Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][NH2:10].[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH:18]=[C:19]([C:21](OCC)=[O:22])[N:20]=2)[CH:17]=1>>[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH:18]=[C:19]([C:21]([NH:10][CH2:9][C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])=[O:22])[N:20]=2)[CH:17]=1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Reactant: NCc1c(F)cccc1F
Product: O=C(NCc1c(F)cccc1F)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate I, using (2,6-difluorophenyl)methanamine and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1/[CH:11]=[CH:12]/[C:13]1[N:18]=[C:17](O)[CH:16]=[C:15]([CH3:20])[N:14]=1.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:17]1[CH:16]=[C:15]([CH3:20])[N:14]=[C:13]([CH:12]=[CH:11][C:4]2[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=2[O:2][CH3:1])[N:18]=1
Reactant: COc1ccc(/C=C/c2nc(C)cc(O)n2)c(OC)c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc(C=Cc2nc(C)cc(Cl)n2)c(OC)c1
Yield: 59.2 %

Procedure:
In analogy to example 12c), by heating (E)-2-[2-(2,4-dimethoxy-phenyl)-vinyl]-6-methyl-pyrimidin-4-ol (0.33 g, 1.22 mmol) in POCl3 (2.24 ml, 24.5 mmol) at 130° C. for 4.5 h there was obtained 4-chloro-2-[2-(2,4-dimethoxy-phenyl)-vinyl]-6-methyl-pyrimidine (0.21 g, 60%) as a light yellow solid. EI mass spectrum, m/e: 290 (M calculated for C15H15ClN2O2: 290).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][N:15]=[CH:16]3)=[CH:11][CH:10]=2)O1.[NH2:20][C:21]1[C:30]2[C:25](=[C:26](Br)[C:27]([CH3:31])=[CH:28][CH:29]=2)[N:24]=[N:23][C:22]=1[C:33]([NH2:35])=[O:34]>>[NH2:20][C:21]1[C:30]2[C:25](=[C:26]([C:9]3[CH:18]=[C:17]4[C:12]([CH:13]=[CH:14][N:15]=[CH:16]4)=[CH:11][CH:10]=3)[C:27]([CH3:31])=[CH:28][CH:29]=2)[N:24]=[N:23][C:22]=1[C:33]([NH2:35])=[O:34]
Reactant: Cc1ccc2c(N)c(C(N)=O)nnc2c1Br
Reactant: CC1(C)OB(c2ccc3ccncc3c2)OC1(C)C
Product: Cc1ccc2c(N)c(C(N)=O)nnc2c1-c1ccc2ccncc2c1

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 1 using 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline and 4-amino-8-bromo-7-methylcinnoline-3-carboxamide. 1H NMR (500 MHz, CD3OD) δ ppm 2.30-2.36 (m, 3 H), 7.72-7.79 (m, 2 H), 7.94 (d, J=5.86 Hz, 1 H), 8.07-8.14 (m, 2 H), 8.22-8.31 (m, 1 H), 8.46-8.52 (m, 1 H), 9.29 (s, 1 H); ESI-MS m/z [M+H]+ 330.4.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:3]([OH:5])=[O:4].S(Cl)(Cl)=O.[OH-].[Na+].[CH2:20](O)[CH3:21]>>[NH2:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:3]([O:5][CH2:20][CH3:21])=[O:4]
Reactant: CCCCCCCCC(N)C(=O)O
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Product: CCCCCCCCC(N)C(=O)OCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
2-Aminodecanoic acid (J. Am. Chem. Soc., 1946, 68, 450) (16.0 g) was added in portions to a cooled (-10° C.) mixture of absolute ethanol (70 ml) and thionyl chloride (6 ml) with stirring. The resulting solution was set aside for 2 hours, at room temperature, refluxed for 1 hour, cooled, poured into ice-water, and the pH of the solution was adjusted to 9 with aqueous sodium hydroxide. The mixture was extracted with ether, the extract was dried, concentrated, then distilled, giving ethyl 2-aminodecanoate (75%) as a colourless oil, b.p. 82°-4° C./0.2 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:27])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[C:19]([CH2:20]O)=[N:18][N:17]=[C:16]1[CH2:22][CH2:23][N:24]([CH3:26])[CH3:25].[C:28]1(=[O:38])[NH:32][C:31](=[O:33])[C:30]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:29]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:27])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[C:19]([CH2:20][N:32]2[C:31](=[O:33])[C:30]3=[CH:34][CH:35]=[CH:36][CH:37]=[C:29]3[C:28]2=[O:38])=[N:18][N:17]=[C:16]1[CH2:22][CH2:23][N:24]([CH3:25])[CH3:26]
Reactant: CN(C)CCc1nnc(CO)n1-c1ccccc1C(=O)c1ccccc1Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)CCc1nnc(CN2C(=O)c3ccccc3C2=O)n1-c1ccccc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 1B, 2'-chloro-2-[3-[2-(dimethylamino)ethyl]-5-(hydroxymethyl)-4H-1,2,4-triazol-4-yl]benzophenone in tetrahydrofuran is treated with phthalimide, triphenylphosphine and diethylazodicarboxylate to give 2'-chloro-2-[3-[2-(dimethylamino)-ethyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: [F:1][C:2]([F:19])([CH3:18])[CH2:3][O:4][C:5]1[C:6]([CH3:17])=[CH:7][C:8]([C:11](N(OC)C)=[O:12])=[N:9][CH:10]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[F:19][C:2]([F:1])([CH3:18])[CH2:3][O:4][C:5]1[C:6]([CH3:17])=[CH:7][C:8]([CH:11]=[O:12])=[N:9][CH:10]=1
Reactant: CON(C)C(=O)c1cc(C)c(OCC(C)(F)F)cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1cc(C=O)ncc1OCC(C)(F)F
Yield: 99 %

Procedure:
The title compound is prepared in >99% yield (1.01 g, pale orange solid) from 5-(2,2-difluoropropoxy)-N-methoxy-N,4-dimethylpicolinamide (1.25 g, 4.57 mmol, Step-4) and lithium aluminum hydride (87 mg, 2.3 mmol) in a similar manner to Step-2 of Amine-3.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:4]=[CH:5][O:6][C:7]=1[CH2:8][N:9]1[C:14]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[S:17][C:13]=2[C:12](=[O:24])[N:11]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[C:10]1=[O:31].[CH2:32]([O:34][C:35]1[C:44]([O:45][CH3:46])=[CH:43][C:42]2[C:41]([C:47]3[CH:55]=[CH:54][C:50]([C:51](O)=[O:52])=[CH:49][CH:48]=3)=[N:40][C@@H:39]3[CH2:56][CH2:57][S:58][CH2:59][C@@H:38]3[C:37]=2[CH:36]=1)[CH3:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:32]([O:34][C:35]1[C:44]([O:45][CH3:46])=[CH:43][C:42]2[C:41]([C:47]3[CH:48]=[CH:49][C:50]([C:51]([N:28]4[CH2:29][CH2:30][CH:25]([N:11]5[C:12](=[O:24])[C:13]6[S:17][C:16]([C:18]7[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=7)=[CH:15][C:14]=6[N:9]([CH2:8][C:7]6[O:6][CH:5]=[N:4][C:3]=6[CH3:2])[C:10]5=[O:31])[CH2:26][CH2:27]4)=[O:52])=[CH:54][CH:55]=3)=[N:40][C@@H:39]3[CH2:56][CH2:57][S:58][CH2:59][C@@H:38]3[C:37]=2[CH:36]=1)[CH3:33]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Reactant: Cc1ncoc1Cn1c(=O)n(C2CCNCC2)c(=O)c2sc(-c3ccccc3)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5ocnc5C)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
1-[(4-Methyl-1,3-oxazol-5-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (253 mg; compound B94) is reacted with 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (207 mg; compound C10) and HATU (257 mg) in DCM (7 ml) in the presence of DIPEA (0.27 ml) according to the procedure described in example 52 to afford the title compound after purification by preparative HPLC as a solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH3:11][C:12]1[CH:16]=[CH:15][NH:14][C:13]=1[CH:17]=O>N1CCCCC1.C(O)C>[CH3:11][C:12]1[CH:16]=[CH:15][NH:14][C:13]=1[CH:17]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]1=[O:10]
Reactant: Cc1cc[nH]c1C=O
Reactant: O=C1Cc2ccccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc[nH]c1C=C1C(=O)Nc2ccccc21
Temperature: 90 °C
Reaction time: 3 h
Yield: 67.4 %

Procedure:
A reaction mixture of 133.0 mg of oxindole, 130.9 mg of the 3-methylpyrrole-2-carboxaldehyde, and 3 drops of piperidine in 2 mL of ethanol was stirred at 90° C. for 3 h. After cooling, the precipitate was filtered, washed with cold ethanol, and dried to yield 150.9 mg (67%) of the title compound as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].Cl.Cl.[CH3:27][C@H:28]1[CH2:33][NH:32][CH2:31][CH2:30][N:29]1[CH2:34][CH2:35][CH3:36]>>[OH:14][C:13]1[N:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([N:32]3[CH2:31][CH2:30][N:29]([CH2:34][CH2:35][CH3:36])[C@@H:28]([CH3:27])[CH2:33]3)=[O:20])=[CH:17][N:16]=2)[N:11]=[CH:10][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[CH3:24]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CCCN1CCNC[C@@H]1C
Agent: Cl
Product: CCCN1CCN(C(=O)c2ccc(-n3ncc(-c4ccc(C#N)cc4C)c3O)nc2)C[C@@H]1C

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)-2-methyl-1-propylpiperazine dihydrochloride. 1H NMR (500 MHz, DMSO-d6) δ ppm 0.86 (t, J=7.32 Hz, 3H) 0.90-1.15 (m, 3H) 1.35-1.56 (m, 2H) 2.31-2.41 (m, 2H) 2.43 (s, 3H) 2.58-2.73 (m, 2H) 2.81-3.01 (m, 1H) 3.02-3.17 (m, 2H) 3.44-3.65 (m, 1H) 4.02 (br. s., 1H) 7.62 (dd, J=8.05, 1.71 Hz, 1H) 7.69 (d, J=0.98 Hz, 1H) 7.86 (d, J=7.81 Hz, 1H) 8.03 (dd, J=8.54, 2.20 Hz, 1H) 8.08 (s, 1H) 8.41 (d, J=8.30 Hz, 1H) 8.52 (d, J=1.95 Hz, 1H); ESI-MS m/z [M+H]+ 445.3.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[N:20]=[C:19]([CH3:21])[NH:18][N:17]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[Cl:28][C:29]1[CH:34]=[C:33]([CH2:35]Cl)[CH:32]=[CH:31][N:30]=1>CN(C=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:15]=[C:14]([C:16]3[N:20]=[C:19]([CH3:21])[N:18]([CH2:35][C:33]4[CH:32]=[CH:31][N:30]=[C:29]([Cl:28])[CH:34]=4)[N:17]=3)[O:13][N:12]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc(-c2nc(-c3ccc(C(C)(C)C)cc3)no2)n[nH]1
Reactant: ClCc1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1nc(-c2nc(-c3ccc(C(C)(C)C)cc3)no2)nn1Cc1ccnc(Cl)c1
Reaction time: 0.08 h
Yield: 44.5 %

Procedure:
3-(4-(tert-Butyl)phenyl)-5-(5-methyl-1H-1,2,4-triazol-3-yl)-1,2,4-oxadiazole (140 mg, 0.495 mmol) was placed in DMF (10 mL) and Cs2CO3 (193 mg, 0.594 mmol) was added. The reaction was stirred for 5 min and 2-chloro-4-(chloromethyl)pyridine (96 mg, 0.594 mmol) was added. The reaction was stirred at 45° C. overnight and was then partitioned between H2O (25 mL) and EtOAc (25 mL). The organic layer was separated, washed with H2O (2×25 mL) and brine (15 mL), dried over Na2SO4, filtered, and concentrated to afford the crude product which was purified by silica gel chromatography (EtOAc/Hexane 0%-100% EtOAc) to afford 3-(4-(tert-butyl)phenyl)-5-(1-((2-chloropyridin-4-yl)methyl)-5-methyl-1H-1,2,4-triazol-3-yl)-1,2,4-oxadiazole as a yellow solid (90 mg, 45%). MS (ES+) C21H21ClN6O requires: 408. found 409 [M+H]+; 1H NMR (600 MHz, CDCl3) δ 8.42 (d, J=5.2 Hz, 1H), 8.16 (d, J=8.5 Hz, 2H), 7.52 (d, J=8.5 Hz, 2H), 7.16 (s, 1H), 7.05 (d, J=5.2 Hz, 1H), 5.46 (s, 2H), 2.57 (s, 3H), 1.37 (s, 9H).
Reaction SMILES: N12CCCN=C1CCCCC2.Cl[C:13]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:24])[C:14]=1[NH:25][C:26](=[O:29])[CH2:27][CH3:28].[CH3:30][O:31][CH2:32][CH2:33][OH:34]>>[C:26]([NH:25][C:14]1[C:15](=[O:24])[C:16]2[C:21]([C:22](=[O:23])[C:13]=1[O:34][CH2:33][CH2:32][O:31][CH3:30])=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:29])[CH2:27][CH3:28]
Reactant: CCC(=O)NC1=C(Cl)C(=O)c2ccccc2C1=O
Reactant: COCCO
Solvent: C1CCC2=NCCCN2CC1
Product: CCC(=O)NC1=C(OCCOC)C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
15.2 g (0.1 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene in 50 ml of ethylene glycol monomethyl ether are added to a suspension of 26.35 g (0.1 mol) of 3-chloro-2-propionylamino-1,4-naphthoquinone in 100 ml of ethylene glycol monomethyl ether, and the mixture is stored at room temperature overnight. After cooling to 0° C., the mixture is filtered and the precipitate is thoroughly washed with cold methanol. Yield: 19.3 g (64% of theory), melting point 116°-17° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[C:10]([N:16]2[CH2:27][CH2:26][C:19]3([C:23](=[O:24])[N:22]([CH3:25])[CH2:21][CH2:20]3)[CH2:18][CH2:17]2)[C:9]=1[Cl:28])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[CH:13]=[C:12]([CH:11]=[C:10]([N:16]2[CH2:27][CH2:26][C:19]3([C:23](=[O:24])[N:22]([CH3:25])[CH2:21][CH2:20]3)[CH2:18][CH2:17]2)[C:9]=1[Cl:28])[C:14]#[N:15]
Reactant: CN1CCC2(CCN(c3cc(C#N)cc(NC(=O)OC(C)(C)C)c3Cl)CC2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC2(CCN(c3cc(C#N)cc(N)c3Cl)CC2)C1=O
Yield: 70 %

Procedure:
tert-butyl-(2-chloro-5-cyano-3-(2-methyl-1-oxo-2,8-diazaspiro[4.5]decan-8-yl)phenyl)carbamate (336 mg, 0.802 mmol) in DCM (3 mL) was treated with TFA (1.174 mL, 15.24 mmol) at room temperature for 2 h. Solvent was evaporated and the residue was redissolved in DCM and concentrated again. The reaction mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate. The aqueous layer was extracted with dichloromethane two more times. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel using an automated ISCO system (40 g column, eluting with 0-10% methanol/dichloromethane). 3-amino-4-chloro-5-(2-methyl-1-oxo-2,8-diazaspiro[4.5]decan-8-yl)benzonitrile (179 mg) was obtained as alight yellow oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:11])[CH2:7][CH2:8][CH2:9][CH2:10][C:2]1=2.[H-].[Na+].[CH3:14][O:15][C:16](=O)[O:17]C>>[O:11]=[C:6]1[C:3]2[CH:4]=[CH:5][O:1][C:2]=2[CH2:10][CH2:9][CH2:8][CH:7]1[C:16]([O:15][CH3:14])=[O:17]
Reactant: O=C1CCCCc2occc21
Reactant: COC(=O)OC
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C1CCCc2occc2C1=O

Procedure:
5,6,7,8-Tetrahydro-cyclohepta[b]furan-4-one (J. Chem. Soc., Perkin Trans. 1, 1980, 2081-2083) (0.1 g, 0.7 mmol) in dimethylcarbonate (2 mL) was treated with a 60% dispersion of sodium hydride (0.06 g, 0.15 mmol) as described in Example 1A to yield the title product. NMR in CDCl3 indicates a 70:30 mixture of keto and enol forms: 1H NMR (300 MHz, CDCl3) δ 13.02 (s, 0.3H), 7.29 (d, J=2.03 Hz, 0.4H), 7.23 (d, J=2.03 Hz, 0.6H), 6.73 (d, J=2.03 Hz, 0.6H), 6.72 (d, J=2.03 Hz, 0.4H) 3.78 (s, 1.2H), 3.75 (s, 1.8H), 3.72 (dd, J=9.99, 3.9 Hz, 0.6H), 3.02 (m, 1.2H), 2.96 (t, J=6.6 Hz, 0.8H), 2.56 (t, 0.8H), 1.84-2.2 (m, 3.5H); MS (DCI/NH3) m/z 209 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:10][NH2:11]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:5]=[N:11]/[CH3:10])[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: CN
Solvent: ClCCl
Product: C/N=C/c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
A mixture of 3-chloro-benzoaldehyde (Aldrich, 97%) (4.21 g, 30.0 mmol) and methyl amine (2.0 M in THF, Aldrich, 22.5 mL, 45.0 mmol) in CH2Cl2 (50 mL) was stirred at rt overnight. The reaction mixture was concentrated and the residue was dried under reduced pressure to afford [[1-(3-chloro-phenyl)-meth-(E)-ylidene]-methyl-amine (4.60 g, 100%) as colorless oil which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([S:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:4]([CH:7]=[CH:8][C:9]=1[I:10])[CH:5]=O.Cl.[NH2:17][OH:18]>C(O)C.O>[Br:1][C:2]1[C:3]([S:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:4]([CH:7]=[CH:8][C:9]=1[I:10])[CH:5]=[N:17][OH:18]
Reactant: NO
Reactant: CC(C)(C)Sc1c(C=O)ccc(I)c1Br
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(C)(C)Sc1c(C=NO)ccc(I)c1Br
Yield: 70 %

Procedure:
A mixture of 3-bromo-2-tert-butylsulfanyl-4-iodo-benzaldehyde (1.5 g, 3.8 mmol) and hydroxylamine hydrochloride in ethanol (20 mL) and water (4 mL) was heated to reflux for 2 h. The reaction mixture was cooled and concentrated. The residue was treated with water (40 mL) and then saturated aqueous sodium bicarbonate solution until the pH was ˜8.0. The mixture was extracted with ethyl acetate (2×40 mL). The combined organic fractions were dried over anhydrous sodium sulfate, filtered and concentrated. Purification by column chromatography (25% ethyl acetate:hexanes) afforded 1.1 g (70%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.34 (s, 9H), 7.41 (d, J=8.7 Hz, 1H), 7.77 (d, J=8.7 Hz, 1H), 8.47 (s, 1H), 8.51 (br. s, 1H); MS (ESI): 414, 416 [M+H]+.
Reaction SMILES: C(#N)C.Br[C:5]1[CH:6]=[C:7]([C:11]2[C:12]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:21]([O:30][CH3:31])=[CH:20][C:13]=3[N:14]([CH3:19])[C:15](=[O:18])[CH2:16][N:17]=2)[CH:8]=[CH:9][CH:10]=1.[C:32]1(C#C)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cu](I)I.Cl[Pd]Cl.C(N(CC)CC)C>[C:37]([C:5]1[CH:6]=[C:7]([C:11]2[C:12]3[CH:23]=[C:22]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:21]([O:30][CH3:31])=[CH:20][C:13]=3[N:14]([CH3:19])[C:15](=[O:18])[CH2:16][N:17]=2)[CH:8]=[CH:9][CH:10]=1)#[C:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: C#Cc1ccccc1
Reactant: COc1cc2c(cc1-c1ccccc1)C(c1cccc(Br)c1)=NCC(=O)N2C
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCC#Cc1cccc(C2=NCC(=O)N(C)c3cc(OC)c(-c4ccccc4)cc32)c1
Temperature: 50 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
To 10 mL of degazed acetonitrile, 5-(3-bromo-phenyl)-8-methoxy-1-methyl-7-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one Example 62 (200 mg, 0.46 mmol), phenylacetylene (715 μL, 2.30 mmol), copper iodide (15 mg, 0.08 mmol), triphenylphosphine (30 mg, 0.11 mmol), PdCl2 (10 mg, 0.06 mmol) and triethylamine (0.9 mL) were added. The mixture was stirred for 16 hours at 50° C. under nitrogen atmosphere. The working solution was evaporated under vacuum. The residue was partitioned from water and ethyl acetate and extracted two more times with ethyl acetate. The organic phase was dried over Na2SO4 and concentrated until dryness. The residue was purified by chromatography (eluant: Hexane/EtOAc: 1/1). The title compound was crystallised from ether/pentane to afford 134 mg of the title compound: beige solid, yield=90%.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:11](N(OC)C)=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:25]1([Mg]Br)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[Si:1]([O:8][CH2:9][C@@H:10]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[C:11](=[O:12])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CON(C)C(=O)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CO[Si](C)(C)C(C)(C)C)C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
(R)-tert-butyl 3-(tert-butyldimethylsilyloxy)-1 (methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (22) (2.2 g, 6.0 mmol, 1.0 equiv.) was added to a 250 mL RBF followed by THF (60 mL). The mixture was cooled to 0° C. via an ice bath and a 1.0 M solution of PhMgBr in THF (18.0 mL, 18.0 mmol, 3.0 equiv.) was added over 8 min. The reaction stirred for 1.0 h at 0° C. and the ice bath was removed. The reaction stirred for an additional 1.0 h at rt. and was again cooled to 0° C. via an ice bath. Next, the reaction was quenched by addition of 1.0 M HCl (55 mL). The solution was transferred to a separatory funnel with additional 1.0 M HCl (40 mL) and extracted with EtOAc (3×100 mL). The organic layers were washed with sat. NaCl (1×50 mL) and dried over Na2SO4. The solution was then concentrated on a rotary evaporator and dried under vacuum to give 2.5 g of crude material. The residue was purified by flash column chromatography (10% EtOAc/Hexanes) to give 2.0 g (89%) of 23 as a colorless oil. Rf=0.29 (10% EtOAc/Hexanes); [α]D23.5=−12.3 (c 1.26, MeOH); IR (film) 3433, 3360, 3062, 2952, 2929, 2883, 2856, 1715, 1688, 1498, 1253, 1167, 1114 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.97 (d, J=7.0 Hz, 2H, Ph-H), 7.61 (t, J=7.0 Hz, 1H, Ph-H), 7.50 (t, J=7.0 Hz, 2H, Ph-H), 5.73 (d, J=7.5 Hz, 1H, carbamate-NH), 5.35 (m, 1H, Boc-NH—CH), 3.97 (dq, J=9.5, 2.5 Hz, 2H, CH—CH2), 1.50 (s, 9H, Boc-t-butyl-CH3), 0.79 (s, 9H, Si-t-butyl-CH3), −0.07 (s, 3H, Si—CH3), −0.12 (s, 3H, Si—CH3); 13C (125 MHz, CDCl3) δ 197.9, 155.5, 135.6, 133.5, 128.8, 128.7, 79.9, 64.5, 57.4, 28.5, 25.8, 18.2, −5.6, −5.7; LRMS (ESI-MS m/z): Mass calcd for C20H33NO4Si [M]+, 379.57. Found 380.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12].[Cl:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22]Cl)[CH:17]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>CCOCC>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([CH2:15][Cl:14])[CH:17]=1
Reactant: COC(=O)CCc1ccccc1O
Reactant: ClCc1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: COC(=O)CCc1ccccc1OCc1cccc(CCl)c1
Yield: 54.6 %

Procedure:
A mixture of 1.8 g (10 mmol) of 2-hydroxybenzenepropanoic acid methyl ester, 14 g (80 mmol) of α,α'-dichloro-m-xylene, 4.25 g (30.8 mmol) of anhydrous, granular potassium carbonate, and 70 mL of acetonitrile was stirred and refluxed for 4 hr. After being cooled, the resulting mixture was diluted with 200 mL of ether and filtered with suction. The solids were washed thoroughly with ether and then the filtrate and washes were combined and concentrated in vacuo. The oily residue was chromatographed on 100 g of silica gel. Elution with 19:1 hexane-ether afforded 1.74 g (54.6%) of 2-[3-(chloromethyl)phenylmethoxy]benzenepropanoic acid methyl ester as a colorless oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:10][C:9]2[S:11][C:12]([Cl:14])=[CH:13][C:8]=2[C:7]=1[Cl:15])=[O:5])C.Cl>>[Cl:14][C:12]1[S:11][C:9]2[NH:10][C:6]([C:4]([OH:5])=[O:3])=[C:7]([Cl:15])[C:8]=2[CH:13]=1
Reactant: CCOC(=O)c1[nH]c2sc(Cl)cc2c1Cl
Agent: Cl
Product: O=C(O)c1[nH]c2sc(Cl)cc2c1Cl
Temperature: 25 °C

Procedure:
2,4-Dichloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid ethyl ester was hydrolyzed according to Procedure E (reflux for 12 h before allowing to cool to room temperature; acidification with concentrated HCl; no purification).
Reaction SMILES: [N+:1]([C:4]1[CH:28]=[CH:27][CH:26]=[CH:25][C:5]=1[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][C:17]3[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:11][CH:10]=1)=[O:7])([O-])=O.O.O.[Sn](Cl)Cl>CCO>[NH2:1][C:4]1[CH:28]=[CH:27][CH:26]=[CH:25][C:5]=1[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[S:16][C:17]3[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:13][CH:14]=1)=[O:7]
Reactant: Cc1ccc2nc(-c3ccc(NC(=O)c4ccccc4[N+](=O)[O-])cc3)sc2c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Cc1ccc2nc(-c3ccc(NC(=O)c4ccccc4N)cc3)sc2c1
Yield: 13.7 %

Procedure:
Prepared as described in the Nitro Reduction section using 2-nitro-N-[4-(6-methylbenzothiazol-2-yl)-phenyl]-benzamide (0.5 g, 1.28 mmol) and tin (II) chloride dihydrate (1.45 g, 6.42 mmol) in EtOH (50 ml) to give the title compound (0.063 g, 14%) as a tan needles after recrystallisation from EtOH.