Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18](B3OC(C)(C)C(C)(C)O3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11].I[C:31]1[CH:32]=[N:33][N:34]([C@H:36]2[CH2:41][CH2:40][C@H:39]([OH:42])[CH2:38][CH2:37]2)[CH:35]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:31]3[CH:32]=[N:33][N:34]([C@H:36]4[CH2:41][CH2:40][C@H:39]([OH:42])[CH2:38][CH2:37]4)[CH:35]=3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11]
Reactant: C[C@H](c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: O[C@H]1CC[C@H](n2cc(I)cn2)CC1
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: C1COCCO1
Product: C[C@H](c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(-c3cnn([C@H]4CC[C@H](O)CC4)c3)cc12

Procedure:
A mixture of 3-[(S)-1-(2,6-Dichloro-3-fluorophenyl)ethyl]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (60.0 mg, 0.138 mmol), trans-4-(4-iodo-pyrazol-1-yl)cyclohexanol (52.4 mg, 0.179 mmol), Pd(PPh3)4 (8 mg, 0.007 mmol), potassium carbonate (57.2 mg, 0.414 mmol) and 4:1 dioxane:water (7 mL) was heated to 90° C. for 2 h. The organic solvent was removed in vacuo, and the material was transferred to a separatory funnel, extracting with DCM and sat. NaHCO3 solution. The organic layer was dry-loaded onto silica gel, and column chromatography was used to purify, eluting with 3-4% (7N NH3 in MeOH)/DCM. The resulting solid was triturated with MeOH to give the title compound. 1H NMR (400 MHz, CD3OD): δ=1.47-1.59 (m, 2 H), 1.88 (d, J=6.8 Hz, 3 H), 1.90-2.03 (m, 2H), 2.10-2.22 (m, 4 H), 3.66 (tt, J=10.9, 4.2 Hz, 1 H), 4.17 (tt, J=11.6, 4.0 Hz, 1 H), 5.27 (q, J=7.0 Hz, 1 H), 7.18 (dd, J=8.4, 8.8 Hz, 1 H), 7.38 (d, J=1.3 Hz, 1 H), 7.44 (d, J=2.0 Hz, 1 H), 7.46 (br. s., 1 H), 7.54 (d, J=0.8 Hz, 1 H), 7.87 (d, J=0.8 Hz, 1 H), 8.32 (d, J=2.0 Hz, 1 H). MS (ES+): m/z 473.01/475.04 (100/70) [MH+]. HPLC: tR=3.36 min (ZQ3, polar—5 min). This material was redissolved in DCM. 2.0 M of HCl in Et2O (0.8 mL) was added at rt and stirred for 20 min. The mixture was concentrated in vacuo to afford the title compound as an HCl salt.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[OH:6][CH2:7][C:8]([OH:10])=[O:9]>>[C:1]([O:6][CH2:7][C:8]([OH:10])=[O:9])(=[O:4])[CH2:2][CH3:3]
Reactant: O=C(O)CO
Reactant: CCC(=O)Cl
Product: CCC(=O)OCC(=O)O

Procedure:
a solution consisting of propionyl chloride (64.7 g, 0.7 mol) and hydroxyacetic acid (19.0 g, 0.25 mol) is heated at 40° C., until the hydroxyacetic acid has completely dissolved. The excess propionyl chloride is then distilled off and 35.6 g of crude product containing 82% of (propionyloxy)acetic acid is obtained as a colorless liquid. The crude product can be used in the subsequent reaction without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:12]([CH3:13])[C:11]3[CH:14]=[C:15](/[CH:20]=[CH:21]/[CH3:22])[CH:16]=[C:17]([O:18][CH3:19])[C:10]=3[O:9]2)=[CH:4][C:3]=1[O:23][CH3:24].[CH3:25][N:26]1[CH:30]([CH3:31])[CH:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:28][CH2:27]1>>[CH3:19][O:18][C:17]1[C:10]2[O:9][C@@H:8]([C:5]3[CH:4]=[C:3]([O:23][CH3:24])[C:2]([OH:1])=[C:7]([CH2:27][N:26]([CH:30]([CH3:31])[CH:29]([OH:28])[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH3:25])[CH:6]=3)[C@H:12]([CH3:13])[C:11]=2[CH:14]=[C:15](/[CH:20]=[CH:21]/[CH3:22])[CH:16]=1
Reactant: C/C=C/c1cc(OC)c2c(c1)[C@@H](C)[C@H](c1ccc(O)c(OC)c1)O2
Reactant: CC1C(c2ccccc2)OCN1C
Product: C/C=C/c1cc(OC)c2c(c1)[C@@H](C)[C@H](c1cc(CN(C)C(C)C(O)c3ccccc3)c(O)c(OC)c1)O2
Yield: 29.5 %

Procedure:
20.0 g of trans-2,3-dihydro-2-(4-hydroxy-3-methoxyphenyl)-7-methoxy-3-methyl-5-(E)-propenylbenzofuran and 21.3 g of 3,4-dimethyl-5-phenyl-1,3-oxazolidine are held in 200 ml of absolute alcohol for 60 hours at 70° C. and subsequently the solvent and excess 3,4-dimethyl-5-phenyl-1,3-oxazolidine are removed, finally in vacuum. After purification by means of a chromatographic column there is obtained 9.1 g of N-(5-(trans-2,3-dihydro-7-methoxy-3-methyl-5-(E)-propenyl-benzofuran-2-yl)-2-hydroxy-3-methoxyphenylmethyl)-N-(1-hydroxy-1-phenyl-2-propyl)-N-methylamin, a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]1[C@@H:14]([OH:27])[C@H:15]([NH:23][C:24](=[O:26])[CH3:25])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28][CH:29]([CH3:35])[CH2:30][CH2:31][C:32](O)=[O:33].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:32](=[O:33])[CH2:31][CH2:30][CH:29]([CH3:35])[CH3:28])[CH2:10][C@@H:9]1[C@@H:14]([OH:27])[C@H:15]([NH:23][C:24](=[O:26])[CH3:25])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)CCC(=O)O
Reactant: CC(=O)N[C@H](Cc1ccccc1)[C@H](O)[C@H]1CNCCN1C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N[C@H](Cc1ccccc1)[C@H](O)[C@H]1CN(C(=O)CCC(C)C)CCN1C(=O)OC(C)(C)C
Yield: 48.6 %

Procedure:
Dissolve 2-(R)-(2-(R)-Acetylamino-1-(S)-hydroxy-3-phenyl-propyl)-piperazine-1-carboxylic acid tert-butyl ester (122 mg, 0.32 mmol) in 3 ml of dry CH2Cl2. Add 4-methylpentanoic acid (0.04 ml, 0.32 mmol), EDCI (73.6 mg, 0.38 mmol), HOBT (51.8 mg, 0.38 mmol), triethylamine (0.13 ml, 0.96 mmol) and dimethylaminopyridine (3.9 mg, 0.032 mmol), and stir at room temperature overnight. Dilute with CH2Cl2, and wash with 5% NaHCO3 followed by saturated aqueous sodium chloride. Dry organic layer with MgSO4 and remove the solvent under reduced pressure. Subject residue to silica gel chromatography, eluting with ethyl acetate/methanol 9:1 to obtain 74 mg (48% yield) of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]([N:15]=1)=[C:13]1[C:8]([CH:9]=[CH:10][C:11](=O)[N:12]1C)=[CH:7][CH:6]=2.P(Cl)(Cl)([Cl:20])=O.P(Cl)(Cl)(Cl)(Cl)Cl>>[Cl:20][C:11]1[CH:10]=[CH:9][C:8]2[C:13](=[C:14]3[C:5](=[CH:6][CH:7]=2)[CH:4]=[CH:3][C:2]([Cl:1])=[N:15]3)[N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1c(=O)ccc2ccc3ccc(Cl)nc3c21
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: Clc1ccc2ccc3ccc(Cl)nc3c2n1
Yield: 94 %

Procedure:
Under a stream of argon, to compound (5) (4.26 g; 17.4 mmol), phosphorus oxy-chloride (39 mL) and phosphorus pentachloride (4.48 g; 21.8 mmol) were added in an ice bath. The resulting reaction mixture was stirred and refluxed for 7 hours, and then evaporated under reduced pressure to remove phosphorus oxychloride. To the resulting residue, ice water and concentrated aqueous ammonia were added and the resulting reaction mixture was made alkaline. The solids which precipitated out were separated by filtration and washed with water, and then dried under reduced pressure to give 4.06 g (yield: 94%) of the title compound (6).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[C:5]([CH3:11])=[CH:4][C:3]=1[N:12]=[C:13]=[S:14].CO.[CH2:17]([NH2:20])[CH2:18][NH2:19]>C(Cl)Cl>[CH3:1][C:2]1[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[C:5]([CH3:11])=[CH:4][C:3]=1[NH:12][C:13]([NH:19][CH2:18][CH2:17][NH2:20])=[S:14]
Reactant: Cc1cc(N=C=S)c(C)c2[nH]cnc12
Reactant: NCCN
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(NC(=S)NCCN)c(C)c2[nH]cnc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4,7-dimethyl-5-benzimidazolylisothiocyanate (0.59 g) in CH2Cl2 (50 mL)/methanol (5 mL) is added dropwise over 20 minutes to ethylenediamine (1 mL) in solution in CH2Cl2 (150 mL). The mixture is stirred for 2 hours at room temperature. The resulting suspension is filtered and the solid is dried overnight in vacuo to afford N-(4,7-dimethyl-5-benzimidazolyl)-N'-2-aminoethylthiourea as a white solid.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][C:32](=[O:34])[CH3:33])/[C:27](O)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1.[NH2:60][CH:61]1[C:91](=[O:92])[N:63]2[C:64]([C:75]([O:77][CH:78]([C:85]3[CH:90]=[CH:89][CH:88]=[CH:87][CH:86]=3)[C:79]3[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=3)=[O:76])=[C:65](/[CH:68]=[CH:69]\[CH2:70][O:71][C:72](=[O:74])[CH3:73])[CH2:66][S:67][C@H:62]12>C1COCC1.CCOC(C)=O>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][C:32](=[O:34])[CH3:33])/[C:27]([NH:60][CH:61]2[C:91](=[O:92])[N:63]3[C:64]([C:75]([O:77][CH:78]([C:79]4[CH:80]=[CH:81][CH:82]=[CH:83][CH:84]=4)[C:85]4[CH:90]=[CH:89][CH:88]=[CH:87][CH:86]=4)=[O:76])=[C:65](/[CH:68]=[CH:69]\[CH2:70][O:71][C:72](=[O:74])[CH3:73])[CH2:66][S:67][C@H:62]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC/C=C\C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Reactant: CC(=O)O/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)OC/C=C\C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)/C(=N\OC(C)=O)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Reaction time: 1 h
Yield: 78.2 %

Procedure:
To a mixture of (Z)-2-(tritylaminothiazol-4-yl)-2-acetoxyiminoacetic acid (1.95 g, 4.0 mmol) and 1-hydroxybenzotriazole (600 mg, 4.0 mmol) in THF (14 ml) was added DCC (824 mg, 4.0 mmol) and the mixture was stirred for 1 hr in an ice bath. Diphenylmethyl 7-amino-3-[(Z)-3-acetoxy-1-propenyl]-3-cephem-4-carboxylate (1.30 g, 2.8 mmol) was added to the suspension and the mixture was stirred for 4 hrs at ambient temperature, filterd, and diluted with AcOEt (60 ml). The organic phase was washed with water, dried over MgSO4, and concentrated under reduced pressure. The residue was chromatographed on a column of silica gel (Wakogel C200, 80 g), which was eluted with toluene-AcOEt (6:1). Fractions which contained the product were combined and concentrated in vacuo to give 2.01 g (77%) of diphenylmethyl 7-[(Z)-2-(tritylaminothiazol-4-yl)-2-acetoxyiminoacetamido]-3-[(Z)-3-acetoxy-1-propenyl)-3-cephem-4-carboxylate.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1Cl)([O-:3])=[O:2].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.CC([O-])(C)C.[Na+].C(Cl)(Cl)Cl>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2[C-](N(C)C)C=CC=2)C=CC=CC=1.[CH-]1C=CC=C1.[Fe+2]>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)([O-:3])=[O:2]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccccc1N1CCOCC1
Yield: 43.2 %

Procedure:
According to General Procedure B, a mixture of 2-nitro chlorobenzene (79 mg, 0.50 mmol), morpholine (52 μL, 0.60 mmol), NaOt-Bu (67 mg, 0.70 mmol), Pd2(dba)3.CHCl3 (10 mg, 0.01 mmol) and 12f (0.4 mL of 0.05 M solution in PhMe) in PhMe (2.5 mL) was heated, cooled and filtered. Evaporation of the solvent under reduced pressure and column chromatography of the pre-adsorbed crude material (40% Et2O in hexane, silica gel) gave 52d (45 mg, 43%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.79 (d, 1H, J=8.1 Hz), 7.52-7.47 (m, 1H), 7.15 (d, 1H, J=8.3 Hz), 7.10-7.06 (m, 1H), 3.85-3.83 (m, 4H), 3.07-3.04 (m, 4H); 13C NMR (75.5 MHz, CDCl3) δ 145.8, 143.7, 133.5, 125.9, 122.3, 120.9, 66.8, 52.1.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1([O-])C=C(C)C=C(C)C=1.[K+].[C:18](=[O:20])=[O:19]>>[OH:7][C:1]1[CH:6]=[CH:5][C:4]([C:18]([OH:20])=[O:19])=[CH:3][CH:2]=1
Reactant: O=C=O
Reactant: Oc1ccccc1
Agent: Cc1cc(C)cc([O-])c1
Agent: [K+]
Product: O=C(O)c1ccc(O)cc1
Yield: 78.4 %

Procedure:
A pressure vessel was charged with 4.71 g of phenol, 16.05 g of potassium 3,5-xylenolate being in a dry powder form and 38 g of NeoSK 1400. With stirring, reaction was carried out at a carbon dioxide pressure of 5 kg/cm2 (G) and at 300° C. for one hour. An analysis of the reaction mixture after conversion to acid form showed a para-hydroxybenzoic acid yield of 78.4% on the basis of phenol.
Reaction SMILES: NC(N)=O.[Br:5][C:6]1[CH:10]=[N:9][N:8]([CH3:11])[C:7]=1[C:12]1[CH:13]=[C:14]([NH2:20])[CH:15]=[CH:16][C:17]=1[O:18][CH3:19].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[C:24]([C:31]([F:34])([F:33])[F:32])[CH:23]=1>C(Cl)Cl>[Br:5][C:6]1[CH:10]=[N:9][N:8]([CH3:11])[C:7]=1[C:12]1[CH:13]=[C:14]([NH:20][C:29]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][C:24]=2[C:31]([F:33])([F:32])[F:34])=[O:30])[CH:15]=[CH:16][C:17]=1[O:18][CH3:19]
Reactant: O=C=Nc1ccc(Cl)cc1C(F)(F)F
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Agent: NC(N)=O
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(Cl)cc2C(F)(F)F)cc1-c1c(Br)cnn1C
Yield: 56.9 %

Procedure:
Urea synthesis (General Procedure): To a stirred solution of 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.034 g, 0.12 mol, Example 1.1) in CH2Cl2 (1 mL) was added 4-chloro-2-(trifluoromethyl)phenyl isocyanate (0.029 g, 20.0 μL, 0.13 mmol, 1.05 equiv.) at room temperature. White solid precipitated and was filtered and washed with cold CH2Cl2 to afford Compound 9 (0.037 g, 0.074 mmol, 60%) as a white solid. LCMS m/z (%)=503 (M+H79Br, 77), 439 (M+H81Br, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.82 (s, 1H), 8.22 (d, J=9.6 Hz, 1H), 7.62-7.72 (m, 4H), 7.49 (s, 1H), 7.43 (d, J=2.6 Hz, 1H), 7.15 (d, J=9.0 Hz, 1H), 3.83 (s, 3H), 3.68 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.C(OCC)C.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1.C(N(CC)CC)C>[Cl-].[Cl-].[Zn+2].ClCCCl.CC(O)(C)C>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[N:7]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)(C)O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
2,4-Dichloro-5-(trifluoromethyl)pyrimidine (2.39 g, 11.0 mmol) was stirred in a 1:1 t-BuOH:1,2-dichloroethane mixture (80 mL) at 0° C. and a 1.0 M ZnCl2 solution in diethyl ether (12.6 mL, 12.6 mmol) was added cautiously over 20 minutes and the reaction was left stirring at 0° C. for 30 minutes. A solution of tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate (I2) (2.92 g, 10.5 mmol) in 1:1 t-BuOH:1,2-dichloroethane (40 mL) was added drop-wise over 15 minutes at 0° C. followed by a solution of triethylamine (1.76 mL, 12.6 mmol) in 1:1 t-BuOH:1,2-dichloroethane (40 mL) and the reaction was allowed to warm to room temperature and was stirred for 18 hours. The organic solvents were evaporated in vacuo and the crude yellow oily solid was suspended in water (400 mL), the suspension was sonicated for 30 minutes and the product was collected by filtration, the solid was washed with water (10×20 mL) and dried under a high vacuum to give the title compound (I3) (4.75 g, 98% yield) as a beige solid; 1H NMR (400 MHz, d6-DMSO) δ 10.45 (s, 1H), 8.72 (s, 1H), 7.50 (d, J=8.5 Hz, 2H), 6.96 (d, J=9.0 Hz, 2H), 3.50-3.42 (m, 4H), 3.09-3.02 (m, 4H), 1.42 (s, 9H). LCMS Method C: rt 6.56 min; m/z 456.2, 458.1 [M−H]−.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[C:8]12([C:18]3[CH:19]=[C:20]([CH:25]=[CH:26][C:27]=3[OH:28])[C:21]([O:23][CH3:24])=[O:22])[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2.[CH3:29][N:30]([CH3:34])[C:31](Cl)=[S:32]>O>[C:8]12([C:18]3[CH:19]=[C:20]([CH:25]=[CH:26][C:27]=3[O:28][C:31]([N:30]([CH3:34])[CH3:29])=[S:32])[C:21]([O:23][CH3:24])=[O:22])[CH2:9][CH:10]3[CH2:16][CH:14]([CH2:13][CH:12]([CH2:11]3)[CH2:17]1)[CH2:15]2
Reactant: CN(C)C(=S)Cl
Reactant: COC(=O)c1ccc(O)c(C23CC4CC(CC(C4)C2)C3)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC(=S)N(C)C)c(C23CC4CC(CC(C4)C2)C3)c1
Yield: 6 %

Procedure:
Into a round bottom flask, there are introduced 2.4 g (0.08 mole) of sodium hydride (80% in oil) and 250 ml of DMF. Under a nitrogen current, there are slowly added 22.9 g (0.08 g mole) of methyl 3-(1-adamantyl)-4-hydroxybenzoate. The mixture is stirred until the cessation of gaseous emission. There are then added, all at once, 12.9 g (0.104 mole) of dimethylthiocarbamoyl chloride and the mixture is stirred for 16 hours at ambient temperature. The reaction medium is poured into water and extracted with ethyl ether. The organic phase is decanted, dried on magnesium sulfate and evaporated. The resulting residue is purified by chromatography on a silica column eluted with a 70:30 mixture of dichloromethane and hexane. After evaporation of the solvents, 1.8 g (63% yield) of the expected product having a melting point of 174°-175° C. are recovered.
Reaction SMILES: [N+:1]([C:4]1[N:8]2[CH:9]=[C:10]([S:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH:11]=[CH:12][C:7]2=[N:6][CH:5]=1)([O-])=O.[H][H]>[Pd].O1CCOCC1>[NH2:1][C:4]1[N:8]2[CH:9]=[C:10]([S:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH:11]=[CH:12][C:7]2=[N:6][CH:5]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cnc2ccc(Sc3ccccn3)cn12
Agent: [Pd]
Solvent: C1COCCO1
Product: Nc1cnc2ccc(Sc3ccccn3)cn12

Procedure:
A solution of 0.542 gm. (0.002 mole) of 3-nitro-6-(2-pyridylthio) imidazo [1,2-a] pyridine in 20 ml. of dioxane is reduced at 40 psi. under a hydrogen atmosphere with 0.500 g. of 5% palladium on carbon as catalyst. When the uptake of hydrogen is complete, the catalyst is removed by filtration. The filtrate is evaporated in vacuo to yield 3-amino-6-(2-pyridylthio) imidazo [1,2-a] pyridine.
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH:19]5[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]5)[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[N:38][N:39]([CH2:41][C:42](OCC)=[O:43])[CH:40]=2)O1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(N1C(C2SC3CCOC4C=C(C5C=NN(CCO)C=5)C=CC=4C=3N=2)=NC=N1)(C)C>>[CH3:25][N:22]1[CH2:21][CH2:20][CH:19]([N:15]2[C:14]([C:8]3[S:9][C:10]4[CH2:11][CH2:12][O:13][C:4]5[CH:3]=[C:2]([C:36]6[CH:37]=[N:38][N:39]([CH2:41][CH2:42][OH:43])[CH:40]=6)[CH:27]=[CH:26][C:5]=5[C:6]=4[N:7]=3)=[N:18][CH:17]=[N:16]2)[CH2:24][CH2:23]1
Reactant: CN1CCC(n2ncnc2-c2nc3c(s2)CCOc2cc(Br)ccc2-3)CC1
Reactant: CCOC(=O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(-c3cnn(CCO)c3)ccc1-2
Agent: [Al+3]
Agent: [H-]
Product: CN1CCC(n2ncnc2-c2nc3c(s2)CCOc2cc(-c4cnn(CCO)c4)ccc2-3)CC1

Procedure:
Similarly to as described in General Procedure C: 8-Bromo-2-[2-(1-methyl-piperidin-4-yl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetate. The crude ester was reduced with lithium aluminum hydride as described for 2-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-ethanol. The product was purified by HPLC to give 303 as a colorless solid (27 mg). LCMS: 478.2.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](\[CH3:15])/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1OCCC.[CH3:20][NH:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.O>CN(C)C=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:15]/[C:9](=[CH:8]\[C:5]1[CH:4]=[CH:3][C:2]([C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:21][CH3:20])[CH:27]=2)=[CH:7][CH:6]=1)/[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CNc1cccc(B(O)O)c1
Reactant: CCCOc1cc(/C=C(\C)C(=O)OCC)ccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C(C)=C/c1ccc(-c2cccc(NC)c2)cc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 78.7 %

Procedure:
1.6 g (4.3 mmol) of ethyl (E)-3-(4-iodo-3-propoxyphenyl)-2-methylacrylate are dissolved in 10 mL of a 4/1v/v mixture of dimethylformamide and of aqueous 2 M potassium phosphate solution. 0.9 g (5.7 mmol) of 3-methylaminophenylboronic acid prepared as described in Example 31e, 58 mg (0.2 mmol) of palladium acetate and 152 mg (0.4 mmol) of dicyclohexylbiphenylphosphine are added. The mixture is stirred for 3 hours at 90° C. After cooling and adding water, the medium is extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with an 8/2 heptane/ethyl acetate mixture. 1.0 g (65%) of ethyl (E)-2-methyl-3-(3′-methylaminobiphenyl-4-yl)acrylate is obtained.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:3].[NH2:15][C:16]1[CH:24]=[C:23]2[C:19]([CH:20]([CH2:41][Cl:42])[CH2:21][N:22]2[C:25](=[O:40])/[CH:26]=[CH:27]/[C:28]2[N:29]([CH3:39])[CH:30]=[C:31]([NH:33][C:34](=[O:38])[CH2:35][CH2:36][CH3:37])[CH:32]=2)=[CH:18][CH:17]=1.O>N1C=CC=CC=1>[C:34]([NH:33][C:31]1[CH:32]=[C:28](/[CH:27]=[CH:26]/[C:25]([N:22]2[C:23]3[C:19](=[CH:18][CH:17]=[C:16]([NH:15][C:2]([O:4][CH2:5][C:6]4[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=4)=[O:3])[CH:24]=3)[CH:20]([CH2:41][Cl:42])[CH2:21]2)=[O:40])[N:29]([CH3:39])[CH:30]=1)(=[O:38])[CH2:35][CH2:36][CH3:37]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: CCCC(=O)Nc1cc(/C=C/C(=O)N2CC(CCl)c3ccc(N)cc32)n(C)c1
Solvent: c1ccncc1
Solvent: O
Product: CCCC(=O)Nc1cc(/C=C/C(=O)N2CC(CCl)c3ccc(NC(=O)OCc4ccc([N+](=O)[O-])cc4)cc32)n(C)c1
Temperature: 20 °C
Yield: 70.4 %

Procedure:
4-Nitrobenzyl chloroformate (52 mg, 0.24 mmol) was added to a solution of 8 (48 mg, 0.12 mmol) in dry pyridine (6 mL) and the yellow solution was stirred at 20° C. More 4-nitrobenzyl chloroformate (52 mg, 0.24 mmol) was added after 30 min. After a further 1 h water was added and the mixture stirred for 30 min until the oil that separated had solidified. The solid was filtered off, washed with water, dried, and triturated with hot EtOAc to give 1-[(E)-4-butyramido-1-methyl-2-pyrroleacryloyl]-3-(chloromethyl)-6-[(4-nitrobenzyloxy)carbonyl]aminoindoline (8a) (49 mg, 71%) as a yellow solid, mp 207-209.5° C. 1H NMR [(CD3)2SO] δ6 9.91 (s, 1 H, NH), 9.76 (s, 1 H, NH), 8.40 (s, 1 H, H-7), 8.27 (d, J=8.7 Hz, 2 H, ArHo to NO2), 7.70 (d, J=8.7 Hz, 2 H, ArHm to NO2), 7.54 (d, J=15.0 Hz, 1 H. H-β) 7.28 (d, J=8.2 Hz, 1 H, H-4), 7.22 (d, J=1.5 Hz, 1 H, H-5′), 7.16 (d, J=8.2 Hz, 1 H, H-6), 6.71 (d, J=1.4 Hz, 1 H. H-3′), 6.64 (d, J=15.0 Hz, 1 H, H-α), 5.30 (s, 2 H, ArCH2O), 4.48-4.39 (m, 1 H, H-2), 4.12 (dd, J=10.5, 4.1 Hz, 1 H, ArCH2O), 4.48-4.39 (m, 1 H, H-2), 4.12 (dd, J=10.5, 4.1 Hz, 1 H, H-2), 3.98-3.92 (m, 1 H, CHCH2Cl), 3.85-3.76 (m, 2 H, CHCH2Cl), 3.68 (s, 3H, NCH3), 2.20 (t, J=7.3 Hz, 2 H, CH2CH2CH3), 1.58 (sx, J=7.4 Hz, 2 H, CH2CH2CH3), 0.89 (t, J=7.4 Hz, 3 H, CH2CH2CH3).