 with a coupling reaction between (S)-tert-butyl 3-(1H-indol-3-yl)-2-(4-nitrophenylsulfonamido)propyl(5-bromothiazol-2-yl)carbamate and commercially available 2-oxo-2,3-dihydrobenzo[d]thiazol-6-ylboronic acid using PdCl2(PPh3)2 as the catalyst instead of tetrakis-(triphenylphosphine)palladium. MS m/z: 422 (M+1). 1H NMR (400 MHz, CD3OD): δ ppm 3.11-3.20 (m, 2H), 3.57 (d, J=7.04 Hz, 2H), 3.66-3.72 (m, 1H), 3.76-3.86 (m, 1H), 7.05-7.18 (m, 3H), 7.25 (s, 1H), 7.33-7.42 (m, 3H), 7.52 (d, J=1.56 Hz, 1H), 7.60 (d, J=7.82 Hz, 1H).
Reaction SMILES: C([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:29][C:30]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[C:34]([C:39]4[C:44]([F:45])=[CH:43][C:42]([CH2:46][O:47][CH3:48])=[CH:41][C:40]=4[F:49])[N:33]=3)=[O:31])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=O)C.C1COCC1.[OH-].[Na+]>CO>[F:45][C:44]1[CH:43]=[C:42]([CH2:46][O:47][CH3:48])[CH:41]=[C:40]([F:49])[C:39]=1[C:34]1[N:33]=[C:32]([C:30]([NH:29][C:12]2[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21][C:22](=[O:23])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:15]3)=[C:8]3[CH2:7][CH2:6][CH:5]([OH:4])[C:9]3=[N:10][CH:11]=2)=[O:31])[CH:37]=[CH:36][C:35]=1[F:38]
Reactant: COCc1cc(F)c(-c2nc(C(=O)Nc3cnc4c(c3N3C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C3)CCC4OC(C)=O)ccc2F)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COCc1cc(F)c(-c2nc(C(=O)Nc3cnc4c(c3N3C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C3)CCC4O)ccc2F)c(F)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To the amide intermediate, THF (6 mL), MeOH (6 mL) and 1.0 M aq. NaOH (6.32 mL, 6.32 mmol) were added. The mixture was stirred at room temperature for 20 min. The volatile solvents were removed under reduced pressure. The resulting residue was extracted with EtOAc (2×). The combined organic phases were washed with brine, dried over Na2SO4, and then concentrated to dry to give tert-butyl ((3S,5R)-1-{3-[({6-[2,6-difluoro-4-(methoxymethyl)phenyl]-5-fluoropyridin-2-yl}carbonyl)amino]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate as a second intermediate.
Reaction SMILES: N1CC(=O)C1.[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH:11]([C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)[N:12]1[CH2:15][CH:14]([OH:16])[CH2:13]1.CS(C)=O.C(Cl)(=O)C(Cl)=O>ClCCl.C(N(CC)CC)C>[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH:11]([C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)[N:12]1[CH2:13][C:14](=[O:16])[CH2:15]1
Reactant: OC1CN(C(c2cccs2)c2cccs2)C1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C1CNC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C1CN(C(c2cccs2)c2cccs2)C1
Yield: 80.6 %

Procedure:
1-[Bis-thien-2-yl)methyl]azetidin-3-one may be prepared by carrying out the operation as described in Example 73, starting with 4 g of 1-[bis(thien-2-yl)methyl]azetidin-3-ol, 2.6 cm3 of dimethyl sulfoxide, 7.7 cm3 of triethylamine, 7.7 cm3 of oxalyl chloride, and 100 cm3 of dichloromethane. The residue obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 3 cm, height 30 cm) with, as eluent, a mixture of cyclohexane/ethyl acetate (1/1 by volume). The fractions obtained are evaporated to dryness under reduced pressure (2.7 Kpa). 3.2 g of 1-[bis(thien-2-yl)methyl]azetidin-3-one are obtained in the form of cream-colored crystals melting at 70° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1.[CH:26]1(Br)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.CC(C)([O-])C.[K+].Cl>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]([CH:26]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:22]([O:24][CH3:25])=[O:23])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1
Reactant: COC(=O)Cc1ccc(OCc2ccc3ccccc3n2)c(OC)c1
Reactant: BrC1CCCCCCC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(c1ccc(OCc2ccc3ccccc3n2)c(OC)c1)C1CCCCCCC1

Procedure:
7.68 g (23 mmol) of the compound from Example XXIII and 4.4 g (23 mmol) of cyclooctyl bromide are dissolved in 100 ml of dimethylformamide. 3.36 g (30 mmol) of potassium tertiary butoxide, dissolved in 30 ml of DMF, are added dropwise to this mixture at 0°-10° C. with stirring. The mixture is subsequently stirred at room temperature for a further two hours and then treated with 30 ml of 1N hydrochloric acid. The solvent is then evaporated in vacuo, the residue is taken up in 200 ml of dichloromethane and the dichloromethane solution is washed twice with 100 ml of water. After drying with sodium sulphate, it is concentrated to a small volume in vacuo and the residue is separated by column chromatography (silica gel 60, eluent: toluene/ethyl acetate=4:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=O)[CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])=[CH:18][CH:17]=1.Cl.[OH-].[Na+]>O1CCCC1>[Cl:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[O:26][CH2:25][CH2:24][CH2:23][NH:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:17][CH:18]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)CCOc4ccccc4Cl)cc3)c2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(NCCCOc4ccccc4Cl)cc3)c2cc1OC
Temperature: 0 °C
Yield: 79.8 %

Procedure:
N1-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}-3-(2-chlorophenoxy)propaneamide (200 mg) was dissolved in tetrahydrofuran (10 ml) to prepare a solution. A 1 M solution (1.3 ml) of a borane-tetrahydrofuran complex in tetrahydrofuran was then added to the solution, and the mixture was stirred with heating under reflux for 2 hr. The reaction solution was cooled to 0° C. and was adjusted to pH=1 by the addition of 1 N hydrochloric acid, followed by stirring with heating under reflux for 30 min. The reaction solution was cooled to 0° C., was adjusted to pH=12 by the addition of a 1 N aqueous sodium hydroxide solution, and was extracted with chloroform. After the concentration of the extract, the residue was purified on a column using chloroform/methanol to give the title compound (155 mg, yield 80%). Mass spectrometry value (ESI-MS, m/z): 466 (M++1)
Reaction SMILES: [NH2:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[OH:11].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C1COCC1>[CH3:19][S:20]([NH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[O:11][S:20]([CH3:19])(=[O:22])=[O:21])(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N[C@@H]1c2ccccc2C[C@@H]1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 93.3 %

Procedure:
(1R,2S)-1-Amino-2-hydroxyindan (3.0 g, 20mmol) was dissolved in dry THF (40 ml) and triethylamine (8.4 ml, 60.0 mmol) at 10° C. Methane sulphonyl chloride (5.0 g, 44.0 mmol) dissolved in THF (10 ml) was added at such a rate that the internal temperature remained below 15° C. Following the addition the mixture was stirred at room temperature for 20 hours and then evaporated. To the residue was added EtOAc (100 ml) and the mixture washed with saturated aqueous sodium bicarbonate and then water. The organic solution was dried over magnesium sulphate and evaporated to give (1R,2S)-1-methanesulphonamido-2-methylsulphonyloxyindan (5.7 g, 93%) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[C:8]([C@@:10]1([OH:32])[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@@H:12]([CH2:13][CH2:14][C@@H:15]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C:20](=[O:22])[CH3:21])[CH2:11]1)#[CH:9]>>[OH:32][C@:10]1([C:8]#[C:9][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@H:12]([CH2:13][CH2:14][C@@H:15]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C:20](=[O:22])[CH3:21])[CH2:11]1
Reactant: C#C[C@@]1(O)CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(C)=O)CC[C@@H]32)C1
Reactant: Brc1cccnc1
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@@](O)(C#Cc5cccnc5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 23 °C
Reaction time: 0.75 h
Yield: 16.2 %

Procedure:
A solution of 3-bromopyridine (70 mg, 0.44 mmol), 3β-ethynyl-3α-hydroxy-5α-pregnan-20-one (150 mg, 0.44 mmol) in dry degassed diethylamine (1 mL) was stirred under argon at 23° C. Bis(triphenylphosphine)palladium chloride (10 mg) and CuI (5 mg) were added and the mixture was stirred at this temp. for 45 min. CH2Cl2 (4 mL) was added and the mixture was stirred at 23° C. for 1.5 hr. TLC showed 100% conversion of the starting material, hence, the solvent was removed and the residue was purified by chromatography on silica gel. Elution with hexane:acetone (3:1) gave 3α-hydroxy-3β-(3-pyridyl)ethynyl-5β-pregnan-20-one (30 mg) as a colorless solid; mp 230-35° C., TLC Rf (hexane:acetone 7:3)=0.24.
Reaction SMILES: [F:1][CH2:2][C:3]1([N:14]2[CH:18]=[C:17]([C:19]3[C:20]4[CH:27]=[CH:26][N:25]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:21]=4[N:22]=[CH:23][N:24]=3)[CH:16]=[N:15]2)[CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.Cl.O1CCOCC1.C(#N)C.C(N(CC)CC)C.[CH2:53]([S:55](Cl)(=[O:57])=[O:56])[CH3:54]>>[CH2:53]([S:55]([N:5]1[CH2:6][C:3]([N:14]2[CH:18]=[C:17]([C:19]3[C:20]4[CH:27]=[CH:26][N:25]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:34])([CH3:33])[CH3:35])[C:21]=4[N:22]=[CH:23][N:24]=3)[CH:16]=[N:15]2)([CH2:2][F:1])[CH2:4]1)(=[O:57])=[O:56])[CH3:54]
Reactant: CCS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC(CF)(n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N1CC(CF)(n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl 3-(fluoromethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate (0.120 g, 0.239 mmol) was treated with 4.00 M of hydrogen chloride in 1,4-dioxane (1.0 mL, 4.0 mmol) at rt for 1 h, then evaporated to dryness under reduced pressured. LCMS (M+H) 403.4. To the resultant crude HCl salt in acetonitrile (4 mL, 80 mmol) was added triethylamine (0.0998 ML, 0.716 mmol) followed by ethanesulfonyl chloride (0.0317 mL, 0.334 mmol). The mixture was stirred at rt for 30 min. After quenching with aq. sodium bicarbonate, the mixture was extracted with dichloromethane. The combined organic layers were washed with water, brine and dried over sodium sulfate, evaporated to dry. The residue was used directly in next step. LCMS calculated for C21H32FN6O3SSi(M+H)+: m/z=495.2; Found: 495.4.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]#[C:11][Si](C)(C)C.C(=O)([O-])[O-].[K+].[K+].O>CO>[C:10]([C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1)#[CH:11]
Reactant: C[Si](C)(C)C#Cc1cc2ccccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C#Cc1cc2ccccc2o1

Procedure:
A solution of Example 652 (0.74 g, 3.47 mmol) and potassium carbonate (1.45 g, 10.41 mmol) in methanol (3 mL) was stirred at room temperature for about 2 hours. The solution was poured into water and was extracted with diethyl ether. The combined organic extracts were dried (MgSO4), filtered and concentrated under vacuum to provide Example 653. 1H NMR (300 MHz, CDCl3) δ 3.49 (s, 1H), 7.01 (s, 1H), 7.25 (m, 1H), 7.35 (m, 1H), 7.46 (m, 1H), 7.56 (m, 1H).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[F:19])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[CH:20]1[C:28]2[C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[O:25][C:24]=2[CH:23]=[CH:22][C:21]=1[CH:33]=O>>[CH:20]1[C:28]2[C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[O:25][C:24]=2[CH:23]=[CH:22][C:21]=1[CH2:33][N:1]1[CH:2]([C:11]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=2[F:19])[CH2:3][CH:4]([CH3:10])[C:5]1=[O:7]
Reactant: CCOC(=O)C(C)CC(N)c1c(F)cccc1OC
Reactant: O=Cc1ccc2oc3ccccc3c2c1
Product: COc1cccc(F)c1C1CC(C)C(=O)N1Cc1ccc2oc3ccccc3c2c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2-fluoro-6-methoxyphenyl)-2-methylbutanoate with commercially available dibenzo[b,d]furan-2-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.96 min.; [M+H]+: 403.87 g/mol.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.[O-2].[Ca+2].[H][H]>[Pd].CO>[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:5]3[N:4]=[N:3][CH:2]=[CH:7][CH:6]=3)[CH2:9][CH2:10]2)=[CH:19][CH:18]=1
Reactant: COc1ccc(N2CCN(c3ccc(Cl)nn3)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: [Ca+2]
Agent: [O-2]
Solvent: CO
Product: COc1ccc(N2CCN(c3cccnn3)CC2)cc1
Yield: 63.2 %

Procedure:
A mixture of 7.3 parts of 3-chloro-6-[4-(4-methoxyphenyl)-1-piperazinyl]pyridazine, 2 parts of calcium oxide and 200 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off over Hyflo and the filtrate was evaporated. The residue was crystallized from 2-propanol, yielding 4.1 parts (63.2%) of 3-[4-(4-methoxyphenyl)-1-piperazinyl]pyridazine; mp. 133.4° C. (compound 272).