Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:13])[C:9]([O:11][CH3:12])=[O:10].[K].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH:26]=[CH:25][C:24]([OH:27])=[N:23]2)=[CH:18][CH:17]=1>CS(C)=O>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[CH:26]=[CH:25][C:24]([O:27][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[C:8](=[O:13])[C:9]([O:11][CH3:12])=[O:10])=[N:23]2)=[CH:20][CH:21]=1
Reactant: COC(=O)C(=O)c1ccccc1F
Reactant: Oc1ccn(-c2ccc(Cl)cc2)n1
Agent: [K]
Solvent: CS(C)=O
Product: COC(=O)C(=O)c1ccccc1Oc1ccn(-c2ccc(Cl)cc2)n1
Temperature: 60 °C

Procedure:
A solution of 4.2 g of methyl 2-fluorophenylglyoxalate in 30 ml of anhydrous dimethyl sulfoxide was added dropwise to a solution of 5.0 g of the potassium salt of 1-(4-chlorophenyl)-3-hydroxy-pyrazole in 30 ml of anhydrous dimethyl sulfoxide. The batch was heated at 60° C. for 3.5 more hours, cooled and divided into two halves. One half was poured into ice-water/methyl tert-butyl ether for working-up. After the organic phase had been separated off, the aqueous phase was extracted three more times with methyl tert-butyl ether. The combined organic phases were dried over sodium sulfate and concentrated. The crude product was purified by chromatography over silica gel (eluent heptane/ethyl acetate 80/20→70/30). This gave 1.0 g of the title compound as a pale oil.
Reaction SMILES: [Br:1][C:2]1[C:22]([Br:23])=[CH:21][C:20]([Br:24])=[CH:19][C:3]=1[C:4]([C:6]1[N:10]([CH3:11])[C:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8][C:7]=1[CH3:18])=[O:5].Cl[C:26]1C=CC(C(C2N(C)C(CC(OCC)=O)=CC=2C)=O)=CC=1>>[Br:1][C:2]1[C:22]([Br:23])=[CH:21][C:20]([Br:24])=[CH:19][C:3]=1[C:4]([C:6]1[N:10]([CH3:11])[C:9]([CH:12]([CH3:26])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8][C:7]=1[CH3:18])=[O:5]
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2cc(Br)cc(Br)c2Br)n1C
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(Cl)cc2)n1C
Product: CCOC(=O)C(C)c1cc(C)c(C(=O)c2cc(Br)cc(Br)c2Br)n1C

Procedure:
The methylation procedure of Example 77A is repeated, except that an equivalent quantity of ethyl 5-(2′,3′,5′-tribromobenzoyl)-1,4-dimethylpyrrole-2-acetate (from Example 91) is methylated instead of the ethyl 5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate used in Example 77A, to yield ethyl 5-(2′,3′,5′-tribromobenzoyl)-1,4,α-trimethylpyrrole-2-acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:44]=[C:43]([O:45][CH3:46])[CH:42]=[CH:41][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26][N:27]([CH2:37][CH:38]([CH3:40])[CH3:39])[CH:28]4[CH2:31][CH:30]([CH2:32][CH2:33][C:34](O)=[O:35])[CH2:29]4)[CH2:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.C(N(CC)C(C)C)(C)C.[C:56]([C:60]1[CH:61]=[C:62]([NH2:67])[C:63]([NH2:66])=[CH:64][CH:65]=1)([CH3:59])([CH3:58])[CH3:57]>CN(C)C=O>[NH2:67][C:62]1[CH:61]=[C:60]([C:56]([CH3:59])([CH3:57])[CH3:58])[CH:65]=[CH:64][C:63]=1[NH:66][C:34](=[O:35])[CH2:33][CH2:32][CH:30]1[CH2:31][CH:28]([N:27]([CH2:26][C@@H:18]2[C@@H:19]3[C@@H:20]([O:21][C:22]([CH3:24])([CH3:25])[O:23]3)[C@H:16]([N:13]3[C:9]4[N:10]=[CH:11][N:12]=[C:7]([NH:6][CH2:5][C:4]5[CH:41]=[CH:42][C:43]([O:45][CH3:46])=[CH:44][C:3]=5[O:2][CH3:1])[C:8]=4[CH:15]=[CH:14]3)[CH2:17]2)[CH2:37][CH:38]([CH3:39])[CH3:40])[CH2:29]1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(CC(C)C)C3CC(CCC(=O)O)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(CC(C)C)C3CC(CCC(=O)Nc4ccc(C(C)(C)C)cc4N)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
N,N,N′,N′-Tetramethyl-0-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (1.52 g, 4.01 mmol) added to a solution of 3-(3-((((3aR,4R,6R,6aS)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)(isobutyl)amino)cyclobutyl)propanoic acid (1.7 g, 2.7 mmol) and N,N-Diisopropylethylamine (1.54 ml, 8.82 mmol) and 4-tert-butylbenzene-1,2-diamine (0.527 g, 3.21 mmol) in N,N-Dimethylformamide (16.6 ml). The reaction was stirred overnight at RT, partially concentrated to ca. 2 mls and then NaHCO3 (saturated) added. Them mixture was extracted with EtOAc 3× and the combined organics were dried with MgSO4 filtered, concentrated and purified by flash chromatography (DCM/7N NH3 in MeOH 95:5) to yield the desired amide (1.71 g) as a solid,
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:9][CH:10]([OH:14])[CH2:11][CH:12]=[CH2:13].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[Br:8][C:6]1[CH:7]=[C:2](/[CH:13]=[CH:12]/[CH2:11][CH:10]([OH:14])[CH3:9])[CH:3]=[N:4][CH:5]=1
Reactant: C=CCC(C)O
Reactant: Brc1cncc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(O)C/C=C/c1cncc(Br)c1
Temperature: 140 °C
Yield: 33.5 %

Procedure:
A mixture of 3,5-dibromopyridine (23.60 g, 100.0 mmol), 4-penten-2-ol (10.8 g, 125.0 mmol), palladium(II) acetate (230 mg, 1.02 mmol), tri-o-tolylphosphine (1.20 g, 3.94.mmol), triethylamine (29.7 mL, 213.45 mmol), and acetonitrile (40 mL) was heated in a sealed glass tube at 140° C. for 14 h. The reaction mixture was cooled to ambient temperature, diluted with water, and extracted with chloroform (3×200 mL). The combined chloroform extracts were dried over sodium sulfate and filtered. Removal of solvent by rotary evaporation, followed by column chromatography over silica gel eluting with acetone-chloroform (1:9, v/v) furnished 8.10 g (34.0%) of a pale-yellow oil.
Reaction SMILES: [NH2:1][C:2]1[NH:3][CH2:4][CH2:5][CH:6]=1.C([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([O:18]CC)=O)=O.[CH2:21](O)C>>[C:10]1([C:15]2[C:16](=[O:18])[N:1]=[C:2]3[CH2:6][CH2:5][CH2:4][N:3]3[CH:21]=2)[CH:9]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:10]1([C:15]2[C:16](=[O:18])[N:3]3[CH2:4][CH2:5][CH2:6][C:2]3=[N:1][CH:21]=2)[CH:9]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NC1=CCCN1
Reactant: CCOC(=O)Cc1ccccc1C=O
Reactant: CCO
Product: O=c1c(-c2ccccc2)cnc2n1CCC2
Product: O=c1nc2n(cc1-c1ccccc1)CCC2

Procedure:
8.4 g. of 2-amino-pyrroline and 19.2 g. of ethyl 2-formyl-phenyl-acetate are heated in 150 ml. ethanol for 5 hours and the reaction mixture is evaporated. The residue is treated with petrol ether, the obtained crystals are filtered. 15.9 g. (75%) of a mixture of 3-phenyl-2-oxo-2,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidine and 3-phenyl-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidine are obtained, melting slowly between 98° to 120° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[Br:12][C:13]1[CH:14]=[C:15]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]1[CH:20]([NH2:26])[CH2:19][CH2:18][CH2:17][C:16]2=1>>[Br:12][C:13]1[CH:14]=[C:15]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]1[CH:20]([NH:26][S:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])(=[O:10])=[O:9])[CH2:19][CH2:18][CH2:17][C:16]2=1
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Product: O=S(=O)(NC1CCCc2c1[nH]c1ccc(Br)cc21)c1ccccc1F

Procedure:
N-(6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-fluorobenzenesulfonamide was prepared from 2-fluorobenzenesulfonylchloride and 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine in a similar manner as described above to give a white solid: 1H-NMR (CDCl3): δ 8.56 (s, 1H), 8.00 (m, 1H), 7.65 (m, 1H), 7.58 (m, 1H), 7.2-7.4 (m, 3H), 5.04 (d, 1H), 4.60 (m, 1H), 2.65 (m, 2H), 1.6-2.1 (m, 4H); MS m/z 421 (M−1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].[NH2:16][C:17]1[CH:25]=[C:24]2[C:20]([CH:21]=[N:22][NH:23]2)=[CH:19][CH:18]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[NH:23]1[C:24]2[C:20](=[CH:19][CH:18]=[C:17]([NH:16][C:2]3[C:11]4[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=4)[N:5]=[CH:4][C:3]=3[C:14]#[N:15])[CH:25]=2)[CH:21]=[N:22]1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: COc1cccc2c(Cl)c(C#N)cnc12
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cccc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc12
Temperature: 100 °C

Procedure:
Using an analogous procedure to that described in Example 141, 328.0 mg (1.5 mmol) of 4-chloro-8-methoxy-3-quinolinecarbonitrile, 219.7 mg (1.65 mmol) of 6-aminoindazole and 105.6 mg (173.3 mmol) of pyridine hydrochloride in 15 mL of 2-ethoxyethanol was heated at 100° C. for 2 hr. The work up gave 373.8 mg (79%) of the product as a yellow solid, m.p. 242° C. (dec.), mass (electrospray, m/e): M+H 315.9. HRCIMS: calcd 315.112 for C18H13N5O (M+), obsd 315.1126.
Reaction SMILES: C1CCN(CCCN2CC3C4C=CC(F)=CC=4C(NC=3CC2)=O)CC1.[CH2:26]([N:33]1[C:41]2[CH:40]=[CH:39][CH:38]=[C:37]([C:42]([O:44]C)=[O:43])[C:36]=2[C:35]([CH2:46][CH2:47][NH:48][C@@H:49]2[CH:54]3[CH2:55][CH2:56][N:51]([CH2:52][CH2:53]3)[CH2:50]2)=[N:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O.[OH-].[Li+:59]>>[CH2:26]([N:33]1[C:41]2[CH:40]=[CH:39][CH:38]=[C:37]([C:42]([O-:44])=[O:43])[C:36]=2[C:35]([CH2:46][CH2:47][NH:48][C@@H:49]2[CH:54]3[CH2:55][CH2:56][N:51]([CH2:52][CH2:53]3)[CH2:50]2)=[N:34]1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1.[Li+:59]
Reactant: COC(=O)c1cccc2c1c(CCN[C@H]1CN3CCC1CC3)nn2Cc1ccccc1
Agent: O=c1[nH]c2c(c3ccc(F)cc13)CN(CCCN1CCCCC1)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])c1cccc2c1c(CCN[C@H]1CN3CCC1CC3)nn2Cc1ccccc1
Yield: 101 %

Procedure:
Following general procedure GP-L, (R)-methyl 1-benzyl-3-(2-(quinuclidin-3-ylamino)ethyl)-1H-indazole-4-carboxylate (1.1 mg, 2.63 mmol) and lithium hydroxide monohydrate (332 mg, 7.89 mmol) were converted lithium (R)-1-benzyl-3-(2-(quinuclidin-3-ylamino)ethyl)-1H-indazole-4-carboxylate (1.09 g, quant. yield) which was used in the next step without further purification: 1H NMR (300 MHz, CDCl3) δ 7.37-7.34 (m, 1H), 7.30-7.26 (m, 3H), 7.25-7.11 (m, 3H), 7.06-7.03 (m, 1H), 5.54 (s, 2H), 3.27 (m, 2H), 2.85-2.70 (m, 4H), 2.67-2.50 (m, 3H), 2.18-2.12 (m, 1H), 1.75-1.45 (m, 3H), 1.40-1.15 (m, 2H): MS (ESI+) m/z 405 (M+H).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([CH3:17])=[CH:11][C:12](=[O:16])[O:13]2)=[CH:8][CH:7]=1>C1(C)C=CC=CC=1.O1CCOCC1>[N:5]([C:6]1[CH:15]=[C:14]2[C:9]([C:10]([CH3:17])=[CH:11][C:12](=[O:16])[O:13]2)=[CH:8][CH:7]=1)=[C:1]=[O:2]
Reactant: O=C(Cl)Cl
Reactant: Cc1cc(=O)oc2cc(N)ccc12
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(=O)oc2cc(N=C=O)ccc12
Temperature: 100 °C
Reaction time: 12 h
Yield: 25 %

Procedure:
A 200-mL three-neck flask fitted with a dry ice condenser and magnetic stirrer was charged with a solution of 20% phosgene in toluene solution (2.0 mL) and dioxane (80 mL). To this mixture was added 7-amino-4-methyl-2H-chromen-2-one (2.00 g, 11.4 mmol). The mixture was stirred at 100° C. for 12 h. The initial yellow colour disappeared and a white solid precipitated. An additional 20% phosgene in toluene solution (7.0 mL) was added and the mixture heated for an additional 5 h, at which time the solution cleared. Excess phosgene and traces of HCl was removed by bubbling nitrogen gas through the solution. The cloudy solution was filtered to remove unreacted 7-amino-4-methyl-2H-chromen-2-one and concentrated to give 76 (0.5 g, 25%) as a white solid. H1 NMR (500 MHz, CDCl3): δ=7.50 (1H, d, J=7.40 Hz, ArH), 7.46 (2H, s, ArH), 6.20 (1H, s, ArH), 2.35 (3H, s, CH3): ir (CH2CL2) 2314 (N═C═O), 1726 and 1615 cm−1.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[Br:11][C:12]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:13]=1[CH:14]=[O:15].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C.O>[Br:11][C:12]1[CH:19]=[CH:18][C:17]([O:20][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[CH:16][C:13]=1[CH:14]=[O:15]
Reactant: O=Cc1cc(O)ccc1Br
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1cc(Oc2ccc([N+](=O)[O-])cc2)ccc1Br
Temperature: 100 °C
Yield: 80.7 %

Procedure:
To a solution of 1-fluoro-4-nitro-benzene (1.1 mL, 10.0 mmol, 1.0 eq.), 2-bromo-5-hydroxy-benzaldehyde (2.0 g, 10.0 mmol, 1.0 eq.) in DMF (30.0 mL) was added K2CO3 (1.7 g, 12.0 mmol, 1.2 eq.) under nitrogen atmosphere. The mixture was heated at 100° C. overnight. After cooling to room temperature, the mixture was poured into EtOAc (30 mL) and sat. H2O (30 mL). The layers were separated and the aqueous phase was extracted with EtOAc (3×20 mL). Combined organic extracts was washed with brine (30 mL), dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. The residue was applied to silica chromatography eluting with EtOAc/Heptanes (0:100 to 100:0) to give 2-bromo-5-(4-nitro-phenoxy)-benzaldehyde as a yellow fine powder. 1H NMR (CHLOROFORM-d) δ: 10.31-10.37 (m, 10H), 8.26 (dd, J=9.0, 0.3 Hz, 15H), 8.21-8.28 (m, 13H), 7.73 (d, J=8.6 Hz, 3H), 7.73 (dt, J=8.7, 0.5 Hz, 7H), 7.62 (dd, J=3.1, 0.3 Hz, 10H), 7.20-7.29 (m, 19H), 7.00-7.10 (m, 23H). Amount obtained, 2.6 g, 80.7% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:4][CH:3]=1.[Cl:15][CH2:16][CH2:17][C:18](Cl)=[O:19]>CC(C)=O>[Cl:15][CH2:16][CH2:17][C:18]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:13][CH:14]=1)=[O:19]
Reactant: O=C(Cl)CCCl
Reactant: Nc1ccc(C(=O)CCC(=O)O)cc1
Solvent: CC(C)=O
Product: O=C(O)CCC(=O)c1ccc(NC(=O)CCCl)cc1
Yield: 74 %

Procedure:
19.2 g (100 millimoles) of 3-(p-aminobenzoyl)-propionic acid were stirred with 24.8 g (195 millimoles) of 3-chloropropionyl chloride in 200 ml of absolute acetone for 10 hours at room temperature. The mixture was then evaporated down, the residue was stirred with 200 ml of water, and the product was filtered off under suction at 10° C., washed with cold acetone and dried at 100° C. under reduced pressure. 21 g (75%) of 3-[p-(3-chloropropionylamino)-benzoyl]-propionic acid were obtained as yellowish crystals of melting point 181°-182° C (acetonitrile).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([C:9]2([CH:15]=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[CH3:19][NH2:20]>>[CH3:19][NH:20][CH2:15][C:9]1([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:18])([F:17])[F:1])[CH:4]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CN
Reactant: O=CC1(c2cccc(C(F)(F)F)c2)CCCCC1
Product: CNCC1(c2cccc(C(F)(F)F)c2)CCCCC1
Yield: 36.9 %

Procedure:
The title compound was prepared from 1-(3-(trifluoromethyl)phenyl)cyclohexane-carbaldehyde (116 mg, 0.5 mmol) and methylamine (2.0 M in THF, 2.5 ml, 5.0 mmol) according to General Procedure H2.The crude product was purified by silica gel column chromatography (MeOH/CH2Cl2, MeOH from 0% to 15%) to give N-methyl-1-(1-(3-(trifluoromethyl)phenyl)cyclohexyl)methanamine (50 mg, 45%). 1H NMR (CDCl3): δ 1.28-1.52 (m 4H), 1.54-1.60 (m, 2H), 1.69-1.76 (m, 2H), 2.12-2.18 (m, 2H), 2.29 (s, 3H), 2.66 (s, 2H), 7.45-7.48 (m, 2H), 7.56-7.59 (m, 1H), 7.61 (s, 1H). 13C NMR (CDCl3) δ 22.3, 26.7, 34.6, 37.4, 42.6, 64.2, 123.0, 123.9, 127.9, 129.1, 130.8, 131.1, 146.7.ESI MS m/z 271.
Reaction SMILES: C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.[CH3:38][N:39]=[C:40]=[O:41].[I:42][C:43]#[C:44][CH2:45][O:46][CH2:47][CH2:48][OH:49]>C(Cl)CCl>[CH3:38][NH:39][C:40](=[O:41])[O:49][CH2:48][CH2:47][O:46][CH2:45][C:44]#[C:43][I:42]
Reactant: OCCOCC#CI
Reactant: CN=C=O
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: ClCCCl
Product: CNC(=O)OCCOCC#CI
Yield: 96.7 %

Procedure:
One milliliter of dibutyltin dilaurate was added under agitation as catalyst to a solution of 3.3 gm (0.058 mol) of methyl isocyanate and 12.8 gm (0.057 mol) of 2-(3-iodo-2-propynyloxy)-ethanol in 50 ml ethylene chloride. Due to the exothermic reaction, the temperature rose gradually from room temperature to 30° C. After a reaction time of 16 hours, the solvent was removed by distillation under vacuum, and the yellowish oil obtained was extracted with n-hexane to separate the catalyst, the hexane phase being discarded. Then, the residual solvent was removed under vacuum,, and 15.6 gm of 2-(3-iodo-2-propynyloxy)-ethyl N-methyl-carbamate (97% of theory) were obtained as a clear, yellowish oil, which crystallized into a colorless solid (melting point: 52°-55° C). Solubility: dissolves readily in ethanol or acetone; almost insoluble in water.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:12][CH2:11][CH2:10][C:9]2[N:8]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=3)[N:7]=[CH:6][C:5]1=2.C([O-])([O-])=O.[K+].[K+].[C:27]1([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:20][C:15]1[CH:14]=[C:13]([N:8]2[C:9]3[CH2:10][CH2:11][CH2:12][CH:4]([CH2:3][CH2:2][N:36]4[CH2:37][CH2:38][CH:33]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH2:34][CH2:35]4)[C:5]=3[CH:6]=[N:7]2)[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: ClCCC1CCCc2c1cnn2-c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Clc1ccc(-n2ncc3c2CCCC3CCN2CCC(c3ccccc3)CC2)cc1Cl
Yield: 45.1 %

Procedure:
A mixture of 4-(2-chloroethyl)-4,5,6,7-tetrahydro-1-(3,4-dichlorophenyl)-1H-indazole (235 mg, 0.71 mmol), K2CO3 (99 mg, 0.71 mmol), 4-phenylpiperidine (97 mg, 0.71 mmol) and a catalytic amount of K1 in 5 mL of DMF is heated to reflux during 18 hours. The solvent is eliminated at reduced pressure, the crude is diluted with ethyl acetate, washed with water, and the organic phase is evaporated at reduced pressure. The resultant crude is purified by chromatography on silica-gel to obtain 1-(3,4-dichlorophenyl)-4,5,6,7-tetrahydro-4-(2-(4-phenylpiperidin-1-yl)ethyl)-1H-indazole (146 mg, 0.32 mmol, 45%, oil).
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[NH:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:16]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:17]([C:22]([NH:24][C:25]2[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[C:27]([Cl:34])[CH:26]=2)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=1.C(N(CC)C(C)C)(C)C.O>ClCCl>[N:1]1[C:6]2[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[N:10]([C:29]([C:28]3[CH:32]=[CH:33][C:25]([NH:24][C:22]([C:17]4[C:16]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[O:23])=[CH:26][C:27]=3[Cl:34])=[O:30])[CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1cnc2c(c1)CNc1ccccc1N2
Reactant: O=C(Cl)c1ccc(NC(=O)c2ccccc2-c2ccccc2)cc1Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(C(=O)N2Cc3cccnc3Nc3ccccc32)c(Cl)c1)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 30.2 %

Procedure:
A mixture of 0.197 g of 6,11-dihydropyrido[2,3-b][1,5]benzodiazepine, 0.444 g of 4-[([1,1'-biphenyl]-2-carbonyl)amino]-2-chlorobenzoyl chloride and 0.155 g of N,N-diisopropylethylamine in 8 ml of dichloromethane is stirred at room temperature for 1.5 hours. The mixture is poured into water and extracted with dichloromethane. The extract is washed with H2O, saturated NaHCO3, H2O, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated to dryness. The residue is chromatographed on thick layer silica gel plates with hexane-ethyl acetate (1:2) to give 0.160 g of solid, m.p. 147° C.-165° C. Anal Found: C, 72.1; H, 5.1; N, 9.1; Cl, 6.3.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:28]([F:31])([F:30])[F:29])=[C:11]([CH2:15][O:16][CH:17]3[CH2:20][N:19]([C:21]([NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]3)[CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[N:32]1([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[C:10]([C:28]([F:31])([F:30])[F:29])=[C:11]([CH2:15][O:16][CH:17]4[CH2:20][N:19]([C:21]([NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]4)[CH:12]=[CH:13][CH:14]=3)=[CH:5][CH:4]=2)[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: CC(C)(C)NC(=O)N1CC(OCc2cccc(-c3ccc(CCl)cc3)c2C(F)(F)F)C1
Reactant: C1COCCN1
Product: CC(C)(C)NC(=O)N1CC(OCc2cccc(-c3ccc(CN4CCOCC4)cc3)c2C(F)(F)F)C1
Yield: 69.7 %

Procedure:
The benzyl chloride (195) (40 mg, 0.088 mmol) and morpholine (3 mL, 31 mmol) were heated to 50° C. for 18 h. The reaction mixture was cooled, excess amine was removed under reduced pressure and the residue partitioned between ethyl acetate and sodium hydroxide (1M). The organic phase was washed with water (2×20 mL) and brine (20 mL), dried (Na2SO4), filtered and the solvent removed under reduced pressure to afford the crude product. Purification by SCX-2 cartridge afforded the title compound (196) as a white solid (31 mg, 70% yield).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([CH:11]=[O:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:5]2=[N:6][CH:7]=1.[Cl:21][C:22]1[CH:30]=[C:29]2[C:25]([C:26]([Sn](CCCC)(CCCC)CCCC)=[N:27][N:28]2[CH3:31])=[CH:24][CH:23]=1>CN(C=O)C.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.[Cu]I>[Cl:21][C:22]1[CH:30]=[C:29]2[C:25]([C:26]([C:2]3[N:3]=[C:4]4[C:10]([CH:11]=[O:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:5]4=[N:6][CH:7]=3)=[N:27][N:28]2[CH3:31])=[CH:24][CH:23]=1
Reactant: C[Si](C)(C)CCOCn1cc(C=O)c2nc(Br)cnc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2cc(Cl)ccc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3c(n2)c(C=O)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
In a round-bottomed flask, 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (400 mg, 1.12 mmol) and 6-chloro-1-methyl-3-tributylstannyl-1H-indazole (1.11 g, 1.7 mmol) were dissolved in DMF (10 mL). The flask was evacuated and backfilled with argon then tetrakis(triphenylphosphine)palladium(0) (65 mg, 0.056 mmol) and copper(I) iodide (43 mg, 0.23 mmol) were added. The reaction mixture was stirred at 80° C. in an oil bath overnight then cooled to room temperature, quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was absorbed on silica gel and chromatographed with EtOAc/hexanes (gradient 0-30% EtOAc) to provide 416 mg (84%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:11]([N+:25]([O-])=O)[CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[H][H]>CO.[Pd]>[NH2:25][C:11]1[CH:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22]
Reactant: [H][H]
Reactant: COC(=O)CCCCCOc1ccc(-c2ccc(C#N)cc2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCCCCOc1ccc(-c2ccc(C#N)cc2)cc1N

Procedure:
Prepared from 4-cyano-4'-(5-methoxycarbonyl-pentyloxy)-3'-nitro-biphenyl by hydrogenating with hydrogen under 5 bars of pressure in methanol in the presence of 10% palladium/charcoal at ambient temperature.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:11][C:12]1[O:16][C:15]([CH:17]=O)=[CH:14][CH:13]=1.C([O:21][C:22](=O)[C:23](=[O:30])[CH2:24][C:25](=[O:29])[CH2:26][CH2:27][CH3:28])C>C(O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:17]([C:15]4[O:16][C:12]([CH3:11])=[CH:13][CH:14]=4)[C:24]([C:25](=[O:29])[CH2:26][CH2:27][CH3:28])=[C:23]([OH:30])[C:22]3=[O:21])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Nc1ccc2[nH]cnc2c1
Reactant: CCCC(=O)CC(=O)C(=O)OCC
Reactant: Cc1ccc(C=O)o1
Solvent: CCO
Product: CCCC(=O)C1=C(O)C(=O)N(c2ccc3[nH]cnc3c2)C1c1ccc(C)o1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
1H-Benzoimidazol-5-ylamine (1 mmol) and 5-Methyl-furan-2-carbaldehyde (1 mmol) were added to ethanol (5 ml). After 30 min 2,4-Dioxo-heptanoic acid ethyl ester (1 mmol) was added. The reaction was heated to 50° C. and stirred for 24 h. After evaporation of the solvent the residue was purified with chromatographic methods.