Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([S:39][C:40]2[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=2)([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][C:23]([O:31][Si](C(C)(C)C)(C)C)=[C:24]([O:29][CH3:30])[CH:25]=3)[CH2:20]2)[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([S:39][C:40]2[CH:41]=[CH:42][C:43]([CH3:46])=[CH:44][CH:45]=2)([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][C:23]([OH:31])=[C:24]([O:29][CH3:30])[CH:25]=3)[CH2:20]2)[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C(C#N)(CCCCCN2CCc3cc(OC)c(O[Si](C)(C)C(C)(C)C)cc3C2)Sc2ccc(C)cc2)cc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1cc2c(cc1O)CN(CCCCCC(C#N)(Sc1ccc(C)cc1)c1ccc(OC)c(OC)c1)CC2
Reaction time: 5 h
Yield: 100.3 %

Procedure:
To a solution of 1.0 g of α-(3,4-dimethoxyphenyl)-7-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3,4-dihydro-6-methoxy-α-[(4-methylphenyl)thio]-2(1H)-isoquinolineheptanenitrile in 30 mL of tetrahydrofuran is added 3.02 mL of a 1.0M solution of tetrabutylammonium fluoride in tetrahydrofuran. This is sealed and stirred for 5 hours. The reaction mixture is evaporated and the residue taken up in ethyl acetate. The solution is washed three times with water, and the organic phase is separated and evaporated. The gum remaining is redissolved in chloroform and the solution evaporated in yacuo at 66° C. This process is repeated twice more affording 0.83 g of the desired product as a brown gum.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:12]([NH2:13])=[CH:11][C:10]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:9][N:8]=2)[CH2:3][CH2:2]1.Cl[C:21]1[C:30]2[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=2)[N:24]=[C:23]([C:32]2[CH:33]=[N:34][CH:35]=[C:36]([F:38])[CH:37]=2)[C:22]=1[CH3:39].Cl.O1CCOCC1.CN1C(=O)CCC1>>[N:4]1([C:7]2[C:12]([NH:13][C:21]3[C:30]4[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=4)[N:24]=[C:23]([C:32]4[CH:33]=[N:34][CH:35]=[C:36]([F:38])[CH:37]=4)[C:22]=3[CH3:39])=[CH:11][C:10]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[CH:9][N:8]=2)[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: Cc1c(-c2cncc(F)c2)nc2cc(F)ccc2c1Cl
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: Cc1c(-c2cncc(F)c2)nc2cc(F)ccc2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Temperature: 150 °C

Procedure:
Prepared according to Procedure K, method 2 using 2,5-dimorpholinopyridin-3-amine (43 mg, 0.16 mmol; described herein), 4-chloro-7-fluoro-2-(5-fluoropyridin-3-yl)-3-methylquinoline (47 mg, 0.16 mmol; described herein), 4.0M hydrochloric acid in 1,4-dioxane (4 μL, 0.1 equiv, 16 μmol), and NMP (190 μL, 1.9 mmol). The reaction was heated in a microwave at 150° C. for 4 h. Purification afforded N-(2,5-di-4-morpholinyl-3-pyridinyl)-7-fluoro-2-(5-fluoro-3-pyridinyl)-3-methyl-4-quinolinamine as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 8.69 (1H, m), 8.60 (1H, d, J=2.7 Hz), 7.84 (1H, m), 7.76 (2H, m), 7.64 (1H, d, J=2.7 Hz), 7.33 (1H, m), 6.81 (1H, s), 6.21 (1H, d, J=2.7 Hz), 3.89-3.97 (4H, m), 3.72-3.79 (4H, m), 3.24 (4H, m), 2.89-2.98 (4H, m), 2.33 (3H, s). Mass Spectrum (ESI) m/e=519.0 (M+1).
Reaction SMILES: [BH4-].[Na+].[C:3]1([N:9]2[C:13]3[CH:14]=[N:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[C:18](=[O:20])[CH3:19])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl-].[NH4+]>CO>[C:3]1([N:9]2[C:13]3[CH:14]=[N:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[CH:18]([OH:20])[CH3:19])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)c1nc2ccncc2n1-c1ccccc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CC(O)c1nc2ccncc2n1-c1ccccc1
Reaction time: 0.25 h
Yield: 86.4 %

Procedure:
Sodium borohydride (0.27 g, 7.17 mmol) was added to a stirred suspension of 1-(3-phenyl-3H-imidazo[4,5-c]pyridin-2-yl)ethanone (0.85 g, 3.58 mmol) in methanol (20 mL) at 0° C. under nitrogen. The reaction mixture was stirred for 15 minutes then poured into saturated aqueous ammonium chloride solution and extracted with EtOAc (3×50 mL). The combined EtOAc extracts were washed with water, dried (Na2SO4) and concentrated in vacuo to give the title compound as a white solid (0.74 g, 87%). LCMS (method H): Rt 1.76 min, [M+H]+ 240.
Reaction SMILES: NC1C=C(OC)C(OC)=CC=1C(C1C=CC=CC=1Cl)=O.NC1C(C)=NN(CC=C)C=1Cl.[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]1[C:45]2[CH:46]=[C:47]([O:52][CH3:53])[C:48]([O:50][CH3:51])=[CH:49][C:44]=2[N:43]=[C:42]2[N:54](CC=C)[NH:55][C:56]([CH3:57])=[C:41]2[N:40]=1.[H-].C([Al+]CC(C)C)C(C)C>>[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]1[C:45]2[CH:46]=[C:47]([O:52][CH3:53])[C:48]([O:50][CH3:51])=[CH:49][C:44]=2[N:43]=[C:42]2[NH:54][NH:55][C:56]([CH3:57])=[C:41]2[N:40]=1
Reactant: C=CCN1NC(C)=C2N=C(c3ccccc3Cl)c3cc(OC)c(OC)cc3N=C21
Agent: C=CCn1nc(C)c(N)c1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: COc1cc(N)c(C(=O)c2ccccc2Cl)cc1OC
Product: COc1cc2c(cc1OC)C(c1ccccc1Cl)=NC1=C(C)NNC1=N2

Procedure:
5-(2-chlorophenyl)-1,2-dihydro-7,8-dimethoxy-3-methyl-pyrazolo[3,4-b][1,4]benzodiazepine (IVx) was prepared by reacting 0.00093 moles of (2-amino-4,5-dimethoxyphenyl)(2-chlorophenyl)-methanone (Xx) with 4-amino-5-chloro-3-methyl-1-(2-propenyl)-1H-pyrazole (XIII), and subsequent dealkylation of the intermediate, 5-(2-chlorophenyl)-1,2-dihydro-7,8-dimethoxy-3-methyl-1-(2-propenyl)-pyrazolo[3,4-b][1,4]benzodiazepine (XIVx) with diisobutylaluminum hydride in a manner analogous to Example 72. MH+/Z=369.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH:4]([O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2)[CH3:5].O1CCOCC1.[OH-].[Na+].Cl>CO>[CH3:5][CH:4]([O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2)[C:3]([OH:16])=[O:2]
Reactant: COC(=O)C(C)Oc1cccc2[nH]ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CC(Oc1cccc2[nH]ccc12)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
To a solution of 2-methylindol-4-yloxyacetic acid methyl ester (5.4 g) in methanol (18 ml)—dioxane (36 ml) was added 5N aqueous solution of sodium hydroxide (15 ml), and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added 2N hydrochloric acid to give the title compound (3.5 g) having the following physical data.
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][N:5]=[C:4]([NH2:9])[CH:3]=1.[CH3:10][N:11]1C(=O)CCC1>[C-]#N.[Zn+2].[C-]#N>[NH2:9][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([C:10]#[N:11])=[CH:6][N:5]=1
Reactant: CN1CCCC1=O
Reactant: Nc1cc(Cl)c(I)cn1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cnc(N)cc1Cl
Temperature: 135 °C

Procedure:
(Tsuruoka, A., et. al. ibid) Zinc cyanide (0.254 g, 2.17 mmol) and tetrakistriphenylphosphine palladium (0) (0.460 g, 0.394 mmol) were added to a solution of compound ii (1.00 g, 3.94 mmol) in NMP (10 mL). The reaction mixture was heated under N2(g) to 135° C. for 2 h, cooled to room temperature and partitioned between EtOAc (30 mL) and aqueous ammonia solution (0.35%, 50 mL). The organic fraction was separated, washed successively with water (2×100 mL) and brine (30 mL), dried (MgSO4) and reduced in vacuo onto SiO2. Column chromatography (SiO2), eluting with 2:1 Petrol-EtOAc to 1:1 Petrol-EtOAc, afforded compound iii. (0.360 g, 2.35 mmol, 60%) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:33]=[CH:32][C:23]([C:24]([NH:26][CH2:27][C@@H:28]([OH:31])[CH2:29][OH:30])=[O:25])=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=O)=[C:4]([F:34])[CH:3]=1.Cl.[NH2:36][OH:37].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:21]=[CH:22][C:23]([C:24]([NH:26][CH2:27][C@@H:28]([OH:31])[CH2:29][OH:30])=[O:25])=[CH:32][CH:33]=2)[CH2:9]/[C:10](=[N:36]\[OH:37])/[C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[C:4]([F:34])[CH:3]=1
Reactant: NO
Reactant: Cn1cc(C(=O)CC(c2ccc(C(=O)NC[C@@H](O)CO)cc2)c2ccc(Cl)cc2F)ccc1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(/C(CC(c2ccc(C(=O)NC[C@@H](O)CO)cc2)c2ccc(Cl)cc2F)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, 4-(1-(4-chloro-2-fluorophenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)-N—((R)-2,3-dihydroxypropyl)benzamide was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as a colourless solid containing <10% of the corresponding Z isomer, MS (ESI+): m/z=502.1 [M+H]+.
Reaction SMILES: C(OC([C:8]1([NH2:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:15][O:16][CH2:17][C:18](Cl)=[O:19]>>[NH2:14][CH:8]1[CH2:9][CH2:10][N:11]([C:18](=[O:19])[CH2:17][O:16][CH3:15])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)C1(N)CCNCC1
Reactant: COCC(=O)Cl
Product: COCC(=O)N1CCC(N)CC1

Procedure:
Starting from 4-amino-piperidine-4-carboxylic acid tert-butyl ester and methoxy-acetyl chloride the title compound is obtained as slightly brown oil.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[CH:18]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)([CH3:20])[CH3:19]>>[F:17][C:4]1[CH:3]=[C:2]([C:24]2[CH:25]=[CH:26][C:21]([CH:18]([CH3:20])[CH3:19])=[CH:22][CH:23]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: CC(C)c1ccc(B(O)O)cc1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(C(C)C)cc4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, off-white solid (69 mg, 82%), MS (ISP) m/z=337.5 [(M+H)+], mp 177° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 4-isopropyl-phenylboronic acid (53.3 mg, 0.325 mmol).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]([CH3:23])[C:7](=[O:22])[N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)=[C:4](Cl)[N:3]=1.O.[NH2:26][NH2:27]>C(O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]([CH3:23])[C:7](=[O:22])[N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)=[C:4]([NH:26][NH2:27])[N:3]=1
Reactant: NN
Reactant: COc1ccc(Cn2c(=O)n(C)c3c(Cl)nc(N)nc32)cc1OC
Solvent: CCO
Solvent: O
Product: COc1ccc(Cn2c(=O)n(C)c3c(NN)nc(N)nc32)cc1OC
Temperature: 92.5 °C
Yield: 73.1 %

Procedure:
A mixture of 2-amino-6-chloro-9-[(3,4-dimethoxyphenyl)methyl]-7-methyl-purin-8-one obtained in step 3 (9.0 g, 25.73 mmol), Hydrazine hydrate (16 ml, 257.3 mmol) and ethanol (675 ml) were heated at 90-95° C. for 40 hours. The reaction mixture was concentrated and solid obtained was filtered off and dried to obtain 2-amino-9-[(3,4-dimethoxyphenyl)methyl]-6-hydrazino-7-methyl-purin-8-one (6.5 g, 74%) as an off white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C1N2CN3CN(C2)CN1C3.[C:21](O)(=[O:23])C>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([CH:21]=[O:23])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(=O)O
Reactant: Clc1cnc2[nH]ccc2c1
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: O=Cc1c[nH]c2ncc(Cl)cc12
Reaction time: 0.5 h
Yield: 59.2 %

Procedure:
In a round bottom flask, 5-chloro-1H-pyrrolo[2,3-b]pyridine (1, 10.0 g, 65.5 mmol) was combined with hexamethylenetetramine (11.9 g, 85.2 mmol), acetic acid (28.3 mL, 0.498 mol) and 56.7 mL of water. The reaction was heated at reflux overnight, then 200 mL of water was added. After 30 minutes, solid material was collected by filtration and dried to give the desired compound (114, 7.0 g).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].O.Cl>C(O)C>[N+:18]([C:15]1[CH:16]=[CH:17][C:12]([N:9]2[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]2)=[CH:13][CH:14]=1)([O-:20])=[O:19]
Reactant: CCOC(=O)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C

Procedure:
The 1-(4-nitrophenyl)piperidine-4-carboxylic acid ethyl ester (2.78 g, 10 mmol) obtained in Example 2(1) was dissolved in ethanol (10 ml), and a 4 N sodium hydroxide aqueous solution (5 ml, 20 mmol) was added thereto. The mixture was refluxed under heat for 1 hour. After cooling to room temperature, water (30 ml) and 2 N hydrochloric acid (10 ml) were added to the mixture, and the precipitate was collected by filtration, thereby obtaining 1-(4-nitrophenyl)piperidine-4-carboxylic acid (2.47 g, 97%) as a yellow solid.
Reaction SMILES: ClC1C=CC=CC=1C(=O)[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[CH:20]=[C:19]([CH3:21])[N:18]=[C:17]1[CH2:22][N:23]1[C:27](=O)C2=CC=CC=C2C1=O.NN>C(O)C>[Cl:15][C:13]1[CH:14]=[CH:9][C:10]2[N:16]3[CH:20]=[C:19]([CH3:21])[N:18]=[C:17]3[CH2:22][N:23]=[C:27]([C:12]3[CH:11]=[CH:10][CH:9]=[CH:14][C:13]=3[Cl:15])[C:11]=2[CH:12]=1
Reactant: Cc1cn(-c2ccc(Cl)cc2C(=O)c2ccccc2Cl)c(CN2C(=O)c3ccccc3C2=O)n1
Agent: NN
Solvent: CCO
Product: Cc1cn2c(n1)CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2

Procedure:
In the manner given in Example 25, 2',5-dichloro-2-[4-methyl-2-(phthalimidomethyl)imidazol-1-yl]benzophenone in ethanol is heated with hydrazine to give 8-chloro-6-(o-chlorophenyl)-2-methyl-4H-imidazo[1,2-a][1,4]benzodiazepine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:14])[N:9]([CH2:11][O:12][CH3:13])[N:10]=[C:4]2[C:3]=1I.[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:14])[N:9]([CH2:11][O:12][CH3:13])[N:10]=[C:4]2[C:3]=1[C:20]1[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=1
Reactant: COCn1nc2c(I)c(Br)ccn2c1=O
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COCn1nc2c(-c3ccc(Cl)cc3)c(Br)ccn2c1=O
Temperature: 20 °C
Yield: 94.9 %

Procedure:
To a degassed mixture of 7-bromo-8-iodo-2-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (3.0 g, 7.8 mmol), 4-chlorophenylboronic acid (1.32 g, 8.6 mmol) and K2CO3 (2.16 g, 15.6 mmol) in 1,4-dioxane (42 mL) and H2O (14 mL) under argon at 20° C. was added Pd(PPh3)4 (450 mg, 0.39 mmol). The reaction mixture was refluxed for 40 h under argon and then cooled to 20° C. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (3×50 mL). The combined organic extract was washed with saturated aqueous NaHCO3 solution (50 mL), then brine (50 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was successively triturated with hexanes and Et2O and dried under high vacuum to obtain the title compound as a light yellow solid (2.7 g, 7.4 mmol) in 85% purity along with bis-4-chlorophenyl coupled by-product. The crude product was used without further purification. MS: [M+H]+=368.0.
Reaction SMILES: [F:1][CH2:2][S:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=O.[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[H+].[B-:36]([F:40])([F:39])([F:38])[F:37]>C(OCC)C>[F:37][B-:36]([F:40])([F:39])[F:38].[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][C:18]=1[S+:3]([CH2:2][F:1])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1
Reactant: Cc1ccc(C)cc1
Reactant: Cc1ccc(S(=O)CF)cc1
Agent: F[B-](F)(F)F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [H+]
Solvent: CCOCC
Product: Cc1ccc([S+](CF)c2cc(C)ccc2C)cc1

Procedure:
1-((fluoromethyl)sulfinyl)-4-methylbenzene (535 mg, 3.38 mmol) of example 5 was dissolved in dry diethyl ether (15 mL) under an argon atmosphere. P-xylene (0.42 mL, 1.0 eq) was added to the previous solution. The mixture was cooled to a temperature below −50° C. After stabilizing the temperature, trifluoromethanesulfonic anhydride (0.52 mL, 0.92 eq) was added slowly maintaining the same temperature. The mixture was stirred, at the same temperature, until the reaction was complete. HBF4 in diethyl ether solution (54%, 1.29 mL, 2.77 eq) was added. The resulting suspension was stirred for 30 minutes. The precipitate tetrafluoroborate salt was isolated by filtration and washed with diethyl ether at 0° C. The desired product was obtained as a slightly yellow oily solid (2.25 g). after heating at room temperature
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][CH:3]=1.S1C=NN=C1NC(=O)C1C=CC=CC=1.[CH3:28][C:29]1[CH:42]=[CH:41][C:32]([C:33]([NH:35][C:36]2[S:37][CH:38]=[N:39][N:40]=2)=[O:34])=[CH:31][C:30]=1B1OC(C)(C)C(C)(C)O1>CC(O)C>[S:37]1[CH:38]=[N:39][N:40]=[C:36]1[NH:35][C:33]([C:32]1[CH:31]=[C:30]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][C:10]([CH3:13])=[N:11][N:12]=3)=[CH:4][CH:3]=2)[C:29]([CH3:28])=[CH:42][CH:41]=1)=[O:34]
Reactant: Cc1nnc(-c2ccc(I)cc2)o1
Reactant: Cc1ccc(C(=O)Nc2nncs2)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C(Nc1nncs1)c1ccccc1
Solvent: CC(C)O
Product: Cc1nnc(-c2ccc(-c3cc(C(=O)Nc4nncs4)ccc3C)cc2)o1

Procedure:
Example 33 was prepared using 2-(4-iodophenyl)-5-methyl-[1,3,4]oxadiazole (Intermediate 15) and 4-methyl-3-4,4,5,5, -tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-([1,3,4]thiadiazol-2-yl)-benzamide (Intermediate 23) with propan-2-ol as the solvent.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]Br.C(O)C.[S:11]([O-:14])([O-:13])=[O:12].[Na+:15].[Na+]>O>[Na+:15].[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][S:11]([O-:14])(=[O:13])=[O:12]
Reactant: BrCCCCCBr
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=S(=O)([O-])CCCCCBr
Yield: 44.8 %

Procedure:
To a solution of 1,5-dibromopentane (23.2 g, 101 mmol), ethanol (40 mL) and water (40 mL) was dropwise added a solution of sodium sulfite (4.24 g, 33.6 mmol) in water (15 mL) under heating under reflux over 2 hr. After heating under reflux for 2 hr, the solvent was distilled away under reduced pressure and n-hexane/ethanol was added. The precipitated crystals were washed with n-hexane and dried in vacuo to give the title compound (3.81 g, 45%).
Reaction SMILES: [C:1]([NH:5][C:6](=[O:41])[CH:7]([NH:17][C:18]([N:20]1[CH2:25][CH2:24][C:23](=[C:26]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[CH:30]=[CH:29][C:28]3[CH:37]=[CH:38][CH:39]=[CH:40][C:27]2=3)[CH2:22][CH2:21]1)=[O:19])[CH2:8][O:9][Si](C(C)(C)C)(C)C)([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>O1CCCC1>[C:1]([NH:5][C:6](=[O:41])[CH:7]([NH:17][C:18]([N:20]1[CH2:25][CH2:24][C:23](=[C:26]2[C:27]3[CH:40]=[CH:39][CH:38]=[CH:37][C:28]=3[CH:29]=[CH:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]2=3)[CH2:22][CH2:21]1)=[O:19])[CH2:8][OH:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)C(CO[Si](C)(C)C(C)(C)C)NC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)C(CO)NC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Reaction time: 0.5 h

Procedure:
113 mg (0.197 mmol) of N-[2-(t-butylamino)-1-({[t-butyl(dimethyl) silyl]oxy}methyl)-2-oxoethyl]-4-(5H-dibenzo[a,d] [7] annulen-5-ylidene)-1-piperidinecarboxamide was dissolved in 3 ml of tetrahydrofuran. 0.22 ml of 1 M tetrabutylammonium fluoride/tetrahydrofuran solution was added to the obtained solution, and they were stirred for 30 minutes. After the purification by the silica gel chromatography (hexane:ethyl acetate=9:1 to 3:2), the title compound was obtained.
Reaction SMILES: O=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:5]=[CH:4][C:3]1=2.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][NH2:31].[BH3-]C#N.[Na+]>Cl[Ti](Cl)(Cl)Cl>[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][NH:31][CH:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: NCCc1ccccc1F
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCC3=O)nc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCCC3NCCc2ccccc2F)nc1
Yield: 83 %

Procedure:
Using a method similar to Example 1, using 6-(5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-nicotinamide (Intermediate 2, 846 mg, 3.00 mmol), 2-(2-fluorophenyl)ethylamine (501 mg, 3.60 mmol), Ti(iPrO)4 (1.70 g, 6.00 mmol), TiCl4 (1.0M/DCM, 6.00 ml, 6.00 mmol), and NaBH3CN (377 mg, 6.00 mmol) gives the title compound (1.01 g) as a white solid. Mass spectrum (ion spray): m/z=406 (M+1); 1HNMR (CDCl3): 8.59 (s, 1H), 8.15 (d, 1H), 7.35 (d, 1H), 7.26-7.16 (m, 2H), 7.09-6.99 (m, 2H), 6.93 (d, 1H), 6.89 (d, 1H), 6.84 (s, 1H), 5.89 (br. s, 2H), 3.81 (t, 1H), 3.07-2.85 (m, 4H), 2.83-2.67 (m, 2H), 1.98-1.80 (m, 3H), 1.73 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])C=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.NC1N=C(N)C(CC2C=C[C:32]([OH:35])=C(OC)C=2)=CN=1>>[CH3:18][O:17][C:16]1[CH:15]=[C:14]([CH:11]=[CH:10][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:32]=[O:35]
Reactant: COc1cc(Cc2cnc(N)nc2N)ccc1O
Reactant: COc1ccc(C=O)cc1OCc1ccccc1
Agent: Cl
Product: COc1cc(C=O)ccc1OCc1ccccc1

Procedure:
In a manner substantially analogous to that described in Example 1, Steps A-C, but substituting for 3-benzyloxy-4-methoxybenzaldehyde used therein, an equimolar amount of 3-methoxy-4-benzyloxybenzaldehyde, there is prepared 2,4-diamino-5-(3'-methoxy-4'-hydroxybenzyl)pyrimidine hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH2:15][C:16]([NH:18][C:19]3([C:27]([O:29]C)=O)[CH2:24][CH2:23][C:22]([F:26])([F:25])[CH2:21][CH2:20]3)=[O:17])[C:9]=2[CH3:31])=[CH:4][CH:3]=1.CN(C)C(=O)C.CC(C)([O-])C.[K+].Cl>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([C:15]3[C:16](=[O:17])[NH:18][C:19]4([CH2:20][CH2:21][C:22]([F:26])([F:25])[CH2:23][CH2:24]4)[C:27]=3[OH:29])[C:9]=2[CH3:31])=[CH:4][CH:3]=1
Reactant: COC(=O)C1(NC(=O)Cc2c(C)ccc(-c3ccc(Cl)cc3)c2C)CCC(F)(F)CC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1ccc(-c2ccc(Cl)cc2)c(C)c1C1=C(O)C2(CCC(F)(F)CC2)NC1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2.55 g (5.29 mmol) of the compound from Example 9A were initially charged in a solution of 5 ml of DMA (N,N-dimethylacetamide), a solution of 5 ml of DMA and 1.88 g (3 eq.) of potassium tert-butoxide was added dropwise at 20° C. and the mixture was stirred at room temperature for 24 h. The mixture was poured into 200 ml of water and the reaction was adjusted to pH 2 using concentrated aqueous hydrochloric acid, and the resulting residue was filtered off with suction. Purification by flash column chromatography (silica gel; ethyl acetate/n-hexane 2:1) gave 0.87 g (31% of theory) of the title compound.