Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:3]([NH:5][C:6]1[N:10]([CH2:11][CH3:12])[N:9]=[C:8]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH:7]=1)=[O:4].C(O)C.Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>C(N(CC)CC)C>[CH2:11]([N:10]1[C:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:7][C:8]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:9]1)[CH3:12]
Reactant: CCOC(=O)CBr
Reactant: CCn1nc(-c2ccncc2)cc1NC(=O)[C@@H](N)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)CN[C@@H](Cc1ccccc1)C(=O)Nc1cc(-c2ccncc2)nn1CC
Temperature: 0 °C
Reaction time: 8 h
Yield: 27.4 %

Procedure:
To a 25 ml flask was added (S)-2-amino-N-(1-ethyl-3-(pyridin-4-yl)-1H-pyrazol-5-yl)-3-phenylpropanamide 101.1.B (132 mg, 0.39 mmole), 3 ml of ethanol and 0.08 ml of triethylamine. The reaction mixture was cooled to 0° C., and then ethyl bromoacetate (48 μl, 0.43 mmole) was added to the mixture. The reaction was stirred at 50° C. for 1 hour and at room temperature overnight. After then, the solution was concentrated, and dissolved in ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. After concentration in vacuo, the residue was chromatographed on silica gel to give 101.1.C (45 mg, 27% yield) as colorless amorphous. 1H NMR (400 MHz, CDCl3) δ ppm 9.73 (s, 1H), 8.61 (d, J=5.9 Hz, 2H), 7.69 (d, J=6.3 Hz, 2H), 7.38-7.26 (m, 5H), 6.87 (s, 1H), 4.19-4.04 (m, 4H), 3.54 (dd, J=8.4, 4.5 Hz, 1H), 3.42 (d, J=17.6 Hz, 1H), 3.32 (d, J=17.6 Hz, 1H), 3.35 (dd, J=14.1, 4.5 Hz, 1H), 3.00 (dd, J=14.1, 8.2 Hz, 1H), 2.05 (brs, 1H), 1.43 (t, J=7.2 Hz, 3H), 1.24 (t, J=7.2 Hz, 3H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[CH:11][C:10]2[CH2:9][NH:8][CH2:7][CH2:6][C:5]=2[N:4]=1.CCN(C(C)C)C(C)C.[CH:22]1([C:25](Cl)=[O:26])[CH2:24][CH2:23]1>ClCCl.Cl>[Cl:2][C:3]1[CH:12]=[CH:11][C:10]2[CH2:9][N:8]([C:25]([CH:22]3[CH2:24][CH2:23]3)=[O:26])[CH2:7][CH2:6][C:5]=2[N:4]=1
Reactant: Clc1ccc2c(n1)CCNC2
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(C1CC1)N1CCc2nc(Cl)ccc2C1
Temperature: 25 °C
Yield: 105.6 %

Procedure:
To a room temperature stirred suspension of 2-chloro-5,6,7,8-tetrahydro-1,6-naphthyridine hydrochloride (50 mg, 0.24 mmol) in dichloromethane (2 ml) under a nitrogen atmosphere was added DIPEA (0.12 ml, 0.73 mmol) followed by cyclopropyl carbonyl chloride (24 μl, 0.27 mmol). The resulting mixture was stirred for 16 hours, diluted with dichloromethane (30 ml) and 1M aq. HCl (2 ml). The organic layer was separated and washed with saturated aqueous NaHCO3 (15 ml) and brine (15 ml), dried (MgSO4), filtered and concentrated at reduced pressure to provide the title compound (60 mg, 95%) which was used without further purification.
Reaction SMILES: [CH2:1]1[O:25][C:4]2=[CH:5][C:6]3[C:12]([C:13]4[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:14]=4[Cl:22])=[N:11][NH:10][C:9](=[O:23])[CH2:8][C:7]=3[CH:24]=[C:3]2[O:2]1.C(O)C.CC(C)=O.O>[Pd].C(O)C>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[C:6]3[CH:5]=[C:4]4[O:25][CH2:1][O:2][C:3]4=[CH:24][C:7]=3[CH2:8][C:9](=[O:23])[NH:10][N:11]=2)=[C:14]([Cl:22])[CH:15]=1
Reactant: O=C1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2Cl)=NN1)OCO3
Agent: [Pd]
Solvent: O
Solvent: CCO
Solvent: CC(C)=O
Product: Nc1ccc(C2=NNC(=O)Cc3cc4c(cc32)OCO4)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 21 %

Procedure:
To a suspension of 7,8-methylenedioxy-1-(2-chloro-4-nitrophenyl)-3,5-dihydro-2,3-benzodiazepin-4(4H)-one (1.4 g, 3.9 mmol) in 1:1:1 ethanol/acetone/water (45 mL) was added 5% Pd/C (106 mg) and HCO2NH4 (2.5 g, 40 mmol). The mixture was stirred at room temperature for 3 h and 15 mL of ethanol was added to the mixture which was then stirred at room temperature for three days. The catalyst was filtered out. The filtrate was extracted with EtOAc (100 mL). The organic phase was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography (1:4 hexane/EtOAc) to afford the title compound as a light yellow solid (0.27 g, 0.82 mmol, 21%), mp: 238°-240° C. 1H NMR (CDCl3) 8.34 (s, 1H), 7.41 (d, J=8.6, 1H), 6.81 (s, 1H), 6.69-6.67 (m, 3H), 6.02 (s, 2H), 3.92 (s, 2H), 3.42 (s, 2H).
Reaction SMILES: [CH:1]1([C:4](=[O:24])[CH2:5][C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[C:10]([O:18][CH2:19][CH2:20][O:21][CH3:22])[C:9]=2[Br:23])=[O:7])[CH2:3][CH2:2]1.[CH2:25]([O:27][CH:28](OCC)OCC)[CH3:26]>C(OC(=O)C)(=O)C>[CH:1]1([C:4](=[O:24])[C:5](=[CH:28][O:27][CH2:25][CH3:26])[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[C:10]([O:18][CH2:19][CH2:20][O:21][CH3:22])[C:9]=2[Br:23])=[O:7])[CH2:3][CH2:2]1
Reactant: CCOC(OCC)OCC
Reactant: COCCOc1c(S(C)(=O)=O)ccc(C(=O)CC(=O)C2CC2)c1Br
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)c1ccc(S(C)(=O)=O)c(OCCOC)c1Br)C(=O)C1CC1
Yield: 100 %

Procedure:
A mixture of 3-cyclopropyl-1-[2-bromo-3-(2-methoxyethoxy)-4-methylsulphonylphenyl]propan-1,3-dione (7.5 g) and triethylorthoformate (10.3 g) in acetic anhydride was stirred and heated at reflux for 3 hours. It was evaporated to dryness and the residue was treated with xylene and re-evaporated to give crude 3-cyclopropyl-1-[2-bromo-3-(2-methoxyethoxy)-4-methylsulphonylphenyl]-2-ethoxymethylenepropan-1,3-dione (8.5 g) as a dark brown oil which was not purified further.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:9][CH2:10][CH2:11][CH2:12][Cl:13]>>[Cl:13][CH2:12][CH2:11][CH2:10][CH2:9][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCCCBr
Reactant: Sc1ccccc1
Product: ClCCCCSc1ccccc1

Procedure:
Prepared by Procedure R and Scheme Z using benzenethiol and 1-bromo-4-chlorobutane.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[CH3:14][O:15][C:16](=[O:20])[C@H:17]([CH3:19])[NH2:18].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>ClCCl.C(OCC)(=O)C>[CH3:14][O:15][C:16](=[O:20])[C@H:17]([CH3:19])[NH:18][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: COC(=O)[C@H](C)N
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a stirred solution of 3,5-difluorophenylacetic acid (6.02 g, 34.97 mmol), L-alanine methyl ester hydrochloride (4.88 g, 34.96 mmol) and HOBt (5.20 g, 38.48 mmol) in dichloromethane (200 mL) under nitrogen at 0° C. was added NMM (8.84 g, 87.39 mmol) and EDAC-HCl (7.38 g, 38.49 mmol). The mixture was allowed to warm gradually to ambient temperature and stir overnight. The reaction was diluted with ethyl acetate and extracted sequentially with aqueous sodium bicarbonate, 1N aqueous HCl and brine. The organic phase was dried, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with 1:1 (v/v) hexanes: ethyl acetate to afford N-[(3,5-difluorophenyl)acetyl]-L-alanine methyl ester (7.91 g, 88% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.39 (d, 3H, J=7.0 Hz), 3.54 (s, 2H), 3.75 (s, 3H), 4.59 (m, 1H), 6.02 (br 1H), 6.67-6.87 (m, 3H). MS APCI, m/z=258 (M+1). LC/MS: 1.68 Lithium hydroxide (1.40 g, 33.33 mmol) in water (60 mL) was added dropwise to a solution of N-[(3,5-difluorophenyl)acetyl]-L-alanine methyl ester (7.79 g, 30.28 mmol) in 1,4-dioxane (150 mL). After 2 h the solvent was evaporated. The residue was dissolved in water and the solution extracted with diethyl ether. The aqueous phase was acidified with 1N aqueous HCl and extracted with ethyl acetate three times. The combined ethyl acetate extracts were dried, filtered and evaporated to afford the title compound (7.16 g, 97% yield) as a white solid. 1H NMR (300 MHz, d6-DMSO) δ 1.28 (d, 3H, J=7.4 Hz), 3.51 (s, 2H), 4.20 (m, 1H), 6.93-7.12 (m, 3H), 8.44 (d, 1H, J=7.0 Hz), 12.46 (br, 1H). HPLC Method A: 2.12 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[CH:12]=[N:13][C:14]2[N:15]([C:17]([C:20]3([C:23]4[CH:24]=[C:25]5[C:30](=[CH:31][CH:32]=4)[N:29]=[CH:28][CH:27]=[CH:26]5)[CH2:22][CH2:21]3)=[CH:18][N:19]=2)[CH:16]=1)[C:5]([OH:7])=O.CN.F[P-](F)(F)(F)(F)F.[N:42]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:46]2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.CO>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[CH:12]=[N:13][C:14]2[N:15]([C:17]([C:20]3([C:23]4[CH:24]=[C:25]5[C:30](=[CH:31][CH:32]=4)[N:29]=[CH:28][CH:27]=[CH:26]5)[CH2:22][CH2:21]3)=[CH:18][N:19]=2)[CH:16]=1)[C:5]([NH:42][CH3:46])=[O:7]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: O=C(O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)c(F)c1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CNC(=O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Fluoro-4-(3-(1-(quinolin-6-yl)cyclopropyl)imidazo[1,2-a]pyrimidin-6-yl)benzoic acid obtained from Step 2 was dissolved in N,N-dimethylformamide (1 mL). To this solution was added methylamine (2M in THF, 0.2 mL), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (110 mg, 0.25 mmol) and N,N-diisopropylethylamine (0.12 mL, 0.68 mmol). The solution was stirred overnight at RT, diluted with MeOH, and purified by RP-HPLC (pH 10) to afford the desired compound. LCMS (M+H): m/z=438.0.
Reaction SMILES: [C:1]([C:3]1[C:4](=O)[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([CH3:13])=[C:8]([CH3:14])[CH:7]=2)#[N:2].P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:4]1[C:3]([C:1]#[N:2])=[CH:12][C:11]2[C:6](=[CH:7][C:8]([CH3:14])=[C:9]([CH3:13])[CH:10]=2)[N:5]=1
Reactant: Cc1cc2cc(C#N)c(=O)[nH]c2cc1C
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc2cc(C#N)c(Cl)nc2cc1C

Procedure:
A mixture was prepared from 67.5 g of 3-cyano-6,7-dimethyl-2(1H)-quinolinone and 340 ml of phosphoryl chloride and this was heated at reflux for 18 hours. The mixture was cooled, excess phosphoryl chloride was removed by vacuum evaporation, and the residue was carefully added to water with vigorous stirring. The solid which formed was separated by filtration and recrystallized from methylene chloride to give 2-chloro-3-cyano-6,7-dimethylquinoline melting at about 189°-190° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10]Cl)[N:9]=1)(=[O:3])[CH3:2].[NH:12]1[CH2:17][CH2:16][CH:15]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)[CH2:14][CH2:13]1.C(=O)([O-])O.[Na+]>CN(C)C=O.O1CCCC1>[C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[CH2:14][CH2:13]2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(CCl)cs1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(CN2CCC(c3c[nH]c4ccccc34)CC2)cs1
Temperature: 25 °C
Yield: 30.5 %

Procedure:
2-Acetylamino-4-chloromethylthiazole (480 mg), 3-(4-piperidyl)indole (500 mg) and sodium hydrogen carbonate (310 mg) was refluxed in a mixture of N,N-dimethylformamide (5 ml) and tetrahydrofuran (7 ml) for 1 hour and 40 minutes. After the reaction mixture cooled to ambient temperature, it was concentrated under reduced pressure. After addition of water (50 ml), the residue was extracted with ethyl acetate (50 ml) twice. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel and elution was carried out with a mixture of chloroform and methanol (30:1 V/V). The eluate gave 2-acetylamino-4-[4-(3-indolyl)piperidinomethyl]thiazole (270 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[S:7])=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>C1C=CC=CC=1>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:13])=[S:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(O)=S)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: Cc1ccc(C(=S)Cl)cc1
Yield: 80 %

Procedure:
A mixture of 56 mmol (8.85 g) p-methylthiobenzoic acid, 40 ml benzene and 112 mmol (7.4 ml) thionyl chloride is boiled under reflux for 24 hours. The benzene and excess thionyl chloride are removed under vacuum to give p-methylthiobenzoyl chloride mp 48-52 in 80% yield.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][NH2:9])=O.[N:10]([CH2:13][CH:14]([CH3:16])[CH3:15])=[C:11]=[S:12].Cl[CH2:18][C:19]1[N:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)[O:21][N:20]=1>>[Cl:30][C:26]1[CH:25]=[C:24]([C:22]2[O:21][N:20]=[C:19]([CH2:18][S:12][C:11]3[N:10]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)=[N:8][N:9]=3)[N:23]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: NNC(=O)c1ccco1
Reactant: ClCc1noc(-c2cccc(Cl)c2)n1
Reactant: CC(C)CN=C=S
Product: CC(C)Cn1c(SCc2noc(-c3cccc(Cl)c3)n2)nnc1-c1ccco1

Procedure:
The title compound was synthesized according to the method described by Graybill et al. Tetrahedron lett. 2002 43, 5305-5309 from furan-2-carboxylic acid hydrazide (55.2 mg, 0.44 mmol), 1-isothiocyanato-2-methyl-propane (47 ml, 0.38 mmol) and 3-chloromethyl-5-(3-chloro-phenyl)-[1,2,4]oxadiazole (45.0 mg, 0.20 mmol) with P-BEMP (136 mg, 0.30 mmol) as base. Purification by flash chromatography (33-66% EtOAc in heptane) gave the product as an oil (12.7 mg, 15.6%). 1H NMR (CDCl3) d (ppm): 8.08 (s, 1 H), 7.97 (d, 1H), 7.55 (d, 2H), 7.45 (t, 1H), 7.10 (d, 1H), 6.56 (d, 1H), 4.62 (s, 2H), 4.01 (d, 2H), 2.03 (m, 1H), 0.86 (d, 6H).
Reaction SMILES: C(OC1C(=O)N=C(CC2(C3C=CC=CC=3)CCCC2)N2CCN(C3CC3)C(=O)C=12)C1C=CC=CC=1.[CH:36]1([CH2:39][N:40]([CH2:70][CH2:71]O)[C:41]([C:43]2[C:48]([O:49][CH2:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)=[C:47]([OH:57])[N:46]=[C:45]([CH2:58][C:59]3([C:64]4[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=4)[CH2:63][CH2:62][CH2:61][CH2:60]3)[N:44]=2)=[O:42])[CH2:38][CH2:37]1>>[CH2:50]([O:49][C:48]1[C:47](=[O:57])[N:46]=[C:45]([CH2:58][C:59]2([C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[CH2:63][CH2:62][CH2:61][CH2:60]2)[N:44]2[CH2:71][CH2:70][N:40]([CH2:39][CH:36]3[CH2:37][CH2:38]3)[C:41](=[O:42])[C:43]=12)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: O=C(c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)CC1CC1
Agent: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(c4ccccc4)CCCC3)n2CCN1C1CC1
Product: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(c4ccccc4)CCCC3)n2CCN1CC1CC1
Yield: 46.3 %

Procedure:
This compound was prepared following the same method as described for 9-benzyloxy-2-cyclopropyl-6-(1-phenyl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (286) from 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid cyclopropylmethyl-(2-hydroxyethyl)-amide (305) (150 mg, 0.29 mmol). The product was obtained as a colourless sticky solid (65 mg, 44.95%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[NH:11][N:10]=[C:9]1[C:14]1[S:31][C:17]2[C:18]3[CH:26]=[CH:25][C:24]([C:27]([O:29]C)=[O:28])=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1.O.[Li+].[OH-]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[NH:11][N:10]=[C:9]1[C:14]1[S:31][C:17]2[C:18]3[CH:26]=[CH:25][C:24]([C:27]([OH:29])=[O:28])=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1
Reactant: COC(=O)c1ccc2c(c1)OCCc1cc(-c3n[nH]c(=O)n3-c3ccccc3Cl)sc1-2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)OCCc1cc(-c3n[nH]c(=O)n3-c3ccccc3Cl)sc1-2
Temperature: 50 °C
Yield: 97.2 %

Procedure:
Methyl 2-(4-(2-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylate (5.83 g, 12.8 mmol) was dissolved in 25 mL of THF and 25 mL of water and treated with LiOH (1.35 g, mono-hydrate). The whole was heated at 50° C. for 3 h, cooled to room temperature and acidified. The resulting precipitate was filtered and washed with water. The filter cake was dried to a constant weight under vacuum to give 2-(4-(2-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylic acid (5.47 g, yield 97%). ESI-MS: 440.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][C@H:8]([C:17]1[NH:18][C:19]([C:22]2[CH:27]=[CH:26][C:25](I)=[CH:24][C:23]=2[F:29])=[CH:20][N:21]=1)[C@H:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:38][Si:39]([C:42]#[CH:43])([CH3:41])[CH3:40].C(OCC)(=O)C>CN(C)C=O.[Cu]I.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>[C:1]([O:5][C:6](=[O:30])[NH:7][C@H:8]([C:17]1[NH:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:43]#[C:42][Si:39]([CH3:41])([CH3:40])[CH3:38])=[CH:24][C:23]=2[F:29])=[CH:20][N:21]=1)[C@H:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H](c1ccccc1)[C@H](NC(=O)OC(C)(C)C)c1ncc(-c2ccc(I)cc2F)[nH]1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H](c1ccccc1)[C@H](NC(=O)OC(C)(C)C)c1ncc(-c2ccc(C#C[Si](C)(C)C)cc2F)[nH]1
Reaction time: 0.08 h
Yield: 96.1 %

Procedure:
A solution of {(1S,2S)-1-[5-(2-fluoro-4-iodo-phenyl)-1H-imidazol-2-yl]-2-phenyl-propyl}-carbamic acid tert-butyl ester (286 mg, 0.55 mmol) (prepared in step 30-E), copper (I) iodide (10.50 mg, 0.055 mmol) and dichlorobis(triphenylphosphine)palladium(II) (39 mg, 0.055 mmol) in N,N-dimethylformamide (5 mL) was degassed with dry nitrogen with stirring for 5 minutes. Triethylamine (229 μL, 1.65 mmol) and trimethylsilylacetylene (233 μL, 1.65 mmol) were added and the resulting solution was stirred for 24 hours at room temperature. The reaction was poured into ethyl acetate (25 mL) and washed with water (2×10 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography over silica gel gradient eluted between 10 and 50% v/v ethyl acetate in hexanes to give {(1S,2S)-1-[5-(2-fluoro-4-trimethylsilanylethynyl-phenyl)-1H-imidazol-2-yl]-2-phenyl-propyl}-carbamic acid tert-butyl ester (260 mg, 96%). HR-MS: calcd for C28H34FN3O2Si [M+H+] 492.2477. Found 492.2475.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:19])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.Br[CH2:21][C:22]([O:24][CH3:25])=[O:23].C(=O)(O)[O-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:19][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)CBr
Reactant: O=c1[nH]c2cc(Cl)ccc2c(O)c1-c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1c(-c2ccccc2)c(=O)[nH]c2cc(Cl)ccc12

Procedure:
A solution of 7-chloro-4-hydroxy-3-phenyl-2(1H)-quinolone (0.5 g) in DMF was stirred for 14 h with methyl bromoacetate (206 μl) and sodium bicarbonate (1.55 g). The reaction mixture was then partitioned between water and ethyl acetate. The aqueous phase was extracted with two further portions of ethyl acetate. The combined organic phases were washed with brine (3×), dried (MgSO4) and the solvent was removed in vacuo to give the crude product which was recrystallised from ethyl acetate-hexane to give the title compound, 208 mg; mp 188°-191° C. (ethyl acetate-hexanes); Found: C, 63.27; H, 4.24; N, 4.07. C18H14ClNO4 requires C, 62.89; H, 4.11; N, 4.07%; δ (360 MHz, DMSO-d6) 3.55 (3H, s, CO2CH3), 4.19 (2H, s, CH2CO2), 7.28 (1H, dd, J=2.6, 8.7 Hz, 6-H), 7.35-7.40 (6H, m, aromatics), 8.01 (1H, d, J=8.7 Hz, 5-H), 11.92 (1H, s, NH); m/z CI+ 344 (M+).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[CH3:13][C:14]1[CH:15]=[C:16]([NH:27][C:28]2[N:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][N:29]=2)[CH:17]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[CH:21]=2)[CH:19]=1>C(Cl)Cl>[CH3:13][C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][S:2]([CH3:1])(=[O:4])=[O:3])[CH:21]=2)[CH:17]=[C:16]([NH:27][C:28]2[N:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][N:29]=2)[CH:15]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cccc(N)c2)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cccc(NS(C)(=O)=O)c2)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Methanesulfonyl chloride (0.017 g, 0.150 mmol) and triethylamine (0.028 ml, 0.200 mmol) were added to a solution of 5-methyl-N3-[4-(trifluoromethyl)pyrimidin-2-yl]biphenyl-3,3′-diamine (0.034 g, 0.100 mmol) in DCM (1.00 ml) and stirred for 14 hours at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in DMSO (1 mL), then purified by mass triggered reverse phase HPLC to give N-(3′-methyl-5′-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-3-yl)methanesulfonamide. MS ESI calcd. for C19H18F3N4O2S [M+H]+ 423, found 423. 1H NMR (600 MHz, DMSO-d6) δ 10.21 (s, 1H), 8.78 (d, J=4.9 Hz, 1H), 7.83 (s, 1H), 7.52 (s, 1H), 7.40 (dt, J=15.7, 4.8 Hz, 2H), 7.30 (d, J=7.7 Hz, 1H), 7.23 (d, J=4.9 Hz, 1H), 7.17 (dd, J=8.0, 1.3 Hz, 1H), 7.04 (s, 1H), 2.99 (s, 3H), 2.32 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[F:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[C:18]([F:21])([F:20])[F:19])[NH2:14]>>[F:10][C:11]1[CH:12]=[C:13]([NH:14][C:2]2[N:7]=[C:6]([NH:14][C:13]3[CH:15]=[CH:16][C:17]([C:18]([F:19])([F:20])[F:21])=[C:11]([F:10])[CH:12]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH:15]=[CH:16][C:17]=1[C:18]([F:19])([F:20])[F:21]
Reactant: Nc1ccc(C(F)(F)F)c(F)c1
Reactant: Fc1cnc(Cl)nc1Cl
Product: Fc1cc(Nc2ncc(F)c(Nc3ccc(C(F)(F)F)c(F)c3)n2)ccc1C(F)(F)F

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-fluoro-4-trifluoromethylaniline were reacted to yield N2,N4-bis(3-fluoro-4-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 8.01 (d, 1H, J=3 Hz), 7.77 (m, 3H), 7.61 (dt, 1H, J=4.2 and 3 Hz), 7.20 (t, 1H, 8.7 Hz), 7.12 (t, 1H, J=9.3 Hz), 6.95 (s, 1H), 6.82 (s, 1H); 19F NMR (CDCl3): δ −17505 (s, 3F), −17517 (s, 3F), −17525 (s, F), −17537 (s, F), −46835 (s, 1F); LCMS: ret. time: 32.39 min.; purity: 95%, MS (m/e): 453 (MH+).
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[CH:12]=[C:11]([N:13](C)[CH2:14]C2C=CC=CC=2)[CH:10]=[C:9]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[N:8]=1)=[O:6])([CH3:3])[CH3:2].CO.[H][H]>[Pd].C(O)(=O)C>[CH:1]([NH:4][C:5]([C:7]1[CH:12]=[C:11]([NH:13][CH3:14])[CH:10]=[C:9]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:30])[F:31])[CH:24]=2)[N:8]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)NC(=O)c1cc(N(C)Cc2ccccc2)cc(Oc2cccc(C(F)(F)F)c2)n1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CNc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NC(C)C)c1

Procedure:
1.12 g (0.0012 mol) of N-(i-propyl)-4-(methyl(phenylmethyl)amino}-6-{3-(trifluoromethyl)phenoxy}-2-pyridine carboxamide were mixed with methanol and then with a small amount of 10% palladium/carbon and acetic acid. The obtained mixture was stirred at room temperature for about 16 hours in a hydrogen atmosphere. The obtained reaction solution was filtered using Hyflo Super Cell and then concentrated. The concentrate was purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.