Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1([CH3:14])[CH:8]([CH3:9])[C:7](=[O:10])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[NH:4]1)[CH3:2].[BH4-].[Na+]>CO>[CH2:1]([C:3]1([CH3:14])[CH:8]([CH3:9])[CH:7]([OH:10])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[NH:4]1)[CH3:2]
Reactant: CCC1(C)CC(=O)C(C)C(C)(CC)N1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCC1(C)CC(O)C(C)C(C)(CC)N1
Reaction time: 1 h
Yield: 86.4 %

Procedure:
19.7 g of 2,6-diethyl-2,3,6-trimethyl-4-piperidone were dissolved in 250 ml of methanol, and 3.7 g of sodium borohydride were added thereto in four portions over a period of 1 hour, with stirring. After stirring the mixture for a further 4 hours, it was allowed to stand overnight and was then concentrated by evaporation under reduced pressure; water was added to the concentrated mixture, which was then extracted with benzene. The resulting benzene solution was dried over potassium carbonate and the benzene was distilled off. The residue was distilled under reduced pressure, giving 17.2 g of the title compound as a colourless liquid (bp 125°-129° C./1.5 mmHg).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1>CN(C)C=O>[N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[CH2:13][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: OCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OCc1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-hydroxybenzyl alcohol (14.46 g) in dry dimethylformamide (100 ml) was added dropwise to a stirred suspension of sodium hydride (60% dispersion in oil, 5.6 g), (washed with petroleum spirit 40°-60° C.) in dry dimethylformamide (50 ml) cooled under an atmosphere of nitrogen at 0°-5° C. The mixture was stirred at room temperature for 0.5 hour then re-cooled to 0°-5° C. and a solution of 2-chloromethylquinoline (20.69 g) in dry dimethylformamide (100 ml) added dropwise. The mixture was stirred overnight at room temperature, concentrated in vacuo and diluted with water. The crude product was obtained after cooling and filtration.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[C:5]2[N:6]=[CH:7][C:8]([NH2:11])=[C:9]([NH2:10])[N:4]2[N:3]=1.[C:13]1([CH2:19][C:20](=[O:25])C(OC)=O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CC(O)=O>[CH3:1][C:2]1[CH:12]=[C:5]2[N:6]=[CH:7][C:8]3[C:9](=[N:10][C:20]([OH:25])=[C:19]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:11]=3)[N:4]2[N:3]=1
Reactant: Cc1cc2ncc(N)c(N)n2n1
Reactant: COC(=O)C(=O)Cc1ccccc1
Solvent: CC(=O)O
Product: Cc1cc2ncc3nc(-c4ccccc4)c(O)nc3n2n1
Temperature: 65 °C
Reaction time: 4 h

Procedure:
A 40-mL scintillation vial containing Compound (10-3) (320 mg, 2.0 mmol, 1 eq.), methyl phenylpyruvate (360 mg, 2.2 mmol, 1.1 eq.), and 20% AcOH (20 mL) was stirred at room temperature for 1.5 hours and at 65° C. for 4 hours. The mixture was allowed to cool and the precipitated solid was filtered and washed successively with water (15 mL) and Et2O (2×10 mL). The solid was dried in vacuo to give Compound (10-4) as a yellowish solid.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[S:6][C:7]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][CH:14]=2)=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3].[NH:21]1[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22]1.C(OC)(OC)OC.C([BH3-])#N.C(=O)C1C=CC=CC=1>COCCOC.CN(C)C(=O)C.C(O)(=O)C>[NH2:1][C:2]([NH:4][C:5]1[S:6][C:7]([C:13]2[CH:14]=[CH:15][C:16]([CH2:19][N:21]3[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22]3)=[CH:17][CH:18]=2)=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3]
Reactant: NC(=O)Nc1sc(-c2ccc(C=O)cc2)cc1C(N)=O
Reactant: OC1CCNC1
Agent: [BH3-]C#N
Solvent: CC(=O)N(C)C
Solvent: CC(=O)O
Solvent: COCCOC
Product: NC(=O)Nc1sc(-c2ccc(CN3CCC(O)C3)cc2)cc1C(N)=O
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 24.1 %

Procedure:
2-[(Aminocarbonyl)amino]-5-(4-formylphenyl)-3-thiophenecarboxamide (100 mg) was stirred in a mixture of 1,2-dimethoxyethane (10 ml) and N,N-dimethylacetamide (5 ml). 3-pyrrolidinol (0.15 g) was added, followed by trimethyl orthoformate (5 ml) and acetic acid (0.5 ml). The reaction was stirred at 80° C. for 20 minutes, and then polymer-supported cyanoborohydride (0.45 g) was added. The reaction was stirred at 80° C. for a further 2 h, and then polymer-supported benzaldehyde (0.5 g) was added. The resins were removed by filtration, and the filtrate was then passed through a 5 g SCX column, washing with methanol (25 ml). The product was eluted using 1M methanolic ammonia (45 ml), and this solution was then evaporated to dryness under reduced pressure. Purification by chromatography on silica, eluting with dichloromethane/methanol (9:1), gave the product as an off-white solid (30 mg).
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[NH:8][C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].C1(C)C=CC(S(O[CH2:32][CH:33]2[CH2:36][CH2:35][CH2:34]2)(=O)=O)=CC=1>>[CH:33]1([CH2:32][N:8]2[C:9]([C:10](=[O:19])[C:11]3[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:21])[NH:6][C:7]2=[O:20])[CH2:36][CH2:35][CH2:34]1
Reactant: Cc1cc(C)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC2)cc1
Product: Cc1cc(C)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2CC2CCC2)c1
Yield: 1.3 %

Procedure:
5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and (cyclobutyl)methyl para-toluenesulfonate were reacted by the same way ith the example 1 to obtain the titled compound (182 mg, yield: 1.3%).
Reaction SMILES: [C:1]([O:9][CH:10]([C@H:12]1[O:21][C@H:15]2[O:16][C:17](C)(C)[O:18][C@H:14]2[CH2:13]1)[CH3:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[NH4+]>Cl>[C:1]([O:9][CH:10]([C@@H:12]1[CH2:13][C@H:14]([OH:18])[CH:15]([O:16][CH3:17])[O:21]1)[CH3:11])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(OC(=O)c1ccccc1)[C@@H]1C[C@@H]2OC(C)(C)O[C@@H]2O1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: COC1O[C@H](C(C)OC(=O)c2ccccc2)C[C@@H]1O
Yield: 3.1 %

Procedure:
A solution of 1-[(3aS,5S,6aS)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]ethyl benzoate (compound 25h, 170 mg, 18 mmol) in the HCl solution (0.1N in MeOH, 3 mL) was stirred at room temperature overnight. The resulting mixture was neutralized by ammonium hydroxide and concentrated in vacuo. The residue was suspended in EtOAc and then filtered, the filtrate was concentrated in vacuo to afford 148 mg crude product of 1-[(2S,4S)-4-hydroxy-5-methoxy-tetrahydrofuran-2-yl]ethyl benzoate (compound 25i), which was used in the next step directly. MS obsd. (ESI+) [(M+H)+]: 267.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].P(Cl)(Cl)(Cl)(Cl)[Cl:13]>C(OCC)C>[I:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:13])=[O:5]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(O)c1ccc(F)cc1I
Solvent: CCOCC
Product: O=C(Cl)c1ccc(F)cc1I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-iodo-4-fluorobenzoic acid (194 mg, 0.73 mmol) and phosphorus pentachloride (152 mg, 0.73 mmol) in diethyl ether (5 mL) was stirred at room temperature for 2 h. The solvent was removed under reduced pressure to yield the 2-iodo-4-fluorobenzoyl chloride.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1)[CH3:2].Br[CH2:14][CH2:15][CH2:16][Cl:17].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:14][CH2:15][CH2:16][Cl:17])[CH:6]=1)[CH3:2]
Reactant: ClCCCBr
Reactant: CCOC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cccc(OCCCCl)c1
Yield: 68.7 %

Procedure:
To a solution of ethyl-3-hydroxybenzoate (5.0 g, 30 mmol) in acetone (250 ml) at rt was added 1-bromo-3-chloro-propane (5.67 g, 36 mmol) and K2CO3 (12.4 g, 90 mmol). The resulting suspension was heated to reflux where it was maintained for 25 h. After this time, the mixture was concentrated under reduced pressure and the resulting solid was partitioned between H2O and EtOAc. The organic phase was separated and the aqueous phase was extracted with additional EtOAc. The combined organic fractions were washed with 1N HCl and brine, dried (Na2SO4), filtered and concentrated under reduced pressure to provide the crude product. Purification by chromatography on silica eluting with 5% EtOAc/hexane gave 3-(3-chloro-propoxy)-benzoic acid ethyl ester as a colourless oil (5.0 g, 68%).
Reaction SMILES: [C:1]1(=[O:7])[O:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]1(=O)O[CH2:10][CH2:9]1>>[CH2:10]([CH:2]1[CH2:3][CH2:4][CH2:5][O:6][C:1]1=[O:7])[CH:9]=[CH2:8]
Reactant: O=C1CCO1
Reactant: O=C1CCCCO1
Product: C=CCC1CCCOC1=O

Procedure:
9.81 g of tetrahydro-3-(2-propenyl)-2H-pyrane-2-one of interest were prepared in the same manner as in Preparation Example 2Z-5 except that 10.01 g (100.0 mmol) of δ-valerolactone were used instead of β-propiolactone described in Preparation Example 2Z-5.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:17]([N:27]1[CH2:34][CH2:33][CH2:32][C@@H:28]1[C:29](O)=[O:30])([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].C(OC1C=CC(NC(C2C=CC=CN=2)=O)=CC=1)C1C=CC=CC=1>>[CH2:20]([O:19][C:17]([N:27]1[CH2:34][CH2:33][CH2:32][C@@H:28]1[C:29](=[O:30])[NH:14][C:13]1[CH:12]=[CH:11][C:10]([O:9][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:16][CH:15]=1)=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: O=C(O)[C@H]1CCCN1C(=O)OCc1ccccc1
Agent: Cl
Agent: O=C(Nc1ccc(OCc2ccccc2)cc1)c1ccccn1
Product: O=C(Nc1ccc(OCc2ccccc2)cc1)[C@H]1CCCN1C(=O)OCc1ccccc1

Procedure:
This compound was prepared from 4-benzyloxyaniline hydrochloride (4.0 g, 17.0 mmol) and (+)-N-carbobenzyloxy-d-proline (4.44 g, 17.8 mmol), using the same method to prepare pyridine-2-carboxylic acid (4-benzyloxyphenyl)amide, to give the product as a colorless solid, which was used without further purification in the subsequent step. 1H NMR(DMSO-d6) δ1.80-1.95 (m, 3H), 2.10-2.27 (m, 1H), 3.35-3.55 (m, 2H), 4.33 (m, 1H), 5.0 (m, 4H), 6.95 (d, 2H), 7.12-7.53 (m, 12H) and 9.95 (d, 1H).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]#[N:14].B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]#[N:14]
Reactant: COc1cccc2c(C#N)cccc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N#Cc1cccc2c(O)cccc12
Temperature: 25 °C

Procedure:
To a solution of 5-methoxynaphthalene-1-carbonitrile (Preparation 11) (880 mg, 4.80 mmol) in DCM (10 mL) under argon at 0° C. was added 1M BBr3 solution in DCM (12.5 mL). After 10 min the mixture was maintained at rt for 4 h. The mixture was partitioned between NaHCO3 solution and EtOAc, the organic phase was washed with 1M HCl, brine and dried (MgSO4). Solvent was removed in vacuo and the residue purified by column chromatography (isohexane:EtOAc, 2:1) to give the title compound: δH (CD3OD): 6.97 (1H, d), 7.50, 7.52 (2H, 2dd), 7.62 (1H, d), 7.94 (1H, d), 8.53 (1H, d).
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].Br[CH2:7][C:8](=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10]>O1CCOCC1>[NH:2]([C:3]1[S:4][CH:7]=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:5]=1)[NH2:1]
Reactant: CCOC(=O)C(=O)CBr
Reactant: NNC(N)=S
Solvent: C1COCCO1
Product: CCOC(=O)c1csc(NN)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.7 %

Procedure:
To a stirred solution of thiosemicarbazide (911 mg, 10 mmol) in dioxane (10 mL) was added ethyl bromopyruvate (1258 μl, 10.00 mmol). The resulting solution was allowed to stir for 16 h at room temperature, then for 2 h at 60° C. Solvent was evaporated and the residue was purified by silica gel column chromatography with gradient of methanol (0-10%) in CH2Cl2 to afford 28 (500 mg, 27%) as an orange solid. LRMS (ESI): calc. 187.1; found 188.1 (MH)+.
Reaction SMILES: C(NC(C)C)(C)C.CCCCCC.C([Li])CCC.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.[CH:26]1([CH:32]=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>O.O1CCCC1>[Cl:19][C:20]1[C:25]([CH:32]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[OH:33])=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: Clc1ccccn1
Reactant: O=CC1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: O
Product: OC(c1cccnc1Cl)C1CCCCC1
Temperature: -40 °C
Reaction time: 1.5 h
Yield: 50.2 %

Procedure:
Diisopropylamine (23 ml, 175 mmol) was added to a tetrahydrofuran (500 ml) solution of 1.6 M hexane solution (100 ml, 160 mmol) of n-butyl lithium at -65° C. or lower, and the mixture was warmed up to -40° C. The reaction solution was mixed with 2-chloropyridine (17 g, 150 mmol) at -70° C. or lower and stirred for 1.5 hours at -70° C. or lower. the reaction solution was mixed with cyclohexanecarbaldehyde (17 g, 151 mmol) at -70° C. or lower and stirred for 2 hours at -70° C. or lower. The reaction solution was mixed with water, warmed to room temperature and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under a reduced pressure. Thereafter, the resulting residue was purified by silica gel column chromatography (chloroform) to give 2-chloro-α-cyclohexyl-3-pyridinemethanol-(17 g, 50%).
Reaction SMILES: Br[CH:2]1[C:8](=O)[C:7]2[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:6]=2[S:5][C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[C:19]([CH2:21][C:22]([NH2:24])=[S:23])#[N:20]>C(O)C>[Cl:14][C:12]1[CH:11]=[CH:10][C:7]2[C:8]3[N:24]=[C:22]([CH2:21][C:19]#[N:20])[S:23][C:2]=3[C:3]3[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=3[S:5][C:6]=2[CH:13]=1
Reactant: N#CCC(N)=S
Reactant: O=C1c2ccc(Cl)cc2Sc2ccccc2C1Br
Solvent: CCO
Product: N#CCc1nc2c(s1)-c1ccccc1Sc1cc(Cl)ccc1-2

Procedure:
To a solution of 11-bromo-7-chloro-11H-dibenzo[b,f]thiepin-10-one (3.75 mmoles) in absolute ethanol (19 ml), 2-cyanothioacetamide (5.63 mmoles) was added. The reaction mixture was heated under stirring and refluxing for 8 hours. Then the solvent was evaporated under reduced pressure and the remaining dry residue was dissolved in water and ethyl acetate. After extraction the organic layers were washed with a saturated aqueous NaHCO3 solution, water and a saturated aqueous sodium chloride solution. After purification by chromatography on a silica gel column a crystalline product was isolated.
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[N:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[CH3:19][C:20]1[N:21]([C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=2)[CH:22]=[CH:23][N:24]=1>>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[N:12]=[CH:13][C:14]([CH2:17][CH3:18])=[CH:15][N:16]=3)[CH2:7][CH2:6]2)[C:29](=[O:30])[C:28]2[CH:27]=[CH:26][C:25]([N:21]3[CH:22]=[CH:23][N:24]=[C:20]3[CH3:19])=[CH:33][CH:32]=2)[CH2:2][CH2:3]1
Reactant: Cc1nccn1-c1ccc(C(=O)O)cc1
Reactant: CCc1cnc(N2CCC(NC3CC3)CC2)nc1
Product: CCc1cnc(N2CCC(N(C(=O)c3ccc(-n4ccnc4C)cc3)C3CC3)CC2)nc1

Procedure:
The title compound is prepared from cyclopropyl-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl]-amine and 4-(2-methyl-imidazol-1-yl)-benzoic acid following a procedure analogous to that described in Example 90. LC (method 19): tR=3.84 min; Mass spectrum (ESI+): m/z=431 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8]C.B(Br)(Br)Br>C(Cl)Cl>[OH:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:10][C:11]([OH:13])=[O:12])=[CH:3][C:2]=1[CH3:1]
Reactant: COc1ccc(CC(=O)O)cc1C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(CC(=O)O)ccc1O
Temperature: 25 °C
Yield: 74.3 %

Procedure:
To a solution of 3-methyl-4-methoxyphenylacetic acid (2.3 g., 12.8 mmol) in anh CH2Cl2, cooled to 0° C., was added 15 ml of a solution of BBr3 (1.0 M in CH2Cl2) via syringe. After addition was complete, the reaction was allowed to warm to room temperature and then quenched with 5 ml water. The CH2Cl2 was removed and the residue was extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered and concentrated to yield the title compound (1.58 g, 75% yield): ES-MS (m/z) 167 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[CH3:9].[C:10](=[O:12])=[O:11]>C1COCC1.[Li]C(C)(C)C>[Br:8][C:4]1[C:3]([CH3:9])=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:10]([OH:12])=[O:11]
Reactant: O=C=O
Reactant: Cc1c(Br)cccc1Br
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cc1c(Br)cccc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.4 %

Procedure:
To a solution of 1,3-dibromo-2-methylbenzene (6.57 g) in dry THF (100 mL), t-BuLi solution (1.5 M in pentane, 17 mL) was added dropwise at −80° C. Then reaction mixture was stirred between −76˜−78° C. for 2 h. Then the mixture was cooled to below −80° C. and dry ice was added after which the mixture was warmed to room temperature naturally. Solvent was removed, 5% NaOH solution (40 mL) added and the aqueous solution was washed with CH2Cl2 (10 mL×2). Then the aqueous layer was acidified with concentrated HCl to pH=1 and extracted with EtOAc (100 mL×2). The combined organic extracts were dried over anhydrous Na2SO4. After removing the solvent, the residue was purified by silica column chomatography, (eluted with petrol. ether: EtOAc=8:1 to 1:1), to obtain 3.58 g of the product. Yield: 63.4%. 1H NMR (400 MHz, CDCl3) δ 2.73 (s, 3H), 7.15 (t, J=8.0 Hz, 1H), 7.77 (dd, J=8.0 Hz, J=1.2 Hz, 1H), 7.94 (dd, J=8.0 Hz, J=1.2 Hz, 1H).
Reaction SMILES: CC(C)([O-])C.[Na+].[Cl:7][C:8]1[CH:9]=[C:10]([C:15]2([C:20]([F:23])([F:22])[F:21])[CH2:19][CH2:18][NH:17][CH2:16]2)[CH:11]=[C:12]([Cl:14])[CH:13]=1.Br[C:25]1[CH:35]=[CH:34][C:28]([CH2:29][NH:30][C:31](=[O:33])[CH3:32])=[C:27]([CH3:36])[CH:26]=1>C1(C)C=CC=CC=1.C(OC)(C)(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[Cl:14][C:12]1[CH:11]=[C:10]([C:15]2([C:20]([F:23])([F:22])[F:21])[CH2:19][CH2:18][N:17]([C:25]3[CH:35]=[CH:34][C:28]([CH2:29][NH:30][C:31](=[O:33])[CH3:32])=[C:27]([CH3:36])[CH:26]=3)[CH2:16]2)[CH:9]=[C:8]([Cl:7])[CH:13]=1
Reactant: CC(=O)NCc1ccc(Br)cc1C
Reactant: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CCNC1
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: Cc1ccccc1
Product: CC(=O)NCc1ccc(N2CCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Temperature: 80 °C
Reaction time: 5 h
Yield: 65.2 %

Procedure:
Sodium tert-butoxide (0.3 g), Tris(dibenzylidene acetone)dipalladium(0) (chloroform adduct)(0.04 g) and xantphos (0.07 g) was added to the solution of 3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidine (0.59 g) and N-(4-bromo-2-methylbenzyl)acetamide (0.5 g) in toluene under argon atmosphere, and the mixture was heated with stirring at 80° C. for 5 hours. The reaction solution was diluted with t-butylmethylether and then washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled away under the reduced pressure, and the residue was then purified by silica gel chromatography to yield N-{4-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-2-methylbenzyl}acetamide (0.6 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[NH:13][C:12](=[O:14])[C:11]2[C:6](=[CH:7][C:8]3[CH2:17][CH2:16][CH:15]([N:18]([C:22]4[CH:34]=[CH:33][C:25]([C:26]([O:28]C(C)(C)C)=[O:27])=[CH:24][CH:23]=4)[CH2:19][C:20]#[CH:21])[C:9]=3[CH:10]=2)[N:5]=1>ClCCl.FC(F)(F)C(O)=O>[CH3:1][O:2][CH2:3][C:4]1[NH:13][C:12](=[O:14])[C:11]2[C:6](=[CH:7][C:8]3[CH2:17][CH2:16][CH:15]([N:18]([C:22]4[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:33][CH:34]=4)[CH2:19][C:20]#[CH:21])[C:9]=3[CH:10]=2)[N:5]=1
Reactant: C#CCN(c1ccc(C(=O)OC(C)(C)C)cc1)C1CCc2cc3nc(COC)[nH]c(=O)c3cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C#CCN(c1ccc(C(=O)O)cc1)C1CCc2cc3nc(COC)[nH]c(=O)c3cc21

Procedure:
A solution of tert-butyl 4-{N-[(6RS)-2-methoxymethyl-4-oxo-3,4,7,8-tetra-hydro-6H-cyclopenta[g]quinazolin-6-yl]-N-(prop-2-ynyl)amino}benzoate (0.069 g, 0.15 mmol) in dichloromethane (1 ml) and trifluoroacetic acid (3 ml) was stirred at room temperature for 1 hour and 10 min, then the solvents were removed in vacuo. The residue was triturated with diethyl ether and the precipitate was collected by filtration, washed with diethyl ether and dried in vacuo over P2O5 to afford the title compound as the tifluoroacetate salt: 0.061 g, m.p. 225° C. (dec); 1H-NMR (250 MHz, DMSO-d6, TMS) 2.23, 2.53 (obscured by DMSO peak) (2×m, each 1H, 7-H), 2.90-3.20 (m, 3H, C≡CH, 8-H), 3.34 (s (obscured by the H2O peak), 3H, OCH3), 3.97 (ABq, J=18.0 Hz, 2H, CH2C≡C), 4.32 (s, 2H, 2-CH2), 5.79 (t, J=8.1 Hz, 1H, 6-H), 7.03 (d, J=9.02 Hz, 2H, 3′, 5′-H), 7.58, (s, 1H, 9-H), 7.81 (m, 3H, 5-H, 2′, 6′-H), 12.17 (s, 1H, N3-H); MS (ESI, m/z) 426 {(M+Na)+, 25%}, 404 {(M+H)+, 70%}.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:8][NH2:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C(O[CH:13]=[C:14]([C:17]#[N:18])[C:15]#[N:16])C>CO>[NH2:18][C:17]1[N:8]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[N:9]=[CH:13][C:14]=1[C:15]#[N:16]
Reactant: CCOC=C(C#N)C#N
Reactant: NNc1ncccc1Cl
Solvent: CO
Product: N#Cc1cnn(-c2ncccc2Cl)c1N
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
3-Chloro-2-hydrazinylpyridine (CAS 22841-92-5) (19.1 g, 133.03 mmol) was suspended in MeOH (200 mL) under nitrogen at −5° C. 2-(ethoxymethylene)malononitrile (CAS 123-06-8) (16.25 g, 133.03 mmol) was added portionwise and the resulting mixture stirred at ˜0° C. for 2 hours. The reaction mixture was heated to reflux for 2 hours then cooled and evaporated to provide 5-amino-1-(3-chloropyridin-2-yl)-1H-pyrazole-4-carbonitrile (29.2 g). 1H NMR (400 MHz, DMSO-d6) δ 6.87 (2H, s), 7.61 (1H, dd), 7.79 (1H, s), 8.21 (1H, dd), 8.55 (1H, dd), m/z (ESI+) (M+H)+=220; HPLC tR=1.17 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH2:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:18]1([C:23]2[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=2)[CH:22]=[CH:21][CH:20]=[N:19]1>C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:27][C:26]2[CH:25]=[CH:24][C:23]([N:18]3[CH:22]=[CH:21][CH:20]=[N:19]3)=[CH:30][CH:29]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: CC(C)(C)OC(=O)COc1cccc(CN)c1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-n3cccn3)cc2)c1

Procedure:
The title compound of Step A was prepared from (3-aminomethyl-phenoxy)-acetic acid tert-butyl ester, of Preparation 20, and 4-pyrazol-1-yl-benzaldehyde, of Preparation 42, using the method described in Example 3, Step A, except no triethylamine was used. 1H NMR (400 MHz, CDCl3) δ 7.89 (m, 1H), 7.68 (m, 1H), 7.63 (d, 2H), 7.41 (d, 2H), 7.23 (m, 1H), 6.93 (m, 2H), 6.77 (dd, 1H), 6.44 (m, 1H), 4.50 (s, 2H), 3.81 (s, 2H), 3.77 (s, 2H), 1.47 (s, 9H); MS 394 (M+1).
Reaction SMILES: C1(NN[C:9](=[O:18])[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(#N)C.C(Cl)(Cl)(Cl)[Cl:42]>>[Cl:42][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: ClC(Cl)(Cl)Cl
Reactant: O=C(NNc1ccccc1)c1ccc(F)cc1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: O=C(Cl)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
To a stirred mixture, under nitrogen, of 49.6 g of 2,4-difluorobenzoic acid, 2-phenylhydrazide, 64.3 g of triphenylphosphine, and 500 ml of anhydrous acetonitrile was added 19.3 ml of carbon tetrachloride. The reaction mixture was stirred at ambient temperature for about 16 hours, concentrated, and extracted with diethyl ether (3×). The diethyl ether extract was filtered and concentrated to a residue, which was flash chromatographed on silica gel, eluting first with ethyl acetate-hexane and, in a subsequent run, with ethyl acetate alone. Concentration of the appropriate fractions yielded 47.5 g (89%) of α-chloro-2,4-difluorobenzaldehyde, phenylhydrazone.