Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([OH:15])=O)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[NH2:47][C:48]1[CH:49]=[C:50]2[C:54](=[CH:55][CH:56]=1)[NH:53][C:52]([CH:57]([CH3:63])[C:58]([O:60][CH2:61][CH3:62])=[O:59])=[CH:51]2>C(#N)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:47][C:48]4[CH:49]=[C:50]5[C:54](=[CH:55][CH:56]=4)[NH:53][C:52]([CH:57]([CH3:63])[C:58]([O:60][CH2:61][CH3:62])=[O:59])=[CH:51]5)=[O:15])[CH2:11][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Reactant: CCOC(=O)C(C)c1cc2cc(N)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.2 %

Procedure:
To a solution of 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (0.079 g, 0.384 mmol) in acetonitrile (1.5 mL) were added HBTU (0.146 g, 0.384 mmol) and Et3N (160 μL, 1.15 mmol) at room temperature. The mixture was allowed to stir at room temperature for 10 min before a solution of ethyl 2-(5-amino-1H-indol-2-yl)propanoate (0.089 g, 0.384 mmol) in acetonitrile (2.16 mL) was added. After addition, the reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated under reduced pressure and the residue was dissolved in dichloromethane. The organic layer was washed with 1 N HCl (1×3 mL) and then saturated aqueous NaHCO3(1×3 mL). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The crude material was purified by column chromatography on silica gel (ethyl acetate/hexane=1/1) to give ethyl 2-(5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-1H-indol-2-yl)propanoate (0.081 g, 50%). 1 H NMR (400 MHz, CDCl3) δ 8.51(s, 1H), 7.67(s, 1H), 7.23-7.19(m, 2H), 7.04-7.01(m, 3H), 6.89(d, J=0.0 Hz, 1H), 6.28(s, 1H), 6.06(s, 2H), 4.25-4.17(m, 2H), 3.91(q, I=7.2 Hz, 1H), 1.72-1.70(m, 2H), 1.61(s, 2H), 1.29(t, J=7.1 Hz, 4H), 1.13-1.11(m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][CH:18]1[CH:25]2[CH2:26][C:21]3([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:22][CH:23]([CH2:27][CH:19]1[CH2:20]3)[CH2:24]2.[Cl:36][C:37]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[C:39]([O:52][CH3:53])[C:38]=1[OH:54]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][CH:18]2[CH:19]4[CH2:20][C:21]5([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:22][CH:23]([CH2:24][CH:25]2[CH2:26]5)[CH2:27]4)=[CH:3][C:2]([C:41]2[CH:40]=[C:39]([O:52][CH3:53])[C:38]([OH:54])=[C:37]([Cl:36])[CH:42]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:16][CH2:15]1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Reactant: CC(C)(C)OC(=O)NC12CC3CC(C1)C(Nc1c(C(=O)C4CC4)cnc4ccc(Br)cc14)C(C3)C2
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(NC4C5CC6CC4CC(NC(=O)OC(C)(C)C)(C6)C5)c3c2)cc(Cl)c1O
Yield: 135.9 %

Procedure:
Following general procedure F, tert-butyl 4-[6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino]adamantylcarbamate (57 mg, 0.100 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (43 mg, 0.150 mmol) to afford the crude product (84 mg) as a brown oil: ESI MS m/z 619 [C35H40ClN3O5+H]+.
Reaction SMILES: [CH2:1]([N:8]([CH2:30][C@@H:31]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[O:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[C:19]([N+:27]([O-])=O)[CH:18]=2)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:27][C:19]1[CH:18]=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:30][C@@H:31]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[O:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][O:34]3)=[CH:12][CH:13]=2)[CH:22]=[CH:21][C:20]=1[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)c1ccc(-c2ccc(CCN(Cc3ccccc3)C[C@H](OC3CCCCO3)c3ccccc3)cc2)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccc(-c2ccc(CCN(Cc3ccccc3)C[C@H](OC3CCCCO3)c3ccccc3)cc2)cc1N
Yield: 86.3 %

Procedure:
To a solution of methyl 4′[2-[benzyl[(2R)-2-phenyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]amino]ethyl]-3-nitro-4-biphenylcarboxylate (1.44 g) in ethanol (30 ml) and water (10 ml) were added iron (406 mg) and ammonium chloride (65 mg) and stirred under reflux for 1.5 hours. The mixture was filtrated through Celite pad and evaporated. The residue was dissolved with ethyl acetate, chloroform and methanol, washed with saturated sodium bicarbonate aqueous solution and brine, dried over magnesium sulfate and evaporated to give methyl 3-amino-4′-[2-[benzyl[(2R)-2-phenyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]amino]ethyl]-4-biphenylcarboxylate (1.18 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:26][CH2:27][NH2:28])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.O.[C:30]([OH:34])(=[O:33])[CH:31]=O.Cl>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH2:26][CH2:27][NH:28][CH2:31][C:30]([OH:34])=[O:33])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:18][CH2:19]1)[N:11]=2
Reactant: O=CC(=O)O
Reactant: NCCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: O=C(O)CNCCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 2-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)-ethanamine (83 mg, 0.213 mmol) was added glyoxylic acid monohydrate (39 mg, 0.426 mmol) and DCM (1 mL) before it was stirred for 5 h at ambient temperature. The reaction mixture was concentrated before adding concentrated hydrochloric acid (2.13 mL, 4.26 mmol) and heating to reflux for 16 h. The reaction mixture was diluted with 75 mL of DCM, added to a separatory funnel, partitioned with water, washed 1 time with 50 mL of water, separated, dried over sodium sulfate, and concentrated via rotovap to give the title compound after preparatory LC. MS (ESI) m/z: Calculated: 447.1; Observed: 448.1 (M++H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2S[C:11]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:18]2[CH:19]=[C:20]([NH:24][S:25]([C:28]3[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=3[F:35])(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=2)[CH:5]=[CH:4][N:3]=1.ClC1N=C(/C=C(/C2C=C(NS(C3C(F)=CC=CC=3F)(=O)=O)C=CC=2)\[OH:45])C=CN=1.C1C(=O)N(Br)C(=O)C1.N1(C(N)=O)CCCC1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[O:45][C:11]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:18]2[CH:19]=[C:20]([NH:24][S:25]([C:28]3[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=3[F:35])(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Nc1cccc(/C(O)=C/c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCCC3)sc2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Agent: NC(=O)N1CCCC1
Agent: O=C1CCC(=O)N1Br
Product: O=S(=O)(Nc1cccc(-c2nc(N3CCCC3)oc2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F

Procedure:
Following a procedure analogous to the procedure described in Intermediate 6 using N-{3-[(Z)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]phenyl}-2,6-difluorobenzenesulfonamide (2.0 g, 4.72 mmol, NBS (0.924 g, 5.19 mmol) and 1-pyrrolidinecarboxamide (1.077 g, 9.44 mmol) heated to 90° C. for 24 h the title compound of Step A was obtained as an orange solid (0.980 g). MS-ESI m/z 518 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1.CO>C1COCC1>[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:1][C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4](=[O:20])[N:5]([CH:12]2[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]2=[O:19])[C:6]3=[O:11])=[O:27])=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Solvent: CO
Solvent: C1CCOC1
Product: O=C1CCC(N2C(=O)c3cccc(NC(=O)c4ccc(Cl)cc4)c3C2=O)C(=O)N1
Yield: 80.9 %

Procedure:
A mixture of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.2 g, 4.5 mmol) and 4-chlorobenzoyl chloride (1.1 mL, 8.8 mmol) in THF (40 mL) was heated to reflux for 15 h. To the mixture was added methanol (5 mL) to give a suspension. The suspension was filtered and washed with ether (2×10 mL) then methanol (5 mL) to give 4-chloro-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-benzamide as a white solid (1.5 g, 81% yield): mp, 261–263° C.; 1H NMR (DMSO-d6) δ 2.05–2.09 (m, 1H, CHH), 2.49–2.65 (m, 2H, CH2), 2.83–2.98 (m, 1H, CHH), 5.18 (dd, J=5.5, 12.8 Hz, 1H, NCH), 7.68–7.72 (m, 3H, Ar), 7.89–8.01 (m, 3H, Ar), 8.52 (d, J=8.2, Hz, 1H, Ar), 10.47 (s, 1H, NH), 11.16 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.99, 30.92, 48.98, 118.48, 119.06, 126.76, 129.10, 129.29, 131.46, 132.13, 136.28, 137.47, 164.08, 166.60, 167.86, 169.67, 172.72; Anal Calcd for C20H14N3O5Cl+0.2 H2O: C, 57.83; H, 3.49; N, 10.12; Cl, 8.53; H2O, 0.87. Found: C, 57.88; H, 3.33; N, 9.93; Cl, 8.53; H2O, 0.73.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([OH:15])=O)=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1.[CH2:16]([C:23]1[N:27]=[C:26]([NH2:28])[NH:25][N:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[NH2:1][C:2]1[C:3]([C:13]([NH:28][C:26]2[NH:25][N:24]=[C:23]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:27]=2)=[O:15])=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:9])([F:10])[F:11])[N:7]=1
Reactant: Nc1nc(C(F)(F)F)c(Br)nc1C(=O)O
Reactant: Nc1nc(Cc2ccccc2)n[nH]1
Product: Nc1nc(C(F)(F)F)c(Br)nc1C(=O)Nc1nc(Cc2ccccc2)n[nH]1

Procedure:
The title compound was prepared analogously to Example 23 from 3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid (Intermediate 2) and 3-benzyl-1H-1,2,4-triazol-5-amine.
Reaction SMILES: [CH3:1][N:2]1[CH:6]2[CH2:7][CH:8]([OH:10])[CH2:9][CH:3]1[CH2:4][CH2:5]2.[Li]CCCC.[Cl:16][C:17]1[N:22]=[C:21](Cl)[N:20]=[C:19]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:18]=1.CCOCC>C1COCC1>[Cl:16][C:17]1[N:18]=[C:19]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[N:20]=[C:21]([O:10][CH:8]2[CH2:9][CH:3]3[N:2]([CH3:1])[CH:6]([CH2:5][CH2:4]3)[CH2:7]2)[N:22]=1
Reactant: CN1C2CCC1CC(O)C2
Reactant: Clc1nc(Cl)nc(N2CCOCC2)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN1C2CCC1CC(Oc1nc(Cl)nc(N3CCOCC3)n1)C2
Temperature: 78 °C
Reaction time: 8 h
Yield: 41.7 %

Procedure:
In a three neck flask equipped with stirring bar under N2 atmosphere tropine (1 g, 4.24 mmol) was suspended in (anhydrous) THF (15 mL). The mixture was cooled to 78° C. and BuLi (2M in THF) (5.53 ml, 1.2 eq) was added dropwise and the mixture was allowed to warm to 25° C. over 30 minutes. To the reaction mixture 2,4-dichloro-6-morpholin-4-yl-[1,3,5]triazine (996 mg, 4.24, mmole) was added and allowed to stir overnight. For work up, ether (100 mL) was added. The organic layer was washed with water (20 mL) and brine (20 mL) and dried over MgSO4. filtered and the solvents were removed to obtain a colorless oil. Further purification by flash-chromatography using CH2Cl2/MeOH/NH3 (15:1:0.1) gave the product as white solid (600 mg, 42% yield); MS (ESI) m/z 340
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:28][N:29]([CH3:33])[C:30](Cl)=[O:31].O>C(Cl)Cl>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:7]1[C:6]2[CH:21]=[C:2]([NH:1][C:30](=[O:31])[N:29]([CH3:33])[CH3:28])[CH:3]=[CH:4][C:5]=2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]=1
Reactant: CN(C)C(=O)Cl
Reactant: CN1C(=O)CN=C(c2ccccc2F)c2cc(N)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CN(C)C(=O)Nc1ccc2c(c1)C(c1ccccc1F)=NCC(=O)N2C
Temperature: 20 °C
Reaction time: 336 h

Procedure:
4.2 g (0.015 M) of 7-amino-5-(o-fluorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one are suspended in 60 ml of absolute methylene chloride, treated with 2.1 g of powdered potassium carbonate and 1.6 ml of dimethylcarbamoyl chloride and stirred at 20° C. for 14 days. The mixture is then poured on to a mixture of ice and water, extracted with methylene chloride and the organic phase is washed 2-3 times with water, dried and sodium sulphate, filtered and concentrated. The residue is purified on a 200 g silica gel column using ethyl acetate as the eluting agent and crystallised from ethanol/petroleum ether. There is obtained 3-[5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]-1,1-dimethylurea which crystallises with 0.5 mol of ethanol and melts at 97° C. with decomposition.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].Cl[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15].C(=O)([O-])[O-].[K+].[K+]>C(O)CC(C)C.Cl[Cu]>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:14](=[O:15])[CH3:13]
Reactant: Oc1ccc2ccccc2c1
Reactant: O=C(CCl)c1ccccc1
Agent: Cl[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)CCO
Product: CC(=O)c1ccccc1Oc1ccc2ccccc2c1

Procedure:
A mixture of 2-naphthol (0.035 mole), 2-chloroacetophenone (0.026 mole), potassium carbonate (0.040 mole) and CuCl (100 mg) in isoamyl alcohol (3 ml) was refluxed overnight. Then the reaction mixture was filtered and the precipitate was washed a few times with ethyl acetate and then the filtrate was washed with a 10% aqueous sodium hydroxide solution and water. The solvent was removed by evaporation under reduced pressure and the residue was distilled under high vacuum to give a pure product in the form of a light yellow liquid.
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[C:8]([C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=3[F:22])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:5]=2[NH:4][N:3]=1.[CH3:23][Si:24]([CH3:31])([CH3:30])[CH2:25][CH2:26][O:27][CH2:28]Cl>CN(C=O)C.C(N(CC)C(C)C)(C)C>[Br:1][C:2]1[C:6]2[N:7]=[C:8]([C:15]3[C:16]([F:22])=[CH:17][CH:18]=[CH:19][C:20]=3[F:21])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:5]=2[N:4]([CH2:28][O:27][CH2:26][CH2:25][Si:24]([CH3:31])([CH3:30])[CH3:23])[N:3]=1
Reactant: Fc1cccc(F)c1-c1nc2c(Br)n[nH]c2c2ccccc12
Reactant: C[Si](C)(C)CCOCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1nc(Br)c2nc(-c3c(F)cccc3F)c3ccccc3c21
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A 50 ml round-bottomed flask equipped with a magnetic stirrer and with a septum having a top-mounted argon intake is charged with 890 mg of 3-bromo-5-(2,6-difluorophenyl)-1H-pyrazolo[4,3-c]isoquinoline in 20 ml of DMF, 2.46 ml of N,N-diisopropylethylamine and 658 μl of 2-(trimethylsilyl)ethoxymethyl chloride. After 16 h at RT, the mixture is poured into 50 ml of ice-water. The aqueous phase is extracted with 3 times 50 ml of AcOEt and the organic extracts are combined, washed with saturated NaCl solution, dried over MgSO4 and concentrated under RP. The product is purified by flash chromatography on silica gel (15-40 μm), eluting with a mixture of cyclohexane and DCM (80/20 by vol.) then (50/50 by vol.), to give on one hand 498 mg of 3-bromo-5-(2,6-difluorophenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]isoquinoline, in the form of a white gum, LC-MS-DAD-ELSD: 492 (+)=(M+H)(+), and on the other hand 200 mg of 3-bromo-5-(2,6-difluorophenyl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-pyrazolo[4,3-c]isoquinoline (white gum), LC-MS-DAD-ELSD: 492 (+)=(M+H)(+).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Br[C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[CH:10]=[O:11].O.N>[Cu].C(OCC)(=O)C>[N:1]1([C:12]2[CH:13]=[C:14]([O:15][CH3:16])[CH:7]=[CH:8][C:9]=2[CH:10]=[O:11])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COc1ccc(C=O)cc1Br
Reactant: c1c[nH]cn1
Agent: [Cu]
Agent: N
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(C=O)c(-n2ccnc2)c1
Temperature: 100 °C
Reaction time: 72 h
Yield: 11.4 %

Procedure:
To an aqueous solution (15 mL) of imidazole (5.69 g), 3-bromo-4-methoxybenzaldehyde (3.00 g) and copper powder (86 mg) were added, and the reaction solution was agitated for three days at 100° C. under nitrogen atmosphere. A concentrated ammonia water and ethyl acetate were added to the reaction mixture, and the organic layer was partitioned. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate), and 321 mg of the title compound was obtained.
Reaction SMILES: NC1C2C(=CC([C:11]3[S:12][C:13]4[C:19]([C:20]5[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=5)=[C:18]([C@H:27]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:17]([CH3:38])=[CH:16][C:14]=4[N:15]=3)=CC=2)N(C)N=1.Br[C:41]1[CH:42]=[C:43]2[C:47](=[CH:48][CH:49]=1)[N:46]([CH3:50])[N:45]=[C:44]2[NH2:51]>>[NH2:51][C:44]1[C:43]2[C:47](=[CH:48][CH:49]=[C:41]([C:11]3[S:12][C:13]4[C:19]([C:20]5[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=5)=[C:18]([C@H:27]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:17]([CH3:38])=[CH:16][C:14]=4[N:15]=3)[CH:42]=2)[N:46]([CH3:50])[N:45]=1
Reactant: Cn1nc(N)c2cc(Br)ccc21
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(N)nn(C)c4c3)sc2c1-c1ccc(Cl)cc1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(c3)c(N)nn4C)sc2c1-c1ccc(Cl)cc1

Procedure:
Prepared in a manner similar to (S)-ethyl 2-(2-(3-amino-1-methyl-1H-indazol-6-yl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate except using 5-bromo-1-methyl-1H-indazol-3-amine instead of 6-bromo-1-methyl-1H-indazol-3-amine. LCMS-ESI+: calc'd for C30H31ClN4O3S: 563.2, 565.2 (M+H+); Found: 563.3, 565.2 (M+H+).
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=O)[C:2]([O:4][CH2:5][CH3:6])=[O:3].C(OC[C:15]([O:17][CH2:18][CH3:19])=[O:16])C.[O-]CC.[Na+].Cl>C1(C)C=CC=CC=1>[CH2:18]([O:17][C:15](=[O:16])[CH:1]([O:8][CH2:9][CH3:10])[C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH3:19]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCOCC(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(OCC)C(=O)OCC
Temperature: 75 °C
Yield: 93.7 %

Procedure:
A mixture of diethyl oxalate (39.23 ml, 1.12 eq.) and ethyl ethoxyacetate (34.95 ml, 1 eq.) was added dropwise to a slurry of sodium ethoxide (18.64 g, 1.07 eq.) in toluene (100 ml) at 45-50° C. After dropping, the resulting solution was heated to 70-80° C. for 2 hrs and poured into 70 ml of 14% HCl with cooling. The resultant mixture was extracted with EA and the combined organic layers were washed with brine and dried in vacuo to give 55.86 g (93.7%) of a product.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2].C(O)(=O)C.[I:16]N1C(=O)CCC1=O>>[CH2:1]([C:3]1[C:11]([I:16])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2]
Reactant: CCc1cc2ccccn2n1
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: CCc1nn2ccccc2c1I
Yield: 75.2 %

Procedure:
2-Ethylpyrazolo[1,5-a]pyridine (4.1 g, 22 mmol) was stirred in acetic acid (2.6 g, 18 mmol) and N-iodosuccinimide (8 g, 40 mmol) was added in portions over 5 hrs. The mixture was evaporated and purified on silica gel with ethyl acetate in hexanes (0-15%) to give the desired compound (4.5 g, 93%). LCMS for C9H10IN2 (M+H)+: m/z=273.1. 1H NMR (300 MHz, DMSO-d6): δ 8.62 (m, 1 H), 7.40 (m, 1 H), 7.27 (m, 1 H), 6.82 (m, 1 H), 2.72 (m, 2 H), 1.22 (m, 3 H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([CH3:7])([SH:6])[CH3:5].CCN(CC)CC.[C:15]1(=[O:22])[O:21][C:19](=[O:20])[CH2:18][O:17][CH2:16]1>C(Cl)Cl>[CH3:5][C:4]([SH:6])([CH3:7])[CH2:3][NH:2][C:19]([CH2:18][O:17][CH2:16][C:15]([OH:22])=[O:21])=[O:20]
Reactant: CC(C)(S)CN
Reactant: O=C1COCC(=O)O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(S)CNC(=O)COCC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To an ice-cooled suspension of 1-amino-2-methyl-2-propanethiol hydrochloride (4.21 g, 29.7 mmol) in CH2Cl2 (50 mL) was added Et3N (4.56 mL, 32.7 mmol) followed by diglycolic anhydride (3.43 g, 29.6 mmol). After stirring at room temperature for 30 minutes the reaction was concentrated under vacuum. Cold 2N HCl (50 mL) was added to the residue. The mixture was extracted with EtOAc (5×30 mL). The combined organic extracts were washed with brine (30 mL) and dried over Na2SO4. Concentration and trituration with Et2O:hexane gave the title compound as a white solid (5.50 g, 84.2%). mp 81-82° C.; 1H NMR (300 MHz, CDCl3) δ 8.80 (br s, 1H), 7.48 (br s, 1H), 4.24 (s, 2H), 4.20 (s, 2H), 3.41 (d, J=6.4 Hz, 2H), 1.59 (s, 1H), 1.38 ((s, 6H); 13C NMR (75 MHz, CDCl3) δ 172.8, 170.4, 70.8, 68.4, 51.9, 44.9, 29.8; mass spectrum (API-TIS) m/z 239 (M+NH4), 222 (M+H).
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[CH:10]=[C:11]([CH2:14]O)[S:12][CH:13]=2)[O:8][CH2:7][CH2:6][O:5]1.CCN(CC)CC.S([Cl:27])(C)(=O)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:27][CH2:14][C:11]1[S:12][CH:13]=[C:9]([C:4]2([CH3:3])[O:8][CH2:7][CH2:6][O:5]2)[CH:10]=1
Reactant: CC1(c2csc(CO)c2)OCCO1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(c2csc(CCl)c2)OCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [4-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-yl]-methanol (256 mg, 1.28 mmol) in dry CH2Cl2 (5.0 mL) was treated at 0° C. with Et3N (0.23 mL, 1.64 mmol) followed by DMAP (16 mg, 0.13 mmol) and Ms-Cl (0.12 mL, 1.55 mmol). After stirring at 0° C. for 30 min and at rt for 1 h, the reaction mixture was quenched with water (10 mL), extracted with CH2Cl2 (10 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give crude 2-(5-chloromethyl-thiophen-3-yl)-2-methyl-[1,3]dioxolane (TLC:rf (1:1 EA-Hept)=0.61). A solution of the crude material in DMF (3 mL) was treated at rt with a solution of (4-nitro-2H-[1,2,3]triazole (124 mg, 1.07 mmol) in DMF (2.0 mL) pre-treated for 30 min with DIPEA (0.40 mL, 2.34 mmol). The resulting mixture was stirred for two weeks at rt. Water (10 mL), followed by EA (10 mL) were added. The org. extract was washed with water (10 mL), dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (hept to 1:1 hept-EA) gave the title compound as a yellow oil: TLC:rf (1:1 hept-EA)=0.48.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7].C1([O-])C=CC=CC=1.[Br:18][C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1.[H-].[Na+]>CN(C)C=O.O1CCCC1>[Br:18][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=1)[O:25][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7]
Reactant: O=Cc1cccc(CBr)c1
Reactant: Oc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=Cc1cccc(COc2cccc(Br)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.4 g of 3-bromomethylbenzaldehyde was dissolved in 3 ml of dimethylformamide, and the solution was added to 5 ml of a tetrahydrofuran solution of phenolate, prepared from 1.5 g of 3-bromophenol and 0.36 g of 60% oily sodium hydride. The mixture was stirred for 2 hours at room temperature. The solvent was evaporated, and water and ethyl acetate were added to the residue to extract it. The extract was worked up in a customary manner to give crude 3-(3-bromophenoxymethyl)benzaldehyde. When the same reaction as in Referential Example 12 was performed using 440 mg of the resulting aldehyde compound, 747 mg of tributyl(3-thienyl)stannane and 10 mg of tetrakis(triphenylphosphine)palladium, 341 mg (yield 77%) of 3-[3-(3-thienyl)phenoxymethyl)benzaldehyde was obtained.