Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.CC([O-])(C)C.[K+].Cl.Br[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1>CS(C)=O>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: Brc1ccncc1
Reactant: OC1CCC2(CC1)OCCO2
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: c1cc(OC2CCC3(CC2)OCCO3)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
1,4-Dioxaspiro[4.5]decan-8-ol (4.93 g, 31.202 mmol, 1.0 eq.) was dissolved in DMSO (100 ml); potassium tert-butylate (10.5 g, 93.61 mmol, 3.0 eq.) was added at 0° C. and the mixture was stirred for 1 hour at RT. 4-Bromopyridine HCl (9.1 g, 46.803 mmol, 1.5 eq.) was then added at 0° C. and stirring was carried out for 16 hours at RT. After monitoring by TLC, the reaction mixture was concentrated and the residue was taken up in water (200 ml) and extracted with DCM (2×200 ml). The combined org. phases were washed with water (200 ml) and sat. NaCl solution (250 ml), dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (silica gel, 40% ethyl acetate in hexane). Yield: 35% (2.6 g, 11.063 mmol)
Reaction SMILES: [I:1]I.[NH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([S:12][CH3:13])[N:5]=1>C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[NH2:3][C:4]1[C:11]([I:1])=[CH:10][C:7]([C:8]#[N:9])=[C:6]([S:12][CH3:13])[N:5]=1
Reactant: CSc1nc(N)ccc1C#N
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: CSc1nc(N)c(I)cc1C#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
3.75 g (1.5 eq) of silver sulfate and 2.85 g (1.4 eq) of iodine are added successively to a solution of 1.32 g (8.02 mmol) of 6-amino-2-(methylthio)nicotinonitrile in 65 ml of ethanol. The reaction medium is stirred at room temperature for 3 hours. The solid is filtered and the residue rinsed thoroughly with methanol. The filtrate is evaporated and redissolved in ethyl acetate. The organic phase is washed with water three times, dried on magnesium sulfate and evaporated to yield 1.89 g (81%) of 6-amino-5-iodo-2-(methylthio)nicotinonitrile in the form of a brown powder.
Reaction SMILES: C[N:2](C)C=O.[OH-].[K+].[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1.NOS(O)(=O)=O>O>[NH2:2][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CN(C)C=O
Agent: NOS(=O)(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Nn1ccc2ccccc21
Yield: 32 %

Procedure:
To 50 ml of N,N-dimethylformamide were added 24.55 g(440 mmol) of potassium hydroxide and 3.201 g(27.3 mmol) of 1H-indole, and 6.15 g (54.4 mmol) of hydroxylamine-0-sulfonic acid was added thereto in small amounts under stirring. After stirring the reaction mixture at room temperature for 1 hour, 50 ml of water was added thereto and it was extracted three times with 100 ml of benzene. The extract was washed with water, dried and concentrated under the reduced pressure. Silica gel column chromatography of the residue using 50% dichloromethane/n-hexane as an eluent gave 1.16 g of the desired compound(32%).
Reaction SMILES: [H-].[Na+].Br[CH2:4][CH:5]([O:18][C:19](=[O:21])[CH3:20])[CH2:6][C:7]1[C:16]([OH:17])=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][CH:11]=[N:12]2>CN(C)C=O>[C:19]([O:18][CH:5]1[CH2:4][O:17][C:16]2[C:7](=[C:8]3[C:13](=[CH:14][CH:15]=2)[N:12]=[CH:11][CH:10]=[CH:9]3)[CH2:6]1)(=[O:21])[CH3:20]
Reactant: CC(=O)OC(CBr)Cc1c(O)ccc2ncccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OC1COc2ccc3ncccc3c2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a suspension of sodium hydride (60%, 0.27 g, 6.6 mmol) in anhydrous N,N-dimethylformamide (30 ml) was added a pre-cooled solution of acetic acid 1-bromomethyl-2-(6-hydroxyquinolin-5-yl)ethyl ester (intermediate 8) (1.96 g, 6.0 mmol) in 10 ml of N,N-dimethylformamide at 0° C. The reaction mixture was stirred at 0° C. for 1 hr, quenched with water, and extracted with methylene chloride. The organic layer was washed with water, dried over anhydrous sodium sulfate and filtered. The solvent was removed under vacuum. Chromatography (10% hexanes-ethyl acetate) afforded 0.89 g (61%) of 2,3-dihydro-1H-pyrano[3,2-f]quinolin-2-yl acetate as a white solid: mp 125.4–127° C. MS ESI m/z 244 [M+H]+. Elemental Analysis for C14H13NO3: Calculated: C, 69.12; H, 5.39; N, 5.76. Found: C, 69.12; H, 5.48; N, 5.64.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1.O1CCCC1.[CH2:25]([Mg]Br)[CH:26]([CH3:28])[CH3:27].[BH4-].[Na+]>CO>[CH3:25][CH:26]([CH3:28])[CH2:27][CH:8]([C:6]1[CH:5]=[CH:4][C:3]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:12][CH:11]=2)=[C:2]([CH3:1])[CH:7]=1)[NH2:9]
Reactant: Cc1cc(C#N)ccc1-c1ccc(C(F)(F)F)cc1
Reactant: CC(C)C[Mg]Br
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C(N)CC(C)C)ccc1-c1ccc(C(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 76.6 %

Procedure:
A microwave reaction vial was charged with 2-methyl-4′-(trifluoromethyl)biphenyl-4-carbonitrile (500 mg, 1.91 mmol) and tetrahydrofuran (5 mL). To the mixture was added isobutylmagnesium bromide (2.87 mL, 5.74 mmol, 2M in THF). The reaction was heated at 100° C. in a microwave for 30 minutes. The reaction mixture was then carefully added to a solution of sodium borohydride (145 mg, 3.83 mmol) in methanol (5 mL). After stirring for 5 minutes, the mixture was concentrated to dryness. Purification by column chromatography gave 3-methyl-1-(2-methyl-4′-(trifluoromethyl)biphenyl-4-yl)butan-1-amine (470 mg). 1H NMR (400 MHz, CD3OD, δ): 7.72 (d, 2H), 7.50 (d, 2H), 7.24 (s, 1H), 7.19 (d, 2H), 3.94 (m, 1H), 2.27 (s, 3H), 1.65 (m, 2H), 1.49 (m, 1H), 0.95 (d, 3H), 0.92 (d, 3H).
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[Cl:5][C:6]1[CH:32]=[CH:31][C:9]([CH2:10][NH:11][C:12]([C:14]2[C:15](=[O:30])[C:16]3[C:17]4[N:18]([CH:29]=2)[CH2:19][C:20](=[O:28])[N:21]([CH3:27])[C:22]=4[CH:23]=[C:24](I)[CH:25]=3)=[O:13])=[CH:8][CH:7]=1>C(NCC)C.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>[Cl:5][C:6]1[CH:32]=[CH:31][C:9]([CH2:10][NH:11][C:12]([C:14]2[C:15](=[O:30])[C:16]3[C:17]4[N:18]([CH:29]=2)[CH2:19][C:20](=[O:28])[N:21]([CH3:27])[C:22]=4[CH:23]=[C:24]([C:3]#[C:2][CH2:1][OH:4])[CH:25]=3)=[O:13])=[CH:8][CH:7]=1
Reactant: CN1C(=O)Cn2cc(C(=O)NCc3ccc(Cl)cc3)c(=O)c3cc(I)cc1c32
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCNCC
Product: CN1C(=O)Cn2cc(C(=O)NCc3ccc(Cl)cc3)c(=O)c3cc(C#CCO)cc1c32
Reaction time: 1.5 h

Procedure:
Propargyl alcohol (50 mg), cuprous iodide (50 mg) and a solution of PdCl2(PPh3)2 (1 mL, 0.15 M in THF) are added to a suspension of N-(4-chlorobenzyl)-9-iodo-1-methyl-2,7-dioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide (Preparation 23, 250 mg) in diethylamine (2.0 mL). The reaction is stirred for 90 min and the product is then extracted into chloroform and is chromatographed on silica gel. The desired product is eluted with 20% methanol/chloroform. Physical characteristics: 1H NMR (DMSO-d6) δ3.40, 4.36, 4.56, 5.22, 5.42, 7.36, 7.40, 7.44, 7.88, 8.76, 10.2. HRMS m/z 436.1064 (C23H18ClN3O4).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:13]([O:17][CH3:18])(=[O:16])[CH:14]=[CH2:15].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CC([O-])=O.CC([O-])=O.[Pd+2].C(#N)C>[NH2:4][C:3]1[CH:5]=[CH:6][C:7]([C:9]([F:12])([F:11])[F:10])=[CH:8][C:2]=1/[CH:15]=[CH:14]/[C:13]([O:17][CH3:18])=[O:16]
Reactant: C=CC(=O)OC
Reactant: Nc1ccc(C(F)(F)F)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1cc(C(F)(F)F)ccc1N
Temperature: 90 °C
Yield: 36.5 %

Procedure:
A 100 ml 3-neck flask with magnetic stirrer was charged with 2-bromo-4-(trifluoromethyl)aniline (500 mg, 2.08 mmol), methyl acrylate (538 mg, 6.25 mmol), Pd(OAc)2 (23.3 mg, 0.104 mmol), P(o-tolyl)3 (64 mg, 0.21 mmol), triethylamine (422 mg, 4.7 mmol) and acetonitrile (20 ml). The flask was purged with N2 and heated to 90° C. overnight. Saturated aqueous NH4Cl (40 ml) was added, and the mixture was extracted with ethyl acetate (10 ml*3). The organic layer was dried over Na2SO4, filtered, and concentrated to dryness. The crude product was purified by silica gel chromatography to give (E)-methyl 3-(2-amino-5-(trifluoromethyl)phenyl)acrylate (185.9 mg, 36.5%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J=16 Hz, 1H), 7.53 (s, 1H), 7.32 (d, J=8.8 Hz, 1H), 6.67 (d, J=8.8 Hz, 1H), 6.34 (d, J=16 Hz, 1H), 4.20 (s, 2H), 3.74 (s, 3H).
Reaction SMILES: [CH2:1]1[C@@H:4]([C:5]([OH:7])=O)[NH:3][CH2:2]1.[CH3:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[NH:19]C(=O)O[C:15](=[O:16])[C:14]=12>CS(C)=O>[CH3:8][C:9]1[C:14]2[C:15](=[O:16])[N:3]3[CH2:2][CH2:1][C@H:4]3[C:5](=[O:7])[NH:19][C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: O=C(O)[C@@H]1CCN1
Reactant: Cc1cccc2[nH]c(=O)oc(=O)c12
Solvent: CS(C)=O
Product: Cc1cccc2c1C(=O)N1CC[C@H]1C(=O)N2

Procedure:
13.0 g (128.4 mmol) of L-azetidine-2-carboxylic acid and 22.7 g (128.4 mmol) of 6-methyl-isatoic acid anhydride in 150 ml of dimethyl sulphoxide are heated to 95° for 3 hours, evaporated to dryness in a high vacuum and the residue obtained is heated to 140° for 2.25 hours. By crystallization from ethyl acetate there is obtained (S)-1,10a-dihydro-5-methyl-2H-azeto[2,1-c][1,4]benzodiazepine-4,10(9H)-dione of melting point 159°-160°.
Reaction SMILES: [C:1]1([S:7][C:8]2(SC3C=CC=CC=3)[C:16]3[S:15][C:14]([NH:17][C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[N:13][C:12]=3[CH2:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH2:21]([NH:20][C:18]([NH:17][C:14]1[S:15][C:16]2[C:8]([S:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:9][CH2:10][CH2:11][C:12]=2[N:13]=1)=[O:19])[CH3:22]
Reactant: CCNC(=O)Nc1nc2c(s1)C(Sc1ccccc1)(Sc1ccccc1)CCC2
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCNC(=O)Nc1nc2c(s1)C(Sc1ccccc1)=CCC2
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To a suspension of N-[7,7-di(phenylsulfanyl)-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl]-N′-ethylurea (700 mg, 1.59 mmol) in THF (14.0 mL) was added DBU (0.36 mL, 2.38 mmol). The reaction mixture was stirred at about 20° C. for about 30 min. The reaction was concentrated in vacuo. The residual yellow oil was taken up in CH2Cl2, washed with AcOH/H2O 1/10 and dried over MgSO4. The organic solvent was removed in vacuo and the residual oil (1.0 g) was used in the next step without further purification.
Reaction SMILES: O[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.C(N(CC)CC)C.C1C=CC(N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:58]([C:60]1[CH:66]=[CH:65][C:63]([NH2:64])=[CH:62][CH:61]=1)#[CH:59]>CN(C=O)C.C(OCC)(=O)C.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.[Cu]I.CO.C(Cl)Cl>[N:10]1[CH:9]=[CH:8][N:6]2[C:5]=1[CH:4]=[CH:3][C:2]([C:59]#[C:58][C:60]1[CH:66]=[CH:65][C:63]([NH2:64])=[CH:62][CH:61]=1)=[N:7]2
Reactant: C#Cc1ccc(N)cc1
Reactant: Oc1ccc2nccn2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ccc(C#Cc2ccc3nccn3n2)cc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a stirring mixture of 6-hydroxyimidazo[1,2-b]pyridazine (3.24 g, 24 mmol, 1 eq) in anhydrous DMF (25 mL) under nitrogen atmosphere was added triethylamine (13.4 mL, 4 eq) and N-phenyl-bis(trifluoromethanesulfonimide) (8.47 g, 1 eq). After 18 hours at room temperature, to the reaction was added triphenylphosphine (157 mg, 0.025 eq), bis(triphenylphosphine)palladium(II) dichloride (1.0 g, 0.06 eq), copper(I) iodide (914 mg, 0.2 eq), and a solution of 4-ethynylaniline (4.342 g, 1.5 eq) in DMF (10 mL) under nitrogen atmosphere. The resulting reaction mixture was heated at 60° C. for four hours. The reaction was then cooled to room temperature, diluted with ethyl acetate, washed sequentially with aqueous ammonium chloride, saturated aqueous sodium bicarbonate, brine, and lastly dried with anhydrous sodium sulfate. The upper solution was decanted, concentrated, the residue mixture was subject to a gradient column chromatography (EtOAc-Hex 1:3 to 3:1). The product fractions were collected, concentrated, and the residue was triturated with EtOAc-Hex (1:5) to give the first batch of as a yellow solid in amount of 1.277 g. The brown solid found as a remainder on top of the syringe column was re-subject to another gradient column chromatography (MeOH-DCM 1:200 to 1:30) to give a second batch of 4-(imidazo[1,2-b]pyridazin-6-ylethynyl)aniline in amount of 829 mg. The total yield was 2.106 g (37%).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]2[CH:12]=[CH:13][C:14]([C:16]([O:18]C)=[O:17])=[CH:15][N:3]12.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=O>C(O)(C)(C)C>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=[C:7]1[C:6]2[N:5]=[C:4]3[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][N:3]3[C:2](=[O:1])[C:11]=2[CH2:10][CH2:9][CH2:8]1
Reactant: COc1ccccc1C=O
Reactant: COC(=O)c1ccc2nc3c(c(=O)n2c1)CCCC3
Solvent: CC(C)(C)O
Product: COc1ccccc1C=C1CCCc2c1nc1ccc(C(=O)O)cn1c2=O
Yield: 31.4 %

Procedure:
1,2,3,4-tetrahydro-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid, methyl ester (2.5 g) was reacted with 2-methoxy-benzaldehyde (2.6 g) in tert.butanol (75 ml) in the presence of potassium tert.butylate (4.3 g) under stirring at reflux temperature for 8 hours. After cooling the solution was concentrated in vacuo to a small volume and the precipitate was filtered and washed with little methanol and then dissolved in water containing NaHCO3 : the solution was acidified with 23% HCl to pH=4 and the precipitate was filtered and washed with water until neutral. Crystallization from acetone gave 1.1 g of 4-(2-methoxy-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid, m.p. 300° C. (dec.), N.M.R. (CDCl3 -CF3COOD) δp.p.m.: 1.93 (m) (2H,C-2 protons), 2.84 (m) (4H, C-1 and C-3 protons), 3.81 (s) (3H, --OCH3), 6.80-7.50 (m) (4H, phenyl protons), 7.70 (bs) (1H, =CH--), 8.17 (d) (1H, C-6 proton), 8.69 (dd) (1H, C-7 proton), 9.73 (d) (1H,C-9 proton).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Br[CH2:16][CH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28].BrCCCN1C(=O)C2=CC=CC=C2C1=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:16][CH2:17][N:18]2[C:22](=[O:23])[C:21]3=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]3[C:19]2=[O:28])[CH2:11][CH2:10]1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: COc1ccccc1N1CCNCC1
Agent: O=C1c2ccccc2C(=O)N1CCCBr
Product: COc1ccccc1N1CCN(CCN2C(=O)c3ccccc3C2=O)CC1
Yield: 45 %

Procedure:
This was carried out with the method and molar ratios of Step (a) of Example I with 0.026 mol of N-(2-methoxyphenyl)piperazine being utilized and with N-(2-bromoethyl)phthalimide being utilized in place of N-(3-bromopropyl)phthalimide. The reaction afforded 4.25 g of a white solid (45% yield); mp 76°-81° C. Spectral data are consistent with the assigned structure. This material was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([S:22][CH2:23][C:24]3[CH:25]=[C:26]([CH:32]=[CH:33][CH:34]=3)[C:27](OCC)=[O:28])[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[C:11]([S:22][CH2:23][C:24]3[CH:34]=[CH:33][CH:32]=[C:26]([CH2:27][OH:28])[CH:25]=3)[NH:12][C:13]=2[C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cccc(CSc2nc(-c3ccc(OC)cc3)c(-c3ccc(OC)cc3)[nH]2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(-c2nc(SCc3cccc(CO)c3)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 0 °C

Procedure:
Part B. A solution of the ester prepared in Part A above (6.57 g, 13.8 mmol) in tetrahydrofuran (20 mL) was added to an ice-cooled slurry of lithium aluminum hydride (1.16 g, 30.5 mmol) in tetrahydrofuran (20 mL). The mixture was warmed to mild reflux for 18 hours, then re-cooled to 0° C. and quenched by the careful sequential addition of water (2 mL), 15% aqueous sodium hydroxide (6 mL), and water (6 mL). The resulting mixture was filtered through celite, dried over anhydrous potassium carbonate, filtered and evaporated to afford the product, 4,5-bis(4-methoxyphenyl)-2-[3-(hydroxymethyl)benzyl]thio-1-H-imidazole, as an oil (5.97 g, 13.8 mmol, 100%). 1H NMR (CDCl3): 7.41-7.07 (8H, m); 6.81 (4H, d, J=8.8 Hz); 4.56 (2H, s); 4.15 (2H, s); 3.79 (6H, s).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16].[Cl:17][C:18]1[S:22][C:21]([CH2:23][C:24](O)=[O:25])=[CH:20][CH:19]=1>>[Cl:17][C:18]1[S:22][C:21]([CH2:23][C:24]([NH:1][N:2]2[N:11]=[C:10]([C:12]([F:15])([F:13])[F:14])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:16])=[O:25])=[CH:20][CH:19]=1
Reactant: O=C(O)Cc1ccc(Cl)s1
Reactant: Nn1nc(C(F)(F)F)c2ccccc2c1=O
Product: O=C(Cc1ccc(Cl)s1)Nn1nc(C(F)(F)F)c2ccccc2c1=O

Procedure:
The product of Example 11B and 2-(5-chlorothiophen-2-yl)acetic acid were treated using a method similar to that described in Example 5 to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.96-11.98 (bs, 1H), 8.43 (d, J=8.4 Hz, 1H), 8.11-8.17 (m, 1H), 7.97-8.10 (m, 2H), 7.01 (d, J=3.8 Hz, 1H), 6.93 (d, J=3.8 Hz, 1H), 3.96 (d, J=0.8 Hz, 2H); MS (ESI) m/z 388 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[O:19]([C:16]1[CH:17]=[CH:18][C:13]([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]([CH:11]=[O:12])=[C:2]2[N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:14][CH:15]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1c(Cl)n(-c2ccc(Oc3ccccc3)cc2)c2ccccc12
Reactant: C1CNCCN1
Product: O=Cc1c(N2CCNCC2)n(-c2ccc(Oc3ccccc3)cc2)c2ccccc12
Yield: 40 %

Procedure:
2-chloro-1-(4-phenoxyphenyl)-1H-indole-3-carboxaldehyde is reacted with piperazine as described in Step 2 of Example 29 to afford 1-(4-phenoxyphenyl)-2-piperazin-1-yl-1H-indole-3-carboxaldehyde (40% yield). ESI/MS 398 (M+H); RT=2.95 min; NMR (CDCl3) 10.28 (1H, s); 8.28 (1H, d, J=9 Hz); 7.46-7.10 (11H, m); 7.00 (1H, d, J=9 Hz); 3.31 (4H, m); 2.81 (4H, m).
Reaction SMILES: C(OC([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21](=[O:37])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[NH:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:18][C:16]1([CH3:19])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21](=[O:37])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[NH:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)=[CH:13][CH:14]=2)[CH2:9][NH:8][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(NC(=O)c3ccccc3NCc3ccc(F)cc3)ccc2C(C)(C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CNCc2cc(NC(=O)c3ccccc3NCc3ccc(F)cc3)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7-[2-(4-Fluoro-benzylamino)-benzoylamino]-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (Step B, 0.57 g, 1.13 mmol) was treated with 10 mL of 50% of TFA in CH2Cl2 and stirred at RT for 1 h. The volatiles were removed under reduced pressure, and the residue was purified by flash column chromatography. The titled compound was obtained as a white solid. MS (ES+): 404 (M+H)+. Calc'd for C25H26FN3O-403.21.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].S(=O)(=O)(O)O.[CH3:17]O>>[CH3:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([O:8][CH3:17])=[O:7]
Reactant: Cc1ccc(C(=O)O)c(O)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C)cc1O
Temperature: 25 °C
Yield: 90 %

Procedure:
4-Methylsalicylic acid (100 g, 658 mmoles) was dissolved in anhydrous methanol (500 mL) and concentrated sulfuric acid (25 mL) was added carefully. The solution was refluxed for 18 hours, then cooled to room temperature. The reaction mixture was concentrated to about 150 mL, and ethyl acetate (250 mL) was added. The ethyl acetate solution was washed twice with saturated aqueous sodium bicarbonate (250 mL portions) and thenwith saturated aqueous sodium chloride (100 mL). The ethyl acetate solutionwas dried over anhydrous sodium sulfate, filtered, and evaporated to a clear, reddish-brown liquid. This crude product was vacuum distilled (oil pump) to afford a clear, viscous liquid that solidified on standing to afford 98.1 g (90% yield) of methyl 4-methylsalicylate.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:11][C:12]1[CH:13]=[C:14]([CH2:21][C:22]([OH:24])=[O:23])[CH:15]=[C:16]([F:20])[C:17]=1[O:18][CH3:19].[CH3:25]I.[Cl-].[NH4+]>C1COCC1.O.C(OCC)(=O)C>[F:11][C:12]1[CH:13]=[C:14]([CH:21]([CH3:25])[C:22]([OH:24])=[O:23])[CH:15]=[C:16]([F:20])[C:17]=1[O:18][CH3:19]
Reactant: COc1c(F)cc(CC(=O)O)cc1F
Reactant: CI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1c(F)cc(C(C)C(=O)O)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 105.1 %

Procedure:
Lithium bis(trimethylsilyl)amide (25.4 mL, 25.35 mmol) was added to 2-(3,5-difluoro-4-methoxyphenyl)acetic acid (2.5 g, 12.37 mmol) in THF (60.8 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 30 minutes. Next Methyl iodide (0.925 mL, 14.84 mmol) was added and the reaction stirred for 30 minutes Ammonium chloride (satd) (50 mL) added with vigorous stirring, ethyl acetate (100 mL) and water (50 mL) were added and the organic phase separated, washed with water (50 mL) and saturated brine (50 mL). The aq layer was acidified with 2M HCl (50 mL) and extracted with ethyl acetate. The organic layers were combined and dried over MgSO4, filtered and evaporated to afford 2-(3,5-difluoro-4-methoxyphenyl)propanoic acid (2.81 g, 105%) which was used without further purification.
Reaction SMILES: [N:1]1([CH:5]2[CH2:10][CH2:9][N:8]([CH2:11][C:12]3[S:13][C:14]4[N:15]=[C:16]([Cl:27])[N:17]=[C:18]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)[C:19]=4[N:20]=3)[CH2:7][CH2:6]2)[CH2:4]C[CH2:2]1.CN(C)C1CCNCC1>>[Cl:27][C:16]1[N:17]=[C:18]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[C:19]2[N:20]=[C:12]([CH2:11][N:8]3[CH2:7][CH2:6][CH:5]([N:1]([CH3:4])[CH3:2])[CH2:10][CH2:9]3)[S:13][C:14]=2[N:15]=1
Reactant: Clc1nc(N2CCOCC2)c2nc(CN3CCC(N4CCC4)CC3)sc2n1
Agent: CN(C)C1CCNCC1
Product: CN(C)C1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3s2)CC1

Procedure:
Prepared according to the method used in the preparation of 2-(4-azetidin-1-ylpiperidin-1-ylmethyl)-5-chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine using dimethylpiperidin-4-ylamine in place of 4-azetidin-1-ylpiperidine. The title compound was obtained as a pale yellow solid (101 mg, 72%).