Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.[H-].[Na+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O.ClCCl>[CH2:20]([O:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](OCc2ccccc2)CN1C(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 108.5 %

Procedure:
(2S,4R)-1-tert-Butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (2.65 g, 10.80 mmol) was dissolved in dimethylformamide (75 ml) and cooled in an ice bath. Sodium hydride (60% in hexanes, 0.57 g, 23.75 mmol) was added and stirred for 10 min. To this solution, benzyl bromide (1.39 ml, 11.69 mmol) dissolved in dichloromethane (9 ml) was dropwise added and the reaction mixture was overnight stirred at room temperature. The solvent was evaporated under reduced pressure and the residue redissolved in ethyl acetate. This organic phase was washed with water, dried over magnesium sulphate, filtered and the solvent evaporated under reduced pressure. 3.93 g (77% yield) of the final product were obtained, pure enough to perform the next synthetic step.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:51]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1.[C:52](Cl)(=[O:54])[CH3:53]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[C:52]([N:48]1[CH2:47][CH2:46][CH:45]([NH:44][C:36]2[CH:37]=[CH:38][C:39]3[NH:40][C:41]4[N:42]=[C:26]([NH:27][C:28]5[CH:29]=[N:30][CH:31]=[C:32]([CH:51]=5)[CH2:33][CH2:34][C:35]=2[CH:43]=3)[N:25]=[CH:24][C:23]=4[Cl:22])[CH2:50][CH2:49]1)(=[O:54])[CH3:53]
Reactant: CC(=O)Cl
Reactant: Clc1cnc2nc1Nc1ccc(NC3CCNCC3)c(c1)CCc1cncc(c1)N2
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCC(Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 57 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using 6-chloro-N-piperidin-4-yl-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine tris(trifluoroacetate) and acetyl chloride as the starting materials in 57% yield. LCMS for C24H27ClN7O (M+H)+: m/z=464.2.
Reaction SMILES: C([O:4][CH2:5][CH:6]([O:12][N+:13]([O-:15])=[O:14])[CH2:7][O:8][N+:9]([O-:11])=[O:10])(=O)C.[OH-].[Na+]>C(O)C>[N+:9]([O-:11])([O:8][CH2:7][CH:6]([O:12][N+:13]([O-:15])=[O:14])[CH2:5][OH:4])=[O:10]
Reactant: CC(=O)OCC(CO[N+](=O)[O-])O[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=[N+]([O-])OCC(CO)O[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2.5 g of 2,3-bis(nitrooxy)propyl acetate in 25 mL of ethanol at 0. ° C. was added 469 mg of crushed NaOH powder. The reaction was stirred at 0° C. for 15 min upon which a cloudy suspension had formed. The resulting mixture was then poured onto ice cold 5% HCl and then extracted 3× with ether. The organics were combined and evaporated to remove most of the ethanol. The oil was then redissolved in ether, dried (Na2SO4), filtered and concentrated in vacuo to give a pale yellow oil which was used immediately without further purification. 1H NMR (500 MHz, acetone-d6): δ 5.59-5.52 (m, 1H), 5.05 (dd, 1H), 4.86 (dd, 1H), 4.60-4.50 (bs, OH), 3.95 (dd, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].C(N(CC)CC)C.[C:20](Cl)(=[O:23])[CH2:21][CH3:22]>O1CCCC1>[C:20]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6])(=[O:23])[CH2:21][CH3:22]
Reactant: CCC(=O)Cl
Reactant: COc1ccc(C(=O)O)cc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(=O)Nc1cc(C(=O)O)ccc1OC
Temperature: 25 °C
Yield: 97.1 %

Procedure:
0.6 g 3-amino-4-methoxybenzoic acid (1.0 g, 6 mmol) is dissolved in dry THF (tetrahydrofuran) in a 25 ml flask, triethylamine (1.2 ml, 12 mmol) is subsequently added to obtain transparent yellow solution. The mixture is stirred under nitrogen protection, propionyl chloride (0.78 ml, 9 mmol) is added into the flask in an ice-water bath. After finishing addition of propionyl chloride the mixture is naturally raised to room temperature. The reacted mixture is filtered, the filtrate is evaporated to dryness and separated using a silica column to obtain 3-propionamido-4-methoxybenzoic acid 1.3 g (yield: 67%).
Reaction SMILES: [CH2:1]([N:5]([CH2:23][CH2:24][CH2:25][CH3:26])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:18][C:17]([CH:19]=O)=[CH:16][CH:15]=2)=[C:8]([O:21][CH3:22])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:27]([C:29]1[C:30](=[C:40]([C:43]#[N:44])[C:41]#[N:42])[O:31][C:32]([CH3:39])([C:35]([F:38])([F:37])[F:36])[C:33]=1[CH3:34])#[N:28]>C(O)C.O1CCCC1>[CH2:23]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:18][C:17]([CH:19]=[CH:34][C:33]3[C:32]([CH3:39])([C:35]([F:38])([F:36])[F:37])[O:31][C:30](=[C:40]([C:41]#[N:42])[C:43]#[N:44])[C:29]=3[C:27]#[N:28])=[CH:16][CH:15]=2)=[C:8]([O:21][CH3:22])[CH:7]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)s2)c(OC)c1
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C(F)(F)F
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(C)C(F)(F)F)s2)c(OC)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
In 4 ml of ethanol and 1.5 ml of tetrahydrofuran were dissolved 100 mg (0.27 mmol) of 5-[2-(4-dibutylamino-2-methoxyphenyl)vinyl]thiophene-2-carboaldehyde and 75 mg (0.3 mmol) of 2-(3-cyano-4,5-dimethyl-5-trifluoromethyl-2(5H)-furanylidene)propanedinitrile. After the mixture was stirred at 50° C. for 2 hours, the solvent was evaporated off. The residue was washed with ethanol to give 120 mg of a brown powdered crystal (yield: 73.5%; mp: 191-193° C.)
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[S:5][CH2:6][CH2:7][N:8]=1.[CH2:9](Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O1CCCC1>[CH2:9]([S:3][C:4]1[S:5][CH2:6][CH2:7][N:8]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: ClCc1ccccc1
Reactant: SC1=NCCS1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc(CSC2=NCCS2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 258.8 %

Procedure:
To a dry, nitrogen (N2)-purged 500 milliliter (mL) round bottom flask was added 1.15 grams (g) (4.8 mmol) sodium hydride. To this was added 150 mL dry tetrahydrofuran and 5.70 g (4.8 mmol) 2-mercaptothiazoline in 24 mL tetrahydrofuran. After approximately 15 minutes of stirring at room temperature, 5.5 mL (4.8 mmol) benzyl chloride was added and stirred for an additional 5 minutes. Tetrahydrofuran was removed by rotary evaporation and product was dissolved in hexane. After filtration, the product was recrystallized from hexane to yield 2.6 g of white crystals (26% yield). 1H NMR (CDCl3): 3.434 ppm, t, 2H; 4.259 ppm, t, 2H; 4.413 ppm, s, 2H; 7.317 ppm, m, 5H.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([C:14]#[N:15])[C:8]=2[N:7]=[C:6]1[C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[F:23].C([O-])([O-])=[O:30].[Na+].[Na+].OO>C(O)C>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([C:14]([NH2:15])=[O:30])[C:8]=2[N:7]=[C:6]1[C:16]1[C:17]([F:23])=[CH:18][CH:19]=[CH:20][C:21]=1[F:22]
Reactant: N#Cc1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To 1-(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole-4-carbonitrile (Example 105) (1.10 g, 2.88 mmol) dissolved in ethanol (100 mL) and 3 M Na2CO3 (10 mL) was added 30% hydrogen peroxide (10 mL). After stirring overnight at room temperature, the reaction was concentrated. The residue was then redissolved in EtOAc, and washed with NaHSO4(10% soln), NaHCO3 (sat. aq) and NaCl (sat. aq). The combined washings were dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography eluting with 2% methanol/CH2Cl2 and recrystallization from methanol, yielding white crystals of 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole-4-carboxylic acid amide (0.83 g, 2.08 mmol, 72% yield). M.p. 260-261° C. 1H-NMR (200 MHz, CD2Cl2): δ 8.10 (dd, J=1.1, 7.7 Hz, 1H, H5), 7.71 (br d, J=8.1 Hz, 1H, H7), 7.59 (m, 1H, H4′), 7.43 (dd, J=7.7, 8.1 Hz, 1H, H6), 7.28 (m, 1H, H4″), 7.13 (m, 2H, H3′,5′), 6.84 (m, 2H, H3″,5″), 5.43 (s, 2H, CH2PhF2), 1.92 (s, 2H, NH2).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:8]=[C:9]([CH:17]=[CH:18][CH:19]=2)[CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[O:6]CCO1.[CH:20]1[CH:25]=[C:24]([CH2:26][O:27][C:28](Cl)=[O:29])[C:23]([Cl:31])=[CH:22][CH:21]=1>>[Cl:31][C:23]1[CH:22]=[CH:21][CH:20]=[CH:25][C:24]=1[CH2:26][O:27][C:28](=[O:29])[NH:16][C:14]1[CH:13]=[N:12][N:11]([CH2:10][C:9]2[CH:17]=[CH:18][CH:19]=[C:7]([C:2](=[O:6])[CH3:1])[CH:8]=2)[N:15]=1
Reactant: CC1(c2cccc(Cn3ncc(N)n3)c2)OCCO1
Reactant: O=C(Cl)OCc1ccccc1Cl
Product: CC(=O)c1cccc(Cn2ncc(NC(=O)OCc3ccccc3Cl)n2)c1

Procedure:
Following general procedure D (step 2) followed by B, starting from 2-[3-(2-methyl-[1,3]dioxolan-2-yl)-benzyl]-2H-[1,2,3]triazol-4-ylamine and 2-chlorobenzylchloroformate.
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH:8]=[CH:9][C:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][C:3]2=[O:21].[CH3:22][Mg]Br>>[CH3:22][C@@H:8]1[CH:9]=[C:10]2[C@:15]([CH3:16])([CH2:14][CH2:13][C:12](=[O:20])[CH2:11]2)[C@@H:17]2[C@@H:7]1[C@H:6]1[C@@:2]([CH2:19][CH2:18]2)([CH3:1])[C:3](=[O:21])[CH2:4][CH2:5]1
Reactant: C[C@]12CCC(=O)C=C1C=C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: C[Mg]Br
Product: C[C@@H]1C=C2CC(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12

Procedure:
Alkylation of androsta-4,6-dien-3,17-dione 17 ketal 1 with methyl magnesium bromide in the presence of cuprous chloride, proceeds via conjugate addition to yield 7α-methylandrost-5-en-3,17-dione 17 ketal 2. Allylic bromination of 2 using N-bromosuccnimide in carbon tetrachloride yields the 6β-bromo-7α-methylandrost-4-en-3,17-dione 17 ketal 3. Lithium aluminum hydride reduction of the ketone in 3 with concomitant double bond migration and loss of bromide should yield 4. Deprotection of the C-17 ketone with aqueous acid yields 3β-hydroxy-7α-methylandrost-5-en-17-one, 5. Higher homologues may be synthesized using the substituted Grignard reagent i.e. R=CH3, C2H5, C3H7. The 7β-epimer can be synthesized by treatment of 2 with DDQ--dichlorodicyanoquinone to generate another olefin at C-7. Catalytic reduction of this olefin should occur from the α face of the steroid to yield the 7β-methyl steroid i.e. 7β-methylandrost-5-en-3,17-dione 17 ketal. Following the same sequence as above yields 3β-hydroxy-7β-methyl-androst-5-en-17-one.
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10]/[C:11](=[CH:12]\[CH:13]=[CH:14]\[CH:15]=[O:16])/[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:17]([O:23][CH3:24])(=[O:22])[CH2:18][C:19]([CH3:21])=[O:20]>>[CH:1]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10]/[C:11](=[CH:12]\[CH:13]=[CH:14]\[CH:15]([OH:16])[CH2:21][C:19](=[O:20])[CH2:18][C:17]([O:23][CH3:24])=[O:22])/[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C/C=C/C=C1\CCCCc2ccccc21
Reactant: COC(=O)CC(C)=O
Product: COC(=O)CC(=O)CC(O)/C=C/C=C1\CCCCc2ccccc21

Procedure:
By the method of Example 1 (E,E)-4-(8,9-Dihydro-6H,7H-benzocyclohepten-5-ylidene)-2-butenal (0.9 g, 4.2 mmol) was reacted with methyl acetoacetate to produce title product, 0.9 g.
Reaction SMILES: Br.[F:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([CH3:13])=[N:10]2)=[C:5]([OH:14])[CH:4]=1.[Br:15][CH2:16][CH2:17]Br>>[Br:15][CH2:16][CH2:17][O:14][C:5]1[CH:4]=[C:3]([F:2])[CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([CH3:13])=[N:10]2
Reactant: BrCCBr
Reactant: Cc1ccc2c(O)cc(F)cc2n1
Agent: Br
Product: Cc1ccc2c(OCCBr)cc(F)cc2n1
Yield: 91 %

Procedure:
The title compound was prepared from 7-fluoro-5-hydroxy-2-methylquinoline hydrobromide and 1,2-dibromoethane using a similar procedure to Description 13, in 91% yield.
Reaction SMILES: [C:1]([O:5][C:6]([C:12]([O:15][C:16](=[C:18]([F:20])[F:19])[F:17])([F:14])[F:13])([C:8]([F:11])([F:10])[F:9])[F:7])([F:4])([F:3])[F:2].[CH:21]([OH:24])([CH3:23])[CH3:22]>>[C:1]([O:5][C:6]([C:12]([O:15][CH:16]([C:18]([C:21]([OH:24])([CH3:23])[CH3:22])([F:19])[F:20])[F:17])([F:13])[F:14])([C:8]([F:11])([F:10])[F:9])[F:7])([F:4])([F:3])[F:2]
Reactant: FC(F)=C(F)OC(F)(F)C(F)(OC(F)(F)F)C(F)(F)F
Reactant: CC(C)O
Product: CC(C)(O)C(F)(F)C(F)OC(F)(F)C(F)(OC(F)(F)F)C(F)(F)F

Procedure:
CF3OCF(CF3)CF2OCFHCF2C(CH3)2OH was prepared by the reaction of CF3OCF(CF3)CF2OCF═CF2 (52.9 g, 0.16 mol) with isopropanol (202 g, 3.37 mol) using LUPEROX 575 (11.4 g) as free radical initiator at 75° C. The resulting product reaction mixture was distilled and the distillation fraction of b.r.=161-166° C. used in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH:10][C:11]([O:13][CH2:14][C:15]([Cl:18])([Cl:17])[Cl:16])=[O:12])[CH2:7][N:6]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:4].[CH3:26]I.[H-].[Na+].O>CN(C=O)C>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([N:10]([CH3:26])[C:11]([O:13][CH2:14][C:15]([Cl:18])([Cl:16])[Cl:17])=[O:12])[CH2:7][N:6]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@H](NC(=O)OCC(Cl)(Cl)Cl)CN1C(=O)OC(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@@H]1C[C@H](N(C)C(=O)OCC(Cl)(Cl)Cl)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2S,4S)-4-(2,2,2-trichloro-ethoxycarbonylamino)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (420 mg, 1 mmol) and methyl iodide (0.18 mL, 3 mmol) in DMF (10 mL) cooled at 0° C. under argon was added sodium hydride (44 mg, 1.1 mmol). The reaction mixture was stirred at RT for 2 h then was poured into water. The desired compound was extracted with EtOAc (2×25 mL), the organic phases were joined, washed with 1N HCl then brine, dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 1:1). MS (UPLC): 436 [M+H]+, 434 [M−H]−; tR (HPLC conditions f): 2.35 min.
Reaction SMILES: Cl.Cl.[CH:3]([N:6]([C:8]([C:10]1[N:19]=[C:18]2[N:12]([CH2:13][CH2:14][O:15][C:16]3[CH:23]=[C:22]([Br:24])[CH:21]=[CH:20][C:17]=32)[CH:11]=1)=[O:9])[NH2:7])([CH3:5])[CH3:4].[CH3:25][O:26][CH2:27][C:28](Cl)=[O:29]>C(Cl)Cl>[CH:3]([N:6]([C:8]([C:10]1[N:19]=[C:18]2[N:12]([CH2:13][CH2:14][O:15][C:16]3[CH:23]=[C:22]([Br:24])[CH:21]=[CH:20][C:17]=32)[CH:11]=1)=[O:9])[NH:7][C:28](=[O:29])[CH2:27][O:26][CH3:25])([CH3:5])[CH3:4]
Reactant: CC(C)N(N)C(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: COCC(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: COCC(=O)NN(C(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2)C(C)C
Temperature: 0 °C
Reaction time: 1.75 h
Yield: 85.9 %

Procedure:
A suspension of 8-bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid N-isopropyl-hydrazide dihydrochloride (2.69 g, 6.1 mmol) in DCM (61 mL) was treated with TEA (3.84 mL, 27.6 mmol). The resultant solution was cooled to 0° C. before methoxyacetyl chloride (1.12 mL, 12.3 mmol) was added dropwise and the reaction stirred at 0° C. for 1.75 h. The reaction was quenched with saturated sodium bicarbonate solution and the phases separated. The aqueous phase was extracted with DCM (×2) before the combined organic phases were washed sequentially with 10% citric acid solution, saturated sodium bicarbonate solution and brine. The organic solution was dried (Na2SO4), concentrated in vacuo and the resultant solid was triturated with diethyl ether to give 8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid N-isopropyl-N′-(2-methoxy-acetyl)-hydrazide as an off-white solid (2.29 g, 5.24 mmol, 86%). LCMS RT=4.29 min, [M+H]+=437/439. 1H NMR 400 MHz (DMSO-d) δ: 9.61 (1H, s), 8.29 (1H, d, J=8.63 Hz), 7.71 (1H, s), 7.27 (1H, dd, J=8.64, 2.06 Hz), 7.21 (1H, d, J=2.06 Hz), 4.84 (1H, t, J=6.91 Hz), 4.45 (4H, s), 3.92 (2H, s), 3.33 (3H, s), 1.15 (6H, d, J=6.66 Hz)
Reaction SMILES: [F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20](I)=[CH:21][C:22]6[O:26][C:25]([C:27]7[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=7)=[C:24]([C:34]([NH:36][CH3:37])=[O:35])[C:23]=6[CH:38]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1.[CH3:40][N:41]1[C:45](B2OC(C)(C)C(C)(C)O2)=[CH:44][CH:43]=[N:42]1>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20]([C:45]6[N:41]([CH3:40])[N:42]=[CH:43][CH:44]=6)=[CH:21][C:22]6[O:26][C:25]([C:27]7[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=7)=[C:24]([C:34]([NH:36][CH3:37])=[O:35])[C:23]=6[CH:38]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(I)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(-c3ccnn3C)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Temperature: 100 °C
Reaction time: 16 h
Yield: 16 %

Procedure:
To a degassed solution of 5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-6-iodo-N-methylbenzofuran-3-carboxamide (100 mg, 0.16 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (100 mg, 0.48 mmol) and K3PO4.3H2O (60 mg, 0.45 mmol) in DMF (2 mL) was added Pd(dppf)Cl2 (20 mg) under N2 protection. The reaction mixture was stirred at 100° C. for 16 hours. The mixture was filtered through a celite pad, and the resulting residue was concentrated to provide crude product. The resulting residue was purified using column chromatography (petroleum ether:EtOAc=1:2) to provide the product of Compound 165 (15 mg, yield: 16%). 1H-NMR (CDCl3, 400 MHz) δ 8.12 (s, 1H), 7.95 (dd, J=8.4, 6.0 Hz, 2H), 7.51 (s, 1H), 7.42 (s, 1H), 7.15 (t, J=8.8 Hz, 5H), 7.02 (d, J=8.0 Hz, 1H), 6.87 (d, J=8.4 Hz, 1H), 6.78 (t, J=8.8 Hz, 1H), 6.24 (s, 1H), 5.96 (s, 1H), 5.88 (s, 2H), 3.38 (s, 3H), 3.00 (d, J=5.2 Hz, 3H). MS (M+H)+: 588.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH2:13]([N:17]=[C:18]=S)[CH:14]([CH3:16])[CH3:15]>C(OCC)(=O)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[S:9](=[O:11])(=[O:10])[N:12]=[C:18]([NH:17][CH2:13][CH:14]([CH3:16])[CH3:15])[NH:1][C:2]=2[CH:7]=1
Reactant: CC(C)CN=C=S
Reactant: Nc1cc(Cl)ccc1S(N)(=O)=O
Solvent: CCOC(C)=O
Product: CC(C)CNC1=NS(=O)(=O)c2ccc(Cl)cc2N1
Temperature: 150 °C
Yield: 41.7 %

Procedure:
A mixture of 2-amino-4-chlorobenzenesulfonamide (5.0 g, 24.18 mmol) and isobutyl isothiocyanate (10 ml, 83.6 mmol) was heated at 150° C. for 3 h. The mixture was allowed to cool and then stirred with 50 ml of ethyl acetate for 30 min. The precipitate was isolated by filtration and recrystallised from ethanol to give 2.9 g (42%) of the pure title compound; m.p. 298-301° C.; 1H-NMR (DMSO-d6): δ 0.91 (d, 6H, CH(CH3)2), 1.83 (m, 1H, CH(CH3)2), 3.05 (t, 2H, CH2), 7.2-7.4 (m, 3H, ArH+NH), 7.67 (d, 1H, ArH), 10.5 (br.s, 1H, NH); MS: m/e 287/289 (M+); (C11H14N3Cl1O2S1) calc. C, 45.91; H, 4.90; N, 14.60; found C, 45.90; H, 5.04; N, 14.66.
Reaction SMILES: I[C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH2:9][CH2:10][N:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[CH:32])=[N:29][CH:30]=2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[C:32][C:2]3[CH:17]=[CH:16][C:5]4[N:6]([CH2:9][CH2:10][N:11]5[CH2:15][CH2:14][CH2:13][CH2:12]5)[CH:7]=[N:8][C:4]=4[CH:3]=3)=[N:29][CH:30]=2)=[CH:23][CH:24]=1
Reactant: Ic1ccc2c(c1)ncn2CCN1CCCC1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: Clc1ccc(-c2ccc(C#Cc3ccc4c(c3)ncn4CCN3CCCC3)nc2)cc1

Procedure:
Prepared according to general working method I from 5-iodo-1-(2-pyrrolidin-1-yl-ethyl)-1H-benzimidazole (150 mg, 0.44 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (94 mg, 0.44 mmol).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([O:17][CH2:18][CH2:19]Cl)[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:21]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([O:17][CH2:18][CH2:19][N:37]3[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]3)[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:21]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: COc1cc(-c2nc3ccc(OCCCl)cc3n2Cc2ccccc2)cc(OC)c1OC
Product: COc1cc(-c2nc3ccc(OCCN4CCN(C)CC4)cc3n2Cc2ccccc2)cc(OC)c1OC

Procedure:
The title compound was prepared essentially as described in Example 77, supra, employing the compound of Example 76, except that 1-methylpiperazine was employed in place of the 4-(piperdin-1-yl)piperidine. IR, NMR, MS 517, mp 113° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]([CH2:24][CH2:25]Cl)[CH:12]=3)[N:8]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:5]2=[N:6][CH:7]=1.[I-:37].[Na+]>CC(=O)CC>[F:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]([CH2:24][CH2:25][I:37])[CH:12]=3)[N:8]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:5]2=[N:6][CH:7]=1
Reactant: COc1cc2c(-c3cc4cc(F)cnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CCCl)c2cc1OC
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: COc1cc2c(-c3cc4cc(F)cnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CCI)c2cc1OC
Yield: 93.8 %

Procedure:
But using 2 g of 5-fluoro-2-[1-(2-chloroethyl)-5,6-dimethoxy-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine, 0.85 g of sodium iodide in 100 ml of 2-butanone. 2.2 g of 5-fluoro-2-[1-(2-iodoethyl)-5,6-dimethoxy-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine are thus obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:14]1([CH:13]=[CH:12][C:9]2[CH:8]=[CH:7][C:6]3[C:11](=[C:2]([OH:1])[CH:3]=[CH:4][CH:5]=3)[N:10]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1ccc2cccc(O)c2n1
Product: Oc1cccc2ccc(C=Cc3ccccc3)nc12
Temperature: 25 °C

Procedure:
A mixture of 8-hydroxyquinaldine (10.02 g) and benzaldehyde (16.8 mL) is heated at reflux overnight. The reaction is cooled to room temperature and vacuum distilled. After the excess benzaldehyde has distilled off, the residue remaining in the flask is dissolved in hot 95% EtOH. Any undissolved material is filtered off. The EtOH filtrate is cooled slowly to give the product as light yellow crystals (5.17 g).