Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([OH:9])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)#[CH:2].Br[C:11]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:24]/[C:25]1[NH:26][CH:27]=[CH:28][C:29]=1[O:30][CH3:31])/[C:14](=[O:23])[NH:15]2>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C.CCN(CC)CC>[OH:9][C:3]1([C:1]#[C:2][C:11]2[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[C:16]3[C:12]=2/[C:13](=[CH:24]/[C:25]2[NH:26][CH:27]=[CH:28][C:29]=2[O:30][CH3:31])/[C:14](=[O:23])[NH:15]3)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: C#CC1(O)CCOCC1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(Br)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(C#CC3(O)CCOCC3)c21

Procedure:
Using Method C above, 4-ethynyl-tetrahydro-pyran-4-ol (43.3 mg, 0.34 mmol) (Example 85A) was coupled with (Z)-1,3-dihydro-4-bromo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2H-indol-2-one (50 mg, 0.14 mmol) (Starting Material 7) using (Ph3P)4Pd (16 mg) and Cul (3.0 mg) as catalyst in DMF (4 mL) and Et3N (4 mL) as solvent at 85° C. for 18 h to give (Z)-1,3-Dihydro-4-[(4-hydroxy-tetrahydro-pyran-4-yl)ethynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2H-indol-2-one. (Yield 30 mg, 53%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[CH:11][S:12][C:3]=12.[C:13]([O:17][C:18]([CH:20]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:19])([CH3:16])([CH3:15])[CH3:14].Cl[CH2:41]Cl>>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[C:11](/[CH:41]=[CH:20]/[C:18]([O:17][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:19])[S:12][C:3]=12
Reactant: N#Cc1cnc2ccsc2c1Cl
Reactant: CC(C)(C)OC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: ClCCl
Product: CC(C)(C)OC(=O)/C=C/c1cc2ncc(C#N)c(Cl)c2s1
Reaction time: 2.5 h

Procedure:
To a solution of 7-chlorothieno[3,2-b]pyridine-6-carbonitrile (100 mg, 0.45 mmol) in 5 mL of dichloromethane is added, in portions, (tert-butoxycarbonylmethylene)triphenylphosphorane (0.645 mL, 1.29 mmol). After stirring for 2.5 hours, the reaction mixture is allowed to stand at room temperature overnight. The mixture is concentrated to ½ its volume and is purified by flash column chromatography eluting with dichloromethane to provide 126 mg of tert-butyl (2E)-3-(7-chloro-6-cyanothieno[3,2-b]pyridin-2-yl)prop-2-enoate as a white solid, mp 193-194° C.; 1H NMR (CDCl3) δ 1.55 (s, 9H), 6.46 (d, J=16 Hz, 1H), 7.26 (s, 1H), 7.70 (s, 1H), 7.77 (d, J=16 Hz, 1H), 8.84 (s, 1H); MS 321.1, 323.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:13])[NH:7][C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[O:14][CH3:15].[Cl:16][C:17]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:18]=1[C:19]([N:21]=[C:22]=[O:23])=[O:20]>C(#N)C.CN1CCCC1=O>[Cl:16][C:17]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:18]=1[C:19]([NH:21][C:22]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:13])[NH:7][C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[O:14][CH3:15])=[O:23])=[O:20]
Reactant: O=C=NC(=O)c1cc(F)c(F)cc1Cl
Reactant: COc1cc2c(=O)[nH]c(=O)[nH]c2cc1N
Solvent: CN1CCCC1=O
Solvent: CC#N
Product: COc1cc2c(=O)[nH]c(=O)[nH]c2cc1NC(=O)NC(=O)c1cc(F)c(F)cc1Cl
Yield: 28.4 %

Procedure:
100 mg (0.53 mmol) of 7-amino-6-methoxy-1H-quinazoline-2,4-dione were suspended in 20 ml of acetonitrile and 2 ml of N-methyl-2-pyrrolidinone, and 200 mg (0.97 mmol) of 2-chloro-4,5-difluorobenzoyl isocyanate (example 1a) were added. The reaction mixture was heated to boiling and then quenched with methanol and concentrated in vacuo. The residue was stirred with acetonitrile, and the resulting precipitate was filtered off. 64 mg (30%) of the desired product were obtained.
Reaction SMILES: C(OC1C=C(C=CC=1OC(C)C)/C=N/[C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1)C.[CH2:24]([C:26]1[CH:27]=[CH:28][C:29]([F:34])=[C:30]([CH:33]=1)[CH:31]=O)[CH3:25].N[C:36]1C=CC(C#N)=CC=1>>[CH2:24]([C:26]1[CH:27]=[CH:28][C:29]([F:34])=[C:30]([CH:33]=1)[CH:31]=[CH:36][C:9]1[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=1)[CH3:25]
Reactant: CCOc1cc(/C=N/c2ccc(C#N)cc2)ccc1OC(C)C
Reactant: CCc1ccc(F)c(C=O)c1
Reactant: N#Cc1ccc(N)cc1
Product: CCc1ccc(F)c(C=Cc2ccc(C#N)cc2)c1

Procedure:
According to procedure for the preparation of Intermediate 1.1, 5-ethyl-2-fluorobenzaldehyde (900 mg, 5.88 mmol) and 4-aminobenzonitrile (694 mg, 5.88 mmol) afforded 950 mg of Intermediate 262.1
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:10]([CH3:11])[NH:9]2)=[CH:4][CH:3]=1.[N-:19]=[N+:20]=[N-:21].[Na+].[Cl-].[NH4+]>CO.O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)([NH2:19])[CH:10]([NH2:9])[CH3:11])=[CH:4][CH:3]=1.[N:19]([C:8]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH:10]([NH2:9])[CH3:11])=[N+:20]=[N-:21]
Reactant: CC1NC1(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CC(N)C(N)(c1ccc(F)cc1)c1ccc(F)cc1
Product: CC(N)C(N=[N+]=[N-])(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 40 h
Yield: 124.9 %

Procedure:
The above-mentioned aziridine compound (342 mg) was dissolved in mixture of methanol (10 mL) and water (2 mL), and sodium azide (439 mg) and ammonium chloride (155 mg) were added to the solution. The mixture was stirred at 60° C. for 40 hours. After the reaction mixture was cooled by standing, the reaction mixture was diluted with ethyl acetate, and the dilution was washed with saturated sodium hydrogen carbonate aqueous solution, water and saturated sodium chloride aqueous solution in this order, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica gel column chromatography (C-300; hexane: ethyl acetate=2:1→1:1) to give the desired compound, 1-azido-1,1-bis(4-fluorophenyl)-2-propaneamine (251 mg). The above-mentioned azide compound (8 mg) was reduced in the presence of 10% palladium carbon catalyst (5 mg) in methanol under 1 atm hydrogen at room temperature. The catalyst was removed by filtration, and then the filtrate was concentrated in vacuo to give the title compound (7 mg).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[C:5]([O:12][CH3:13])[C:4]=1[Cl:14].[CH2:15]([O:17][P:18]([O:22]CC)[O:19][CH2:20][CH3:21])[CH3:16]>C1(C)C=CC=CC=1>[Cl:14][C:4]1[C:5]([O:12][CH3:13])=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[CH2:2][P:18](=[O:22])([O:19][CH2:20][CH3:21])[O:17][CH2:15][CH3:16]
Reactant: CCOP(OCC)OCC
Reactant: COc1c([N+](=O)[O-])ccc(CBr)c1Cl
Solvent: Cc1ccccc1
Product: CCOP(=O)(Cc1ccc([N+](=O)[O-])c(OC)c1Cl)OCC

Procedure:
To a solution of 1-(bromomethyl)-2-chloro-3-methoxy-4-nitrobenzene (Compound 54G, 900 mg, 3.21 mmol) in toluene (10 mL) was added triethylphosphite (586 mg, 3.53 mmol) and heated to reflux for 24 h. Toluene and triethylphosphite were distilled off under reduced pressure to provide the desired compound, 800 mg (79%). 1H NMR (300 MHz, CDCl3) δ 7.77 (d, 1H), 7.35 (d, 1H), 4.19-4.05 (m, 4H), 4.00 (s, 3H), 3.43 (d, 2H), 1.31 (t, 6H).
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.N([O:14][CH2:15][CH2:16][CH:17]([CH3:19])C)=O>O1C=CC=C1>[O:14]1[CH:15]=[CH:16][CH:17]=[C:19]1[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1
Reactant: CC(C)CCON=O
Reactant: Cc1nc2cc(N)ccc2o1
Solvent: c1ccoc1
Product: Cc1nc2cc(-c3ccco3)ccc2o1
Temperature: 30 °C
Yield: 43 %

Procedure:
5-Amino-2-methylbenzoxazole (7.0 g, 0.05 mole), isopentyl nitrite (20 mL), and furan (230 mL) were combined and heated with stirring at 30° C. in a roundbottom flask equipped with a condenser. After heating for 48 hrs, the reaction mixture was removed from the heat, washed with water, and then evaporated to an oil. Distillation afforded the product (4.0 g, 43% yield), bp 130°-140° C. (0.6 mm). Recrystallization from isopropyl alcohol (14 mL) afforded 3.0 g (32% yield), mp 60° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:4][CH2:3]1.C(O[CH:18]1[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:25][C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)(=O)C>C1(C)C=CC=CC=1>[CH:8]1([N:5]2[CH2:6][CH2:7][CH:2]([NH:1][CH:18]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=4[O:25][C:26]4[C:31]3=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:3][CH2:4]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CC(=O)OC1c2ccccc2Oc2ccccc21
Reactant: NC1CCN(C2CCCCC2)CC1
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)Oc1ccccc1C2NC1CCN(C2CCCCC2)CC1

Procedure:
Refluxing 4-amino-1-cyclohexylpiperidine and 9-acetoxyxanthene in dry toluene for 24 hours, then working up as in Example 1 gives N-(N-cyclohexyl-4-piperidinyl)-9-xanthenylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:19][C@H:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:21])[C:16]([OH:18])=O)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[CH3:46][O:47][C:48]1[CH:61]=[CH:60][C:51]([CH2:52][N:53]2[C:57]([NH:58][CH3:59])=[N:56][N:55]=[N:54]2)=[CH:50][CH:49]=1>ClCCl.C([O-])(O)=O.[Na+].CCOC(C)=O>[CH2:25]([O:24][C:22](=[O:23])[C@@H:20]([NH:19][C@H:15]([C:16](=[O:18])[N:58]([C:57]1[N:53]([CH2:52][C:51]2[CH:60]=[CH:61][C:48]([O:47][CH3:46])=[CH:49][CH:50]=2)[N:54]=[N:55][N:56]=1)[CH3:59])[CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[CH:9][CH:10]=1)[CH3:21])[CH3:26]
Reactant: CCOC(=O)[C@H](C)N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)O
Reactant: CNc1nnnn1Cc1ccc(OC)cc1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](C)N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)N(C)c1nnnn1Cc1ccc(OC)cc1
Reaction time: 0.17 h
Yield: 75.5 %

Procedure:
To a suspension of (S)-3-(3′-chloro-biphenyl-4-yl)-2-((S)-1-ethoxycarbonyl-ethylamino)-propionic acid (225 mg, 0.599 mmol) in dichloromethane (4 mL) and saturated aqueous NaHCO3 (1 mL) was added triphosgene (178 mg, 0.599 mmol). After vigorously stirred for 10 min, the reaction mixture was diluted with EtOAc and partially concentrated under reduced pressure. Excess of triphosgene was quenched by adding saturated aqueous NaHCO3 and stirred for 0.5 hour. The mixture was extracted with EtOAc and washed with brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane (5 mL). To the mixture were added triethylamine (0.167 mL, 1.197 mmol) and [1-(4-methoxy-benzyl)-1H-tetrazol-5-yl]-methyl-amine (197 mg, 0.898 mmol) and stirred at 45° C. overnight. Additional triethylamine (0.167 mL, 1.197 mmol) and [1-(4-methoxy-benzyl)-1H-tetrazol-5-yl]-methyl-amine (197 mg, 0.898 mmol) were added and stirred at 45° C. for 30 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: 10% MeOH in DCM) to give (S)-2-((S)-2-(3′-chloro-biphenyl-4-yl)-1-{[1-(4-methoxy-benzyl)-1H-tetrazol-5-yl]-methyl-carbamoyl}-ethylamino)-propionic acid ethyl ester (261 mg). MS: m/z (MH+) 577; HPLC retention time 1.36 min (HPLC condition C).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][CH:15]([C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:47][CH2:48][N:49]1[CH2:54][CH2:53][N:52]([C:55](=[O:57])[CH3:56])[CH2:51][CH2:50]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl.CCCCCCC>[C:55]([N:52]1[CH2:53][CH2:54][N:49]([CH2:48][CH2:47][O:24][C:21]2[CH:22]=[CH:23][C:18]([CH:15]3[CH2:16][CH2:17][N:12]([C:9]4[CH:10]=[CH:11][C:6]5[N:7]([C:3]([C:2]([F:1])([F:25])[F:26])=[N:4][N:5]=5)[N:8]=4)[CH2:13][CH2:14]3)=[CH:19][CH:20]=2)[CH2:50][CH2:51]1)(=[O:57])[CH3:56]
Reactant: CC(=O)N1CCN(CCO)CC1
Reactant: Oc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCCC
Solvent: ClCCl
Product: CC(=O)N1CCN(CCOc2ccc(C3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)cc2)CC1
Temperature: 23.5 °C
Reaction time: 0.17 h
Yield: 85.9 %

Procedure:
Dichloromethane (225.0 mL) and 4-{1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenol (50.0 g, 138 m mol) were charged to a suitable round bottom flask at 22-25° C. Triphenylphosphine (72.2 g, 275 m mol) and 1-[4-(2-hydroxy-ethyl)piperazin-1-yl]ethanone [CAS: 83502-55-0] (47.4 g, 275 m mol) were added successively to the reaction mass and stirred for 10 min at 22-25° C. Di-isopropyl azodicarboxylate (55.65 g, 275 m mol) in dichloromethane (75.0 mL) was added to the reaction mass slowly drop wise at 25-30° C. over a period of 60-90 min. The resulting reaction mass was stirred for 1.0 h at 25-30° C. to complete the reaction. n-Heptane (600.0 mL) was introduced to the reaction mass by drop wise addition over a period of 15-30 min at 22-25° C. and stirred for 30 min at the same temperature. Thus precipitated solid was filtered and washed with n-heptane (150.0 mL). The material was then suck dried for 30 min under reduced pressure. The crude material was purified by slurry washing in methanol (325.0 mL) at 22-25° C. The solid was then collected by filtration and washed with methanol (50.0 mL). The material was dried under reduced pressure with nitrogen gas bleed at 50° C. to afford the desired product 6-[4-[4-[2-(4-acetylpiperazin-1-yl)ethoxy]phenyl]piperidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (61.2 g, 84%) as a free flowing solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[I:15]Cl.O>C(O)(=O)C>[OH:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][C:11]=1[I:15]
Reactant: COC(=O)c1ccc(O)c([N+](=O)[O-])c1
Reactant: ClI
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cc(I)c(O)c([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 91075.4 %

Procedure:
To a solution of methyl 4-hydroxy-3-nitrobenzoate (2.0 g) in acetic acid (15 mL) was added iodine monochloride (1.65 mg) in acetic acid, and the mixture was stirred at 100° C. for 1.5 h. After cooling to room temperature, the mixture was poured into water (200 mL), and stirred for 30 min. The mixture was filtered and washed with water and hexanes. The yellow powder was collected by filtration and dried in vacuum oven overnight to give 2.99 g of the title compound: 1H NMR (300 MHz, CDCl3) δ 11.68, 8.81, 8.72, 3.96.
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]#[C:3][CH3:4].ClC(OCC(C)C)=O.CN1CCOCC1.[NH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28][C:27]([C:35]#[N:36])=[C:26]2[NH:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([Br:44])[CH:39]=1>O1CCCC1>[Br:44][C:40]1[CH:39]=[C:38]([NH:37][C:26]2[C:25]3[C:30](=[CH:31][C:32]([O:33][CH3:34])=[C:23]([NH:22][C:1](=[O:6])[C:2]#[C:3][CH3:4])[CH:24]=3)[N:29]=[CH:28][C:27]=2[C:35]#[N:36])[CH:43]=[CH:42][CH:41]=1
Reactant: COc1cc2ncc(C#N)c(Nc3cccc(Br)c3)c2cc1N
Reactant: CC#CC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC#CC(=O)Nc1cc2c(Nc3cccc(Br)c3)c(C#N)cnc2cc1OC
Yield: 53.3 %

Procedure:
To a solution of 1.44 g (17.14 mmol) of 2-butynoic acid and 2.26 g (16.5 mmol) of isobutyl chloroformate in 30 ml of tetrahydrofuran at 0° C., with stirring , was added 3. 1 g (3.4 mmol) of N-methyl morpholine. This solution of the mixed anhydride was added to a stirred solution of 1.13 g (3.06 mmol) of 6-amino-4-[(3-bromophenyl)amino]-7-methoxy-3-quinolinecarbonitrile in 30 ml tetrahydrofuran in three portions over a 24 hour period. The solvent was removed. The residue was stirred with dilute sodium bicarbonate solution. Solid was collected and washed with water and ether. This was recrystallized from 1-butanol. The resulting solid was taken up in hot tetrahydrofuran and filtered through silica gel. The filtrate was concentrated and diluted with hexanes to give 0.71 g of N-[4-[(3-bromophenyl)amino]-3-cyano-7-methoxy -6-quinolinyl]-2-butynamide as a yellow powder: mass spectrum (electrospray, m/e): M+H 437.1,438.1.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[I:14]I.C(Cl)(Cl)Cl>CC(O)=O.[Hg](OC(C)=O)OC(C)=O>[N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7]([I:14])[C:5]=1[NH2:6])([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: II
Agent: CC(=O)O[Hg]OC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Nc1c(I)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 12 h
Yield: 81.3 %

Procedure:
To a solution of 2,4-dinitroaniline (3.0 g, 16 mmol) and Hg(OAc)2 (6.8 g, 21 mmol) in 40 ml of AcOH was added 5.0 g (19 mmol) of I2 in 100 ml of AcOH dropwise and reaction mixture was stirred for 12 h. The reaction mixture was concentrated in vacuo, yielding a dark residue which was diluted with EtOAC and washed with aqueous NaHCO3. Organic layer was dried over MgSO4 and concentrated in vacuo to produce dark residue which was subjected to column chromatography (CHCl3, neat) to provide 4.1 g (13 mmol, 81%) of 2,4-dinitro-6-iodoaniline.
Reaction SMILES: Cl.[S:2]1[CH:6]=[C:5]([C:7](=[O:24])[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[CH2:12][CH2:11]2)[C:4]2[CH:25]=[CH:26][CH:27]=[CH:28][C:3]1=2.[BH4-].[Na+].O>CO>[S:2]1[CH:6]=[C:5]([CH:7]([OH:24])[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[CH2:12][CH2:11]2)[C:4]2[CH:25]=[CH:26][CH:27]=[CH:28][C:3]1=2
Reactant: COc1ccccc1N1CCN(CCC(=O)c2csc3ccccc23)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccccc1N1CCN(CCC(O)c2csc3ccccc23)CC1
Yield: 30 %

Procedure:
To 500 mg of 1-(benzo[b]thiophen-3-yl)-3-[4-(2-methoxyphenyl)piperazin-1-yl]propan-1-one hydrochloride (1.20×10−3 moles) in 30 ml of MeOH a 0° C. was added NaBH4 for about 20 min until the reaction ceased to evolve. After two hours 50 ml of H2O were added to the medium, it was stirred for a few minutes and was extracted twice with 200 ml of AcOEt. The organic phase was washed three times with H2O, was dried with Na2SO4 and the solvent was removed. It was purified in silica column with AcOEt/hexane (1:1). The free base was thus obtained in form of a white solid. Yield: 30%. Two polymorphic forms of this product were obtained, the melting points of which were 108° C. and 120° C. respectively.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH3:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:22]=[CH:21][CH:20]=[CH:19][C:12]=1[C:13]([NH:15][CH:16]([CH3:18])[CH3:17])=[O:14].C(N(C(C)C)CC)(C)C.COCCO>O>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:22]=[CH:21][CH:20]=[CH:19][C:12]=2[C:13]([NH:15][CH:16]([CH3:18])[CH3:17])=[O:14])[C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: CC(C)NC(=O)c1ccccc1N
Reactant: Cc1cnc(Cl)nc1Cl
Solvent: COCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1cnc(Cl)nc1Nc1ccccc1C(=O)NC(C)C
Temperature: 130 °C
Reaction time: 36 h
Yield: 77 %

Procedure:
A vessel was charged with 2,4-dichloro-5-methylpyrimidine (5.0 g, 28 mmol), 2-amino-N-(1-methyethyl)benzamide (5.46 g, 34.3 mmol), di-isopropyl-ethylamine (7.0 mL, 42 mmol) and 2-(methyloxy)ethanol (30 mL) and sealed and heated with stirring at 130° C. for 36 hours. The reaction was cooled to room temperature and 50 mL water was added dropwise to afford a milky white solution, which was heated to 100° C. to induce precipitation. The solution was cooled and the solid collected by filtration. The collected solid was washed successively with water (2×50 mL) and hexane (3×50 mL). After drying, a white solid was collected (6.56 g, 77% yield) and identified as 2-[(2-chloro-5-methyl-4-pyrimidinyl)amino]-N-(1-methyethyl)benzamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.51 (1H, s) 8.56-8.63 (2H, m) 8.15 (1H, s) 7.81 (1H, dd, J=7.83, 1.52 Hz) 7.58 (1H, dd, J=15.66, 1.52 Hz) 7.17 (1H, dd, J=15.28, 1.14 Hz) 4.13 (1H, dd, J=14.02, 6.69 Hz) 2.18 (3H, s) 1.18 (6H, d, J=6.57 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH2:11][CH2:12][CH2:13][NH2:14])[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[Br:15]N1C(=O)CCC1=O>C(#N)C>[Br:15][C:8]1[C:6]2[N:7]=[C:2]([Cl:1])[N:3]=[C:4]([CH2:11][CH2:12][CH2:13][NH2:14])[C:5]=2[S:10][CH:9]=1
Reactant: NCCCc1nc(Cl)nc2ccsc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: NCCCc1nc(Cl)nc2c(Br)csc12
Temperature: 50 °C
Reaction time: 6 h
Yield: 64.6 %

Procedure:
8.34 g (36.63 mmol) of (2-chlorothieno[3,2-d]pyrimidin-4-yl)propylamine (IV) is dissolved in 60 mL of acetonitrile iii and 7.89 g (44.32 mmol) of N-bromosuccinimide is added. The reaction mixture is stirred for 16 hours at ambient temperature and for 6 hours at 50° C. Then it is concentrated by evaporation and the residue is combined with water. The precipitate formed is suction filtered, washed, and dried. 7.25 g of product V (61%) is obtained as a powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[NH:8][C:7]=1[CH2:17][CH2:18][NH2:19])[CH3:2].[OH-].[Na+].[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[NH:8][C:7]=1[CH2:17][CH2:18][NH:19][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][C:24]([Cl:23])=[CH:25][CH:26]=1)[CH3:2]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1c(CCN)[nH]c2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOC(=O)Cc1c(CCNC(=O)c2ccc(Cl)cc2)[nH]c2ccc(OC)cc12

Procedure:
61.7 g (0.223 mol) of the 2-aminoethyl-5-methoxy-indole-3-acetic acid ethyl ester produced in (d) are dissolved in 600 ml of methylene chloride and the solution is covered with a layer of 150 ml of 2 N sodium hydroxide solution. A solution of 43 g (0.245 mol) of p-chlorobenzoyl chloride is added, at 0°-5°, in the course of 21/2 hours, while stirring vigorously, and extraction by stirring is then carried out for a further hour. The methylene chloride phase is then separated off, washed with water, dried over MgSO4 and concentrated to dryness by evaporation. The residue crystallises on being taken up in ether, to form colourless crystals of 2-[(p-chlorobenzoyl-amino)-ethyl]-5-methoxy-indole-3-acetic acid ethyl ester having a melting point of 136°-138°.