Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:27]=1[C:28](Cl)=[O:29].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:28](=[O:29])[C:27]4[CH:31]=[C:32]([Cl:35])[CH:33]=[CH:34][C:26]=4[Cl:25])=[CH:24][CH:23]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reactant: O=C(Cl)c1cc(Cl)ccc1Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1)c1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 16.4 %

Procedure:
A mixture of 0.625 g (2 mmol) of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine, 0.629 g (3 mmol) of 2,5-dichlorobenzoyl chloride, 0.303 g (3 mmol) of triethylamine and 15 mg of 4-(dimethylamino)pyridine in 10 ml of dichloromethane is stirred at room temperature for 3 hours. The mixture is washed with water, 1N HCl, H2O, 1M NaHCO3, brine and dried (Na2SO4). The solvent is removed to give crystals. Recrystallization from hexane-CH2Cl2 gives 0.16 g of white crystals, m.p. 203°-231° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N:3]=1.[CH:12]1([N:15]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:14][CH2:13]1.C(N(C(C)C)C(C)C)C>ClCCl>[CH:12]1([N:15]2[CH2:21][CH2:20][CH2:19][N:18]([C:2]3[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N:3]=3)[CH2:17][CH2:16]2)[CH2:14][CH2:13]1
Reactant: COC(=O)c1cnc(Cl)nc1
Reactant: C1CNCCN(C2CC2)C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cnc(N2CCCN(C3CC3)CC2)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.3 %

Procedure:
A solution of methyl 2-chloropyrimidine-5-carboxylate (200 mg, 1.16 mmol) in dichloromethane (4.00 mL) was added to a stirred solution of 1-cyclopropyl-1,4-diazepane (247 mg, 1.16 mmol) and N-ethyl-N-propan-2-ylpropan-2-amine (0.902 mL, 5.22 mmol) in dichloromethane (4.00 mL) at 25° C. The resulting solution was stirred at ambient temperature for 18 h. The reaction mixture was evaporated to dryness and redissolved in MeOH (20 mL) and the crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford methyl 2-(4-cyclopropyl-1,4-diazepan-1-yl)pyrimidine-5-carboxylate (312 mg, 97%) as a cream solid. This was used directly with no further purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[C:4]([C:8]([F:11])=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[CH3:13][O:14][C:15]1[CH:25]=[CH:24][C:18]([CH2:19][NH:20][CH2:21][CH2:22][OH:23])=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[C:3]([CH3:12])=[C:4]([C:8]([F:11])=[CH:9][CH:10]=1)[C:5]([N:20]([CH2:21][CH2:22][OH:23])[CH2:19][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH3:13])=[CH:25][CH:24]=1)=[O:7]
Reactant: Cc1c(Br)ccc(F)c1C(=O)O
Reactant: COc1ccc(CNCCO)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN(CCO)C(=O)c2c(F)ccc(Br)c2C)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 420.6 %

Procedure:
To a solution of 3-bromo-6-fluoro-2-methylbenzoic acid (Cpd QQ, 4.8 g, 2.4 mmol), 2-[(4-methoxybenzyl)amino]ethanol (130a, 5.5 g, 23 mmol) and DIPEA (8 g, 62 mmol) in dry DMF (80 mL) was added HATU (12 g, 31 mmol). The mixture was stirred at room temperature for 14 hours. To the reaction mixture was added EtOAc (130 mL). The solution was washed with brine (4×60 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether/EtOAc, 2/1) to give 3-bromo-6-fluoro-N-(2-hydroxyethyl)-N-(4-methoxybenzyl)-2-methylbenzamide (130b, 4 g, 48.8%) as a colorless oil.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:9]=[N:10][CH:11]=[C:12]([CH:15]=1)[C:13]#[N:14].[CH:16]1(B(O)O)[CH2:18][CH2:17]1.C(Cl)Cl>O1CCOCC1.O>[CH:16]1([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([CH:15]=2)[C:13]#[N:14])[CH2:18][CH2:17]1
Reactant: N#Cc1cncc(Br)c1
Reactant: OB(O)C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: N#Cc1cncc(C2CC2)c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
Cesium carbonate (20.8 g, 0.064 mol) was added to a stirred solution of 5-bromonicotinonitrile (6 g, 0.0322 mol) and cyclopropylboronic acid (2.8 g, 0.032 mol) in a mixture of 1,4-dioxan (100 mL) and water (50 mL). The reaction vessel was purged with argon for 20 min and Pd(dppf)2Cl2.DCM (1.3 g, 0.0016 mol) was added to the reaction mixture. The reaction vessel was purged again with argon for 10 min and subsequently allowed to stir at 100° C. for 3 h. The reaction mixture was filtered through a filter bed of CELITE and the filter bed was thoroughly washed with ethyl acetate (3×200 mL). The collected organic fractions were concentrated under vacuum to afford the crude product, which was purified by silica gel column chromatography to afford 5-cyclopropylnicotinonitrile. MS (M+1): 144.8.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.Cl[C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=1>CO.C(OCC)(=O)C>[C:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=2)=[CH:3][CH:4]=1)#[N:10]
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: N#CCc1ccc(N)cc1
Solvent: CCOC(C)=O
Solvent: CO
Product: N#CCc1ccc(Nc2ccc(C(N)=O)cn2)cc1

Procedure:
Combine 4-aminophenylacetonitrile (5.0 g, 37.9 mmol) and 6-chloro-nicotinamide (6.3 g, 40.3 mmol) in a flask and heat at 150° C. for 5 hours. Cool, dissolve the residue in methanol, dilute with ethyl acetate, then wash with saturated aqueous sodium bicarbonate solution. Dry the organic layer over sodium chloride/magnesium sulfate, filtered, and concentrated on a rotary evaporator to yield the crude product (10 g). The crude product was purified by flash column chromatography on silica gel eluting with 10% aqueous ammonium hydroxide in ethanol and chloroform to yield 6-(4-cyanomethyl-phenylamino)-nicotinamide. Triturate the resulting solid with hot isopropanol, collect the precipitate to yield 6-(4-cyanomethyl-phenylamino)-nicotinamide (1.8 g): 1H NMR (DMSO-D6, 300.00 MHz): 9.48 (s, 1H), 8.69 (d, 1H, J=2.1 Hz), 8.03-7.71 (m, 4H), 7.31-7.21 (m, 3H), 6.85 (d, 1H, J=8.8 Hz), 3.97 (s, 2H).
Reaction SMILES: N1[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3](O)=[O:4].C(N(C(C)C)C(C)C)C.[C:18]1(=[O:24])[CH2:23][CH2:22][CH2:21]C=C1.[C:25]1(CC=O)[CH:30]=[CH:29]C=[CH:27][CH:26]=1>C1(C)C=CC=CC=1>[OH:24][C@H:18]1[C@@H:23]2[CH2:22][CH2:21][C@@H:6]([CH2:2][C:3]2=[O:4])[C@@H:7]1[C:8]1[CH:29]=[CH:30][CH:25]=[CH:26][CH:27]=1
Reactant: O=C1C=CCCC1
Reactant: O=CCc1ccccc1
Reactant: O=C(O)[C@H]1CCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: O=C1C[C@@H]2CC[C@H]1[C@H](O)[C@H]2c1ccccc1
Temperature: 45 °C
Reaction time: 72 h

Procedure:
To a mixture of D-proline (2.93 g), N-ethyl-diisopropylamine (4.36 mL) in toluene (70 mL) was added 2-cyclohexen-1-one (10 mL) and phenyl acetaldehyde (14.6 mL) at 20-25° C. The mixture was stirred for 3 d at 45° C. IPC according to LC-MS method 1 indicated>99% conversion. The suspension was cooled to 20-25° C. and filtered. The filter cake was washed with water (3×10 mL), followed by toluene wash (3×10 mL). The filter cake was dried on the filter by sucking air through the filter. Yield: 13.2 g, 60%. 1H-NMR (CDCl3) corresponds to structure of compound ent-2. Chiral HPLC method:enantiomeric ratio=27:73 (2:ent-2), diastereomeric purity: 100%; LC-MS method 1: 100% a/a, tR=1.19.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.B([O-])([O-])O[C:35]1[CH:36]=[CH:37][C:38]2[O:43][CH2:42][CH2:41][CH2:40][C:39]=2[CH:44]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.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>[O:43]1[C:38]2[CH:37]=[CH:36][C:35]([C:2]3[CH:3]=[CH:4][C:5]4[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]5[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]6[CH2:26][CH2:27][O:28][CH2:29][CH2:30]6)=[CH:19][CH:18]=5)=[O:15])=[CH:7][C:6]=4[CH:32]=3)=[CH:44][C:39]=2[CH2:40][CH2:41][CH2:42]1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: [O-]B([O-])Oc1ccc2c(c1)CCCO2
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: Cc1ccccc1
Solvent: CCO
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc5c(c4)CCCO5)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
Under argon atmosphere, a mixture of 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg), 3,4-dihydro-2H-1-benzopyran-6-yl borate (113 mg) and potassium carbonate (160 mg) in toluene/ethanol/water (10/1/1 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (33 mg, 0.029 mmol), and the mixture was refluxed for 6 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give crystals, which were collected by filtration and recrystallized from ethanol to give pale yellow crystals of 7-(3,4-dihydro-2H-1-benzopyran-6-yl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 62) (149 mg).
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:24]1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.C1(N)CCCCCC1>C(O)(=O)C>[CH:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:10]=3[N:9]=[CH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:24]1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Agent: NC1CCCCCC1
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: O=c1c2scc(-c3ccccc3)c2ncn1C1CCCCCC1
Yield: 93 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (80 mg, 0.34 mmol), triethyl orthoformate (0.65 ml), cycloheptylamine (0.08 ml, 0.63 mmol), and acetic acid (0.08 ml) were used to give 103 mg (0.32 mmol, 93% yield) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:12])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:20].CI.[C:24](=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:24][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:11]([NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:12])[CH:6]=2)[C:2]([CH3:21])([CH3:1])[C:3]1=[O:20]
Reactant: CC1(C)C(=O)Nc2cc(C(=O)Nc3ccccc3)ccc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CN1C(=O)C(C)(C)c2ccc(C(=O)Nc3ccccc3)cc21

Procedure:
2.8 g. (10 mmol) 2,3-Dihydro-3,3-dimethyl-N-phenyl-2-oxo-(1H)-indole-6-carboxamide, 2.8 g. (20 mmol) methyl iodide and 2.5 g. (20 mmol) potassium carbonate were stirred in 50 ml. dimethylformamide for 3 hours at 70° C. After cooling, the reaction mixture was mixed with water, decanted and again mixed with water. The residue was purified by column chromatography (RP-18, methanol:water:ammonium hydroxide 80:20:1 v/v/v). Pure fractions were evaporated until the commencement of crystallisation, subsequently filtered off with suction and washed with water. There were obtained 2.3 g. (78% of theory) of the title compound; m.p. 184-186° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)([O-:3])=[O:2].[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.P(Cl)(Cl)(Cl)=O.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:19][CH2:18]1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])CC1
Temperature: 80 °C
Yield: 54.7 %

Procedure:
To a slurry of 212.0 g of 2,4-dinitrobenzoic acid in 1400 ml of toluene was added with agitation 101.0 g of triethylamine, followed by 122.7 g of N-methylpiperazine. Next 75.7 g of phosphorus oxychloride was added dropwise at such a rate to maintain the reaction temperature below 90° C. The mixture was refluxed for 5 hrs, cooled to 80° C., and poured slowly into 1000 ml of aqueous 5% NaHCO3 solution with stirring. The precipitate was filtered, washed with water and recrystallized from hot methanol to yield 161 g of N1 -methyl-N4 -(2,4-dinitrobenzoyl)piperazine, mp 130°-132° C.
Reaction SMILES: C[N:2]1[C:7](=[O:8])[C:6]2=[C:9]([S:26][CH3:27])[N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[N:20]=4)=[CH:15][CH:14]=3)[N:11]=[C:5]2[N:4]2[C@H:28]3[CH2:33][CH2:32][CH2:31][C@H:29]3[N:30]=[C:3]12.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S.N>CO>[CH3:27][S:26][C:9]1[N:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[N:20]=3)=[CH:15][CH:14]=2)[N:11]=[C:5]2[N:4]3[C@H:28]4[CH2:33][CH2:32][CH2:31][C@H:29]4[N:30]=[C:3]3[NH:2][C:7](=[O:8])[C:6]=12
Reactant: CSc1c2c(nn1Cc1ccc(-c3cccc(F)n3)cc1)N1C(=N[C@@H]3CCC[C@@H]31)N(C)C2=O
Agent: N
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: CO
Product: CSc1c2c(nn1Cc1ccc(-c3cccc(F)n3)cc1)N1C(=N[C@@H]3CCC[C@@H]31)NC2=O
Temperature: 150 °C
Yield: 43.8 %

Procedure:
(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(methylthio)-2-(4-(6-fluoropyridin-2-yl)benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one (25 mg, 0.054 mmol) and P4S10 (48.1 mg, 0.108 mmol) are placed in a Biotage microwave vial, and then 1.0 mL of 7N ammonia in MeOH is added. The sealed vial is heated in a Biotage microwave at 150° C. for 6 h. After solvent is removed, the residue is suspended in DMF, and then filtered. The obtained filtrate is purified by a semi-preparative HPLC to give 10.6 mg of pure product as pale yellow solids (yield: 44%). MS (ESI) m/z 449.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[Mg+2].[Cl-].[Cl-].[CH2:12]=[O:13]>C1(C)C=CC=CC=1.C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:12]=[O:13])=[C:4]([OH:8])[CH:3]=1
Reactant: C=O
Reactant: Oc1cccc(Br)c1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Solvent: Cc1ccccc1
Product: O=Cc1ccc(Br)cc1O
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
A solution of 3-bromophenol (100.00 g, 0.576 mol) in a mixture of 600 mL of toluene/acetonitile (2:1) was added MgCl2 (110.6 g, 3.68 mol), paraformaldehyde (40.00 g) and the mixture was maintained at 80° C. for 1.5 h while the by-product was distilled off. A second portion of paraformaldenhyde (40.00 g) was added and the mixture was stirred for 2.5 h at 80° C., and the third portion of paraformaldenhyde (30.6 g) was added and stirred for 2 h at 80° C. The reaction was quenched with cool 2.5 N hydrochloride acid, and the mixture was stirred at room temperature for 1 h to afford a biphasic solution. The aqueous phase was extracted with EtOAc. And the combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to afford 4-bromo-2-hydroxybenzaldehyde. 1H-NMR (400 MHz, CDCl3) 11.10 (s, 1H), 9.86 (s, 1H), 7.40˜7.43 (d, J=8.4 Hz, 1H), 7.15˜7.20 (m, 2H).
Reaction SMILES: C#C.[NH:3]([CH2:7][CH2:8][CH2:9][CH:10]([NH:14][C:15]([C:17]1[S:18][CH:19]=[CH:20][C:21]=1[NH:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]#[C:33][C:34]2[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=2)[CH:27]=1)(=[O:25])=[O:24])=[O:16])[C:11]([OH:13])=[O:12])[C:4]([NH2:6])=[NH:5].[H][H]>O1CCCC1.O.[Pd]>[NH:3]([CH2:7][CH2:8][CH2:9][C@H:10]([NH:14][C:15]([C:17]1[S:18][CH:19]=[CH:20][C:21]=1[NH:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][CH2:33][C:34]2[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=2)[CH:27]=1)(=[O:25])=[O:24])=[O:16])[C:11]([OH:13])=[O:12])[C:4]([NH2:6])=[NH:5]
Reactant: N=C(N)NCCCC(NC(=O)c1sccc1NS(=O)(=O)c1cccc(C#Cc2cccnc2)c1)C(=O)O
Reactant: [H][H]
Agent: [Pd]
Agent: C#C
Solvent: O
Solvent: C1CCOC1
Product: N=C(N)NCCC[C@H](NC(=O)c1sccc1NS(=O)(=O)c1cccc(CCc2cccnc2)c1)C(=O)O

Procedure:
The acetylene (EG00298/5-Guanidino-2-{[3-(3-pyridin-3-ylethynyl-benzenesulfonyl amino)-thiophene-2-carbonyl]amino}-pentanoic acid; approx 10 mg) was dissolved in tetrahydrofuran:water (4:1, 2 mL), palladium on charcoal (approx 10% weight) was added and a hydrogen atmosphere introduced by balloon. The reaction mixture was stirred at 20° C. for 24 hours with occasional refilling of the hydrogen balloon. After this time the reaction mixture was filtered over Celite™ and the solvent removed in vacuo. The yellow residue was purified using preparative LCMS.
Reaction SMILES: C(Cl)(=O)OCC.[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH:15]1[C:20](O)=[O:21])=[O:13])([CH3:10])([CH3:9])[CH3:8].C(N(C(C)C)CC)(C)C.[BH4-].[Na+]>CO.C1COCC1>[OH:21][CH2:20][CH:15]1[CH2:16][O:17][CH2:18][CH2:19][N:14]1[C:12]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:13]
Reactant: CC(C)(C)OC(=O)N1CCOCC1C(=O)O
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOCC1CO
Temperature: 25 °C
Yield: 74.2 %

Procedure:
Ethyl chlorocarbonate (149 μL; TCI) was added to a THF (8 mL) solution of morpholine-3, 4-dicarboxylic acid 4-tert-butyl ester (300 mg; Ast) and diisopropylethylamine (560 μL; WAKO) with ice cooling and the resulting mixture was stirred at room temperature for 1 and half hours. Sodium tetrahydroborate (197 mg; WAKO) was added at room temperature, the resulting mixture was stirred for 15 minutes followed by the addition of methanol (1.2 mL) with ice cooling, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture solution was concentrated under reduced pressure, ethyl acetate and saturated aqueous sodium bicarbonate solution were added to extract the reaction mixture, then the organic layer was dried, and the solvent was evaporated under reduced pressure to give the title compound (209 mg).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:20][O:21][CH2:22]Cl.Cl>C(Cl)Cl>[CH3:20][O:21][CH2:22][O:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(O)cc1
Reactant: COCCl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOc1ccc(CC#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
Ten grams of 4-hydroxybenzyl cyanide was dissolved in 80 ml of methylene chloride, followed by addition of 20 ml of diisopropylethylamine and 9.1 g of chloromethyl methyl ether at 0 C., and stirred overnight at room temperature. The reaction solution was poured into 2N hydrogen chloride, followed by extraction of methylene chloride and washing in saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate to obtain residue. The residue was subjected to chromatography on a silica gel column, which was then eluted with chloroform to produce 12.8 g of 4-methoxymethyloxybenzyl cyanide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[F:21])[O:5][C:6]1[N:11]=[CH:10][N:9]=[C:8]([NH:12][C:13]([CH:15]2[CH2:17][CH2:16]2)=[O:14])[CH:7]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][C:24]=1[C:32]([F:35])([F:34])[F:33]>C1COCC1.C(Cl)Cl>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:1][C:2]2[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=2[F:21])[O:5][C:6]2[N:11]=[CH:10][N:9]=[C:8]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[CH:7]=2)=[O:31])=[CH:25][C:24]=1[C:32]([F:33])([F:34])[F:35]
Reactant: Nc1cc(Oc2cc(NC(=O)C3CC3)ncn2)ccc1F
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Nc1cc(Oc2cc(NC(=O)C3CC3)ncn2)ccc1F
Yield: 76.4 %

Procedure:
Dissolve N-[6-(3-amino-4-fluoro-phenoxy)pyrimidin-4-yl]cyclopropanecarboxamide (400 mg, 1.4 mmol) in THF (4 mL) and DCM (10 mL), add 4-chloro-3-(trifluoromethyl)phenyl isocynate (1.4 g, 6.3 mmol). Stir the reaction at room temperature overnight. Filter and collect the solid to get the title compound (545 mg, 77%). MS: (M+1): 510.2.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[C:14](=[O:16])[CH3:15].[Br:17]Br.[CH2:19]([OH:22])[CH2:20]O.CC1C=CC(S(O)(=O)=O)=CC=1>C(O)CCC.O.C1C=CC=CC=1>[Br:17][CH2:15][C:14]1([C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH2:12][C:13]=3[CH:1]=2)[O:22][CH2:19][CH2:20][O:16]1
Reactant: OCCO
Reactant: CC(=O)c1ccc2c(c1)Cc1ccccc1-2
Reactant: BrBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Solvent: O
Solvent: c1ccccc1
Product: BrCC1(c2ccc3c(c2)Cc2ccccc2-3)OCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
20.8 parts of 1-(9H-fluoren-2-yl)ethanone are dissolved in 240 parts of butanol. At a temperature of 50° C, 16 parts of bromine are added dropwise while the mixture is allowed to reach room temperature. After complete addition of bromine (1 hour), the whole is stirred at room temperature for 1 hour. Then there are added successively 7.5 parts of 1,2-ethanediol, 360 parts of benzene and 2 parts of 4-methylbenzenesulfonic acid. Stirring is continued overnight at reflux temperature with water-separator. After cooling to room temperature, the reaction mixture is evaporated. The residue is taken up in a mixture of 2,2'-oxybispropane and benzene (1:1 by volume). The resulting solution is washed successively with a diluted sodium hydroxide solution and three times with water, dried, filtered and evaporated. The residue is crystallized from methanol. The product is filtered off and dried, yielding 20.5 parts (62%) of 2-(bromomethyl)-2-(9H-fluoren-2-yl)-1,3-dioxolane; mp. 90° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1.C(O)(=O)[CH2:17][C:18]([OH:20])=[O:19].N1CCCCC1.C(=O)=O.Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[CH:17][C:18]([OH:20])=[O:19])=[CH:10][CH:9]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(-c2ccccc2Cl)cc1
Agent: Cl
Agent: O=C=O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1ccc(-c2ccccc2Cl)cc1
Temperature: 0 °C

Procedure:
A mixture of 21.6 g. (0.1 mole) of 4-(2'-chlorophenyl)benzaldehyde is heated on a steam bath with 13.2 g. of malonic acid and 95 ml. of pyridine containing 5 drops of piperidine. The mixture is heated for four hours until the liberation of carbon dioxide ceases. The cooled mixture is poured into a mixture of 110 ml. concentrated hydrochloric acid and 500 ml. of ice water. The solid which separates is filtered, washed and 15 ml. portions of cold water and then resuspended in 200 ml. of cold water, filtered, washed with cold water and dried at 40°C. The residue is then recrystallized from ethanol to obtain 4-(2'-chlorophenyl)cinnamic acid.