Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][NH:12][CH3:13])=[CH:8][C:6]=2[N:7]=1.[C:20](Cl)(=[O:22])[CH3:21].[NH:24]1[C:32]2[C:27](=[CH:28][C:29](B(O)O)=[CH:30][CH:31]=2)[CH:26]=[CH:25]1>>[NH:24]1[C:32]2[C:27](=[CH:28][C:29]([C:2]3[N:3]=[C:4]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[C:5]4[S:10][C:9]([CH2:11][N:12]([CH3:13])[C:20](=[O:22])[CH3:21])=[CH:8][C:6]=4[N:7]=3)=[CH:30][CH:31]=2)[CH:26]=[CH:25]1
Reactant: CC(=O)Cl
Reactant: CNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Product: CC(=O)N(C)Cc1cc2nc(-c3ccc4[nH]ccc4c3)nc(N3CCOCC3)c2s1
Yield: 44 %

Procedure:
1-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-methylmethanamine 55 from Example 11a was reacted with acetyl chloride (1.2 eq) followed by Suzuki coupling of indole-5-boronic acid as per General Procedure K. Complete reaction was confirmed by LCMS and the reaction was concentrated in vacuo to give 33.1 mg of 392 after RP-HPLC purification (44% yield). MS (Q1) 422.2 (M)+
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].Br[CH2:9][C:10]1[CH:32]=[CH:31][C:13]([CH2:14][C:15]2[N:25]([CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:18]3[N:19]=[C:20]([C:23]#[N:24])[N:21]=[CH:22][C:17]=3[CH:16]=2)=[CH:12][CH:11]=1.C(Cl)Cl>CN(C=O)C.CO>[CH3:28][C:27]([CH3:30])([CH3:29])[CH2:26][N:25]1[C:18]2[N:19]=[C:20]([C:23]#[N:24])[N:21]=[CH:22][C:17]=2[CH:16]=[C:15]1[CH2:14][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:32][CH:31]=1
Reactant: c1nc[nH]n1
Reactant: CC(C)(C)Cn1c(Cc2ccc(CBr)cc2)cc2cnc(C#N)nc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)Cn1c(Cc2ccc(Cn3cncn3)cc2)cc2cnc(C#N)nc21
Yield: 57 %

Procedure:
1,2,4-Triazole (0.6 mmol) is dissolved in DMF (1 ml) and sodium hydride (0.6 mmol) is added. The mixture is stirred and 6-(4-bromomethyl-benzyl)-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (0.5 mmol) in DMF (1 ml) is added at 0° C. The mixture is stirred at room temperature for 0.5 h, and quenched with H2O. The mixture is extracted with AcOEt. The organic layer is washed with water and brine, dried over magnesium sulfate and concentrated. The crude product is purified by silica gel column chromatography to give the product in 57% yield. Rf=0.50 (CH2Cl2:MeOH=9:1). 1H NMR (400 MHz, CDCl3) δ 1.04(s, 9H), 4.06(s, 2H), 4.22(s, 2H), 5.36(s, 2H), 6.22(s, 1H), 7.18(d, 2H), 7.23-7.39(m, 2H), 7.98(s, 1H), 8.09(s, 1H), 8.83(s, 1H).
Reaction SMILES: [OH-:1].[Na+].[CH:3]([C:5]1[N:14]=[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]3[O:23][CH2:24][O:25][C:19]=3[CH:18]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:26][CH3:27])[CH:11]=2)[N:6]=1)=[O:4]>O1CCOCC1.[Ag-]=O>[C:3]([C:5]1[N:14]=[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]3[O:23][CH2:24][O:25][C:19]=3[CH:18]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:26][CH3:27])[CH:11]=2)[N:6]=1)([OH:1])=[O:4]
Reactant: [OH-]
Reactant: COc1ccc2nc(C=O)nc(NCc3ccc4c(c3)OCO4)c2c1
Agent: O=[Ag-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc2nc(C(=O)O)nc(NCc3ccc4c(c3)OCO4)c2c1
Temperature: 60 °C
Reaction time: 1.33 h

Procedure:
1.00 g of silver (I) oxide and 15 ml of a 1N aqueous solution of sodium hydroxide were added to a solution of 0.59 g (1.8 mmol) of the 2-formyl-4-(3,4-methylenedioxybenzyl)amino-6-methoxyquinazoline prepared in Example 141 in 20 ml of 1,4-dioxane. The obtained mixture was stirred at 60° C. After 80 minutes, the reaction mixture was filtered through Celite and the filter cake was washed with a small amount of dioxane and water. The filtrate and washings were neutralized with 1N hydrochloric acid and extracted with chloroform/ethanol. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under a reduced pressure to remove the solvent. The crystal thus formed was recovered by filtration and washed with chloroform to give 0.34 g of the title compound as a pale-yellow crystal.
Reaction SMILES: N12CCCN=C1CC[CH2:4][CH2:3][CH2:2]2.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=1[OH:20].BrCC(OC)=[O:24]>CN1CCCC1=O.C(OCC)(=O)C>[Br:19][C:16]1[CH:17]=[CH:18][C:13]2[NH:12][C:2](=[O:24])[CH:3]([CH3:4])[O:20][C:14]=2[CH:15]=1
Reactant: Nc1ccc(Br)cc1O
Reactant: COC(=O)CBr
Reactant: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC1Oc2cc(Br)ccc2NC1=O
Temperature: 180 °C
Yield: 100 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (145.0 μL, 0.975 mmol) was added at room temperature to a solution of 2-amino-5-bromophenol A-1 (200.0 mg, 1.064 mmol) and methyl 2-bromoacetate (115.0 μL, 0.886 mmol) in anhydrous 1-methylpyrrolidin-2-one (4.20 mL) under an atmosphere of argon, in a 10 mL microwave reactor vial. The sealed reaction mixture was heated at 180° C. for 3 mins under microwave irradiation and then diluted with ethyl acetate (25 mL). The organic layer was washed with brine (3×20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (hexanes:ethyl acetate gradient) to give 7-bromo-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one A-2 (217.0 mg, Yield=100%). MS (ESI) [M+1]+ 242, 244.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][N:7]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][CH2:14][C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=2)[CH3:3].[N+:22]([O-])([OH:24])=[O:23].Cl>C(O)(=O)C>[CH3:1][N:2]([CH2:4][CH2:5][CH2:6][N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14][CH2:15][C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]1=2)[CH3:3]
Reactant: O=[N+]([O-])O
Reactant: CN(C)CCCN1c2ccccc2CCc2ccccc21
Agent: Cl
Solvent: CC(=O)O
Product: CN(C)CCCN1c2ccccc2CCc2cc([N+](=O)[O-])ccc21
Temperature: 18 °C
Yield: 51.2 %

Procedure:
Imipramine (26a, 1.925 g, 6.87 mmol) was dissolved in 32 mL acetic acid and cooled to 18° C. Conc. nitric acid (0.79 mL, 13 mmol) in 1.1 mL acetic acid was added dropwise, with stirring, keeping reaction at 17°-18° C., then reaction stirred at that temperature for an additional 20 minutes. The reaction was then poured into 130 mL of 0.15M HCl and washed with Et2O (2×85 mL), then pH adjusted to 13 with conc. NaOH and extracted with CHCl3 (4×100 mL). The CHCl3 extracts were combined, washed with 85 mL brine, dried over Na2SO4, and solvent removed in vacuo. The residue was purified by column chromatography, eluting with THF/Hex/NH4OH (70/30/0.4) to yield 1.145 g (51%) of the desired 2-nitroimipramine (26b) as a red oil. 1H NMR (200 MHz, CDCl3) d 8.0-7.9 (m, 2H), 7.3-7.0 (m, 5H), 3.9 (t, 2H), 3.2 (s, 4H), 2.3 (t, 2H), 2.1 (s, 6H), 1.7 (p, 2H); mass spec (FAB) (M+H)+ 326.
Reaction SMILES: C([Li:5])(C)(C)C.[CH2:6]([N:8]([CH2:19][CH3:20])[C:9]([C:11]1[C:12](OC)=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:10])[CH3:7].CN(C)CCN(C)C.[O:29]1[CH2:33]CCC1>CCCCC>[CH2:19]([N:8]([CH2:6][CH3:7])[C:9]([C:11]1([O:29][CH3:33])[C:16]([Li:5])=[CH:15][CH:14]=[N:13][CH2:12]1)=[O:10])[CH3:20]
Reactant: [Li]C(C)(C)C
Reactant: CCN(CC)C(=O)c1cccnc1OC
Reactant: C1CCOC1
Agent: CN(C)CCN(C)C
Solvent: CCCCC
Product: [Li]C1=CC=NCC1(OC)C(=O)N(CC)CC
Temperature: -80 °C
Reaction time: 0.33 h

Procedure:
Over a period of several minutes 0.0075 mole of tert.butyllithium (4.41 ml of a 1.7 molar solution in pentane) are added to a solution of 1.041 g (0.005 mole) of 3-diethylaminocarbonyl 2-methoxy pyridine and 1.13 ml (0.0075 mole) of tetramethylethylenediamine in 15 ml of tetrahydrofuran cooled to -80° C. while the temperature is maintained below -80° C. After 20 minutes at this temperature, an orange-colored solution of 3-diethylaminocarbonyl 4-lithio 3-methoxy pyridine is obtained which is used as such.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:11][CH:10]2[O:12][CH:6]([CH2:7][N:8]([CH2:13][C@H:14]([OH:25])[CH2:15][O:16][C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)[CH2:9]2)[CH2:5]1.[C:26]1([CH2:32][S:33](Cl)(=[O:35])=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.C(N(CC)CC)C.C(#N)C>[C:21]([C:20]1[CH:19]=[CH:18][C:17]([O:16][CH2:15][C@@H:14]([OH:25])[CH2:13][N:8]2[CH2:9][CH:10]3[O:12][CH:6]([CH2:5][N:4]([CH2:3][CH2:2][NH:1][S:33]([CH2:32][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)(=[O:35])=[O:34])[CH2:11]3)[CH2:7]2)=[CH:24][CH:23]=1)#[N:22]
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: N#Cc1ccc(OC[C@@H](O)CN2CC3CN(CCN)CC(C2)O3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1ccc(OC[C@@H](O)CN2CC3CN(CCNS(=O)(=O)Cc4ccccc4)CC(C2)O3)cc1
Yield: 72 %

Procedure:
4-{(2S)-3-[7-(2-Aminoethyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-2-hydroxypropoxy}benzonitrile (0.096 g, 0.28 mmol; see step Preparation A above) was dissolved in a 1:2 ratio of DCM:acetonitrile (3 mL). Triethylamine (0.17 g, 1.68 mmol) was added, followed by phenylmethanesulfonyl chloride (0.068 g, 0.36 mmol). The mixture was stirred at room temperature overnight with K2CO3 (0.38 g, 2.77 mmol) to ensure that the free base of triethylamine was in the reaction mixture. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. Purification by preparative HPLC gave 0.1 g (72%) of the title compound.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[C:19][C:20]3[CH:30]=[CH:29][C:23]4[S:24][C:25]([CH2:27]O)=[CH:26][C:22]=4[CH:21]=3)=[N:16][CH:17]=2)=[CH:8][CH:7]=1>C(Cl)Cl>[Cl:3][CH2:27][C:25]1[S:24][C:23]2[CH:29]=[CH:30][C:20]([C:19]#[C:18][C:15]3[CH:14]=[CH:13][C:12]([C:9]4[CH:10]=[CH:11][C:6]([Cl:5])=[CH:7][CH:8]=4)=[CH:17][N:16]=3)=[CH:21][C:22]=2[CH:26]=1
Reactant: OCc1cc2cc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)ccc2s1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClCc1cc2cc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)ccc2s1
Temperature: 0 °C
Reaction time: 70 h

Procedure:
1.07 mL (15 mmol) of thionyl chloride was added to a solution of 1.1 g (2.93 mmol) of {5-[5-(4-chlorophenyl)pyridin-2-ylethynyl]benzo[b]thiophen-2-yl}methanol in 20 mL of DCM cooled to 0° C. and the reaction mixture was stirred for 70 hours at RT. It was evaporated down in vacuo, the residue was combined with semisaturated sodium bicarbonate solution, extracted exhaustively with DCM, and the combined organic phases were washed twice with water and dried over magnesium sulfate. After the desiccant and solvent had been eliminated, the residue was purified by chromatography (silica gel, PE/EtOAc 7:3). Yield: 0.65 g (56% of theoretical); C22H13Cl2NS (M=394.317); calc.: molpeak (M+H)+: 394/396/398 (2Cl); found: molpeak (M+H)+: 394/396/398 (2Cl); HPLC-MS: 7.6 minutes (method B).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]2([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[O:17][C:16](=[O:18])[CH2:15][C:14](=[O:19])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH2:25]1CCN2C(=NCCC2)CC1.IC>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]2([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[O:17][C:16](=[O:18])[CH:15]=[C:14]([O:19][CH3:25])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: C1CCC2=NCCCN2CC1
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Solvent: CN(C)C=O
Solvent: CI
Product: COC1=CC(=O)OC(CCc2ccc(OC)c(Cl)c2)(C2CCCC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.2 %

Procedure:
To a solution of 6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione (60 mg, 0.17 mmol) from Example B(87), dissolved in DMF (1.5 mL), were added DBU (0.028 mL, 0.188 mmol) and iodomethane (0.011 mL, 0.17 mmol). The reaction was stirred at room temperature overnight, and then was quenched with water. The reaction was extracted with EtOAc, and the organic layers were combined. After washing with saturated NaCl, the organic layer was dried over Na2SO4. The solids were removed by filtration, and the liquid was concentrated by rotary evaporation. Purification by preparatory HPLC gave the desired product (8.2 mg, 13% yield). 1H NMR (CDCl3) δ: 1.47-1.69 (m, 8H), 1.89-1.95 (m, 2H), 2.25-2.35 (m, 2H), 2.52-2.63 (m, 3H), 3.67 (s, 3H), 3.80 (s, 3H), 6.77 (d, J=8.32 Hz, 1H), 6.94 (dd, J1=8.32 Hz, J2=2.24 Hz, 1H), 7.09 (d, J=1.92 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][NH:15][C:14](=O)[CH2:13]1)=[O:11].F[B-](F)(F)F.C([O+](CC)CC)C.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][N:36]=[C:35]([C:39]([NH:41][NH2:42])=O)[CH:34]=1>ClCCl>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:39]([C:35]3[CH:34]=[C:33]([O:32][CH3:31])[CH:38]=[CH:37][N:36]=3)=[N:41][N:42]=[C:14]2[CH2:13]1)=[O:11]
Reactant: COc1ccnc(C(=O)NN)c1
Reactant: O=C1CN(C(=O)c2ccc(Cl)c(F)c2Cl)CCN1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COc1ccnc(-c2nnc3n2CCN(C(=O)c2ccc(Cl)c(F)c2Cl)C3)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-[(2,4-dichloro-3-fluorophenyl)carbonyl]-2-piperazinone (I37) (0.25 g, 0.859 mmol) in anhydrous Dichloromethane (DCM) (2.147 ml) was added triethyloxonium tetrafluoroborate (0.179 g, 0.945 mmol) and the mixture was stirred overnight at room temperature under argon. The white suspension turned to a solution and 4-(methyloxy)-2-pyridinecarbohydrazide (0.158 g, 0.945 mmol, commercially available from e.g. Matrix Scientific, Anichem or 3B Scientific) was added at once. It was a suspension at first but straight after it changed to a yellow solution. After ½ hour a precipitate formed again. LCMS showed that the major product was the intermediate and very little unreacted starting amide was present.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])[CH:9]=[N:10][C:5]2=[C:4]([NH2:20])[CH:3]=1.C(N(CC)C(C)C)(C)C.[Cl:30][CH2:31][C:32](Cl)=[O:33].C(=O)([O-])[O-].[K+].[K+]>ClCCCl>[CH3:1][C:2]1[N:7]=[C:6]2[N:8]([C:11]3[C:12]([CH3:19])=[CH:13][C:14]([CH3:18])=[CH:15][C:16]=3[CH3:17])[CH:9]=[N:10][C:5]2=[C:4]([NH:20][C:32](=[O:33])[CH2:31][Cl:30])[CH:3]=1
Reactant: O=C(Cl)CCl
Reactant: Cc1cc(C)c(-n2cnc3c(N)cc(C)nc32)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Cc1cc(C)c(-n2cnc3c(NC(=O)CCl)cc(C)nc32)c(C)c1
Temperature: 25 °C

Procedure:
Treat a solution of 5-methyl-3-(2,4,6-trimethylphenyl)imidazolo[5,4-b]pyridin-7-ylamine (0.05 g, 1.9 mmol), and N,N-diisopropylethylamine, (0.04 mL, 0.21 mmol) in 1,2-dichloroethane (5 mL) with chloroacetyl chloride (0.017 mL, 0.21 mmol). Heat the solution to reflux for 3 h, cool to ambient temperature, and pour into an aqueous potassium carbonate solution. Extract the resulting mixture with CH2Cl2 and wash with saturated aq NaCl. Separate the organic layer, dry over Na2SO4, filter, and concentrate. Purify by preparative TLC (5% MeOH in CH2Cl2) to obtain the title compound as a yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([F:12])([F:11])[F:10].BrCC1CCCCO1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]2([C:41]3[C:32](=[CH:33][C:34]4[O:39][CH2:38][CH2:37][O:36][C:35]=4[CH:40]=3)[O:31][CH2:30]2)[C:22]1=[O:42]>>[F:10][C:9]([F:12])([F:11])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]2([C:41]3[C:32](=[CH:33][C:34]4[O:39][CH2:38][CH2:37][O:36][C:35]=4[CH:40]=3)[O:31][CH2:30]2)[C:22]1=[O:42]
Reactant: FC(F)(F)c1ccccc1CCl
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccccc2C(F)(F)F)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 1-(chloromethyl)-2-(trifluoromethyl)benzene to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1′-[2-(trifluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (55%) as a colorless solid: mp 207-208° C. (dichloromethane/diethyl ether); 1H NMR (300 MHz, CDCl3) 7.72 (d, J=7.6 Hz, 1H), 7.51-7.42 (m, 2H), 7.42-7.34 (m, 3H), 7.22-7.12 (m, 1H), 7.07-7.00 (m, 1H), 6.61 (d, J=7.7 Hz, 1H), 6.52 (s, 1H), 6.31 (s, 1H), 5.26 (d, J=17.1 Hz, 1H), 5.07 (d, J=17.0 Hz, 1H), 4.97 (d, J=8.9 Hz, 1H), 4.70 (d, J=8.9 Hz, 1H), 4.24-4.09 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.9, 155.4, 144.8, 141.8, 138.4, 133.9, 132.5, 132.1, 129.0, 128.3 (q, J=30.8 Hz), 127.7, 126.8, 126.4 (q, J=5.8 Hz), 124.4 (q, J=273.7 Hz), 124.1, 123.8, 120.8, 111.5, 109.2, 99.5, 80.3, 64.5, 63.9, 58.2, 40.6; MS (ES+) m/z 454.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](C#N)=[N:6][CH:7]=1.C[Mg+].[Br-].[CH2:13]1[CH2:17][O:16]CC1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:17](=[O:16])[CH3:13])=[N:6][CH:7]=1
Reactant: N#Cc1ncc(Br)cn1
Reactant: C1CCOC1
Agent: C[Mg+]
Agent: [Br-]
Product: CC(=O)c1ncc(Br)cn1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 30.2 %

Procedure:
To a solution of 5-bromopyrimidine-2-carbonitrile (300 mg, 1.63 mmol) in THF (20 mL) was added MeMgBr (5.43 mL, 16.3 mmol) at −78° C. under nitrogen. The solution was stirred at −78° C. for 20 min., quenched with satd aq NH4Cl, and extracted with EtOAc. The combined organic layer was dried over anhydrous Na2SO4 and concentrated to give an oil, which was purified by prep TLC (3:1 PE/EtOAc) to give 1-(5-bromopyrimidin-2-yl)ethanone (99 mg, yield 30.2%). 1H NMR (CDCl3): δ2.70 (s, 3H), 8.90 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1[F:12].N1CCCCC1.Cl[C:20]([CH:22]([O:24][C:25](=[O:27])[CH3:26])[CH3:23])=[O:21]>O1CCCC1>[F:12][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[NH:1][C:20]([CH:22]([O:24][C:25](=[O:27])[CH3:26])[CH3:23])=[O:21])[NH:8][C:7](=[O:11])[CH2:6]2
Reactant: Nc1cc2c(cc1F)CC(=O)N2
Reactant: CC(=O)OC(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: C1CCNCC1
Product: CC(=O)OC(C)C(=O)Nc1cc2c(cc1F)CC(=O)N2
Temperature: 25 °C
Yield: 110.6 %

Procedure:
5-Fluoro-6-amino-1,3-dihydro-indol-2-one 3d (450 mg, 2.71 mmol) was dissolved in 10 ml of tetrahydrofuran under stirring at room temperature. The mixture was cooled down to −45° C. in a dry ice-acetone bath and added with 364 μl of piperidine. A solution of acetic acid 1-chlorocarbonyl-ethyl ester (423 mg, 2.71 mmol) in 10 ml of tetrahydrofuran was added dropwise to the above reaction system. Upon completion of the addition, the ice-acetone bath was removed, and the reaction mixture was allowed to warm up to room temperature and stirred overnight. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was filtered. The filter cake was washed with water, and the resulting solid was dried to obtain the title compound acetic acid 1-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-ylcarbamoyl)-ethyl ester 8a (840 mg) as a white solid to be used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([OH:18])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:19][NH:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[C:16]([N:20]([CH3:19])[C:21]3[CH:22]=[CH:23][C:24]([CH2:27][N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:25][CH:26]=3)=[O:18])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)/C=C/c1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CNc1ccc(CN2CCCCC2)cc1
Product: CN(C(=O)/C=C/c1ccc(-c2ccc(Cl)cc2)cc1)c1ccc(CN2CCCCC2)cc1

Procedure:
Prepared analogously to Example 172 starting from (E)-3-(4′-chloro-biphenyl-4-yl)-acrylic acid and methyl-(4-piperidin-1-ylmethyl-phenyl)-amine.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([NH2:10])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:23][C:24]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:25]=1[CH2:26][NH:27][NH2:28]>C(O)C>[NH2:10][C:6]1[NH:28][N:27]([CH2:26][C:25]2[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:24]=2[Cl:23])[C:4](=[O:3])[CH:5]=1
Reactant: NNCc1cc(Cl)ccc1Cl
Reactant: CCOC(=O)C=C(N)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Nc1cc(=O)n(Cc2cc(Cl)ccc2Cl)[nH]1
Reaction time: 2 h

Procedure:
32.8 g of β-amino-β-ethoxyacrylic acid ethyl ester and 1 g of p-toluenesulphonic acid were dissolved in 120 ml of ethanol and 39 g of 2,5-dichlorobenzylhydrazine were added under nitrogen. After stirring for 2 hours the mixture was left to stand overnight and the compound identified above, which precipitated, was filtered off and recrystallised from ethanol. Melting point: 195°-196° C; Yield: 23 g (43%).
Reaction SMILES: [CH3:1][C:2]1([CH3:37])[C:6]2([CH2:10][CH2:9][N:8]([C:11]([C:13]3([C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31](C)(C)C)=[O:29])[CH2:24][CH2:23]5)=[CH:18][C:17]=4[F:35])[CH2:15][CH2:14]3)=[O:12])[CH2:7]2)[O:5][C:4](=[O:36])[CH2:3]1.C(O)(C(F)(F)F)=O.C(Cl)Cl.C(N(CC)CC)C.ClC(OC)=O>>[CH3:1][C:2]1([CH3:37])[C:6]2([CH2:10][CH2:9][N:8]([C:11]([C:13]3([C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH2:27][CH2:26][N:25]([C:28]([O:30][CH3:31])=[O:29])[CH2:24][CH2:23]5)=[CH:18][C:17]=4[F:35])[CH2:15][CH2:14]3)=[O:12])[CH2:7]2)[O:5][C:4](=[O:36])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C3(C(=O)N4CCC5(C4)OC(=O)CC5(C)C)CC3)c(F)c2)CC1
Agent: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N1CCN(c2ccc(C3(C(=O)N4CCC5(C4)OC(=O)CC5(C)C)CC3)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl 4-(4-{1-[(4,4-dimethyl-2-oxo-1-oxa-7-azaspiro[4.4]non-7-yl)carbonyl]cyclopropyl}-3-fluorophenyl)piperazine-1-carboxylate (25.0 mg, 0.0000485 mol) was treated with TFA. After stirring at rt for 30 min, the volatiles were removed in-vacuo and the residue was dried on high vacuum. The resultant TFA salt was dissolved in methylene chloride (0.25 mL, 0.0039 mol) and to this was added triethylamine (0.0203 mL, 0.000145 mol) followed by methyl chloroformate (0.00749 mL, 0.0000970 mol). The reaction mixture was stirred at rt for 1 h and then the volatiles were removed in-vacuo. The residue was diluted with methanol and applied directly on RP-HPLC to yield the desired product. LCMS (M+H) 474.2.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([S:16][CH2:17][CH2:18][CH3:19])=[C:14]([C:20]([OH:22])=O)[CH:13]=[N:12]2)=[CH:7][CH:6]=1)=[O:4].Cl.[CH:24]12[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH:25]1[NH2:34])[CH2:31]2.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(=O)C>[CH:24]12[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH:25]1[NH:34][C:20]([C:14]1[CH:13]=[N:12][N:11]([C:8]3[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][CH:9]=3)[C:15]=1[S:16][CH2:17][CH2:18][CH3:19])=[O:22])[CH2:31]2
Reactant: NC1C2CC3CC(C2)CC1C3
Reactant: CCCSc1c(C(=O)O)cnn1-c1ccc(C(=O)OC)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCSc1c(C(=O)NC2C3CC4CC(C3)CC2C4)cnn1-c1ccc(C(=O)OC)cc1
Reaction time: 18 h

Procedure:
1-(4-methoxycarbonylphenyl)-5-propylsulfanyl-pyrazole-4-carboxylic acid (Intermediate #7) (160 mg, 0.5 mmol), 2-adamantylamine hydrochloride (94 mg, 0.5 mmol), HOBT (81 mg, 0.6 mmol) and DIPEA (261 μL, 1.5 mmol) were dissolved in DMF (5 mL) and treated at ambient temperature with EDCI (115 mg, 0.6 mmol). The mixture was stirred at ambient for 18 h and then diluted with ethyl acetate (50 mL), washed with water (3×20 mL) and brine, dried (MgSO4) and evaporated to leave a white solid, which was purified by chromatography on silica gel, (12 g silica 0-50% EtOAc/isohexane) to give the title compound as a white solid. (203 mg, 92%)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([SH:12])[CH:7]=1)[CH3:2].Cl[CH2:15][C:16](=[O:18])[CH3:17]>>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][CH2:15][C:16](=[O:18])[CH3:17])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(S)c1
Reactant: CC(=O)CCl
Product: CCOC(=O)Cc1cccc(SCC(C)=O)c1

Procedure:
Prepared according to the procedure described in Example 42, Step 1, using the following starting materials: (3-mercapto-phenyl)-acetic acid ethyl ester and chloroacetone.