Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC=CC=1C1NC(=O)C2C(=CC=CC=2)N=1.[NH2:20][C:21]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:22]=1[C:23]([NH2:25])=[O:24].[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH:36]=O>>[CH3:31][O:32][C:33]1[CH:34]=[C:35]([C:36]2[NH:25][C:23](=[O:24])[C:22]3[C:21](=[CH:29][CH:28]=[C:27]([F:30])[CH:26]=3)[N:20]=2)[CH:38]=[CH:39][CH:40]=1
Reactant: COc1cccc(C=O)c1
Reactant: NC(=O)c1cc(F)ccc1N
Agent: COc1ccccc1-c1nc2ccccc2c(=O)[nH]1
Product: COc1cccc(-c2nc3ccc(F)cc3c(=O)[nH]2)c1
Yield: 45.5 %

Procedure:
According to the preparation of compound 42, 3 (1.0 g, 6.5 mmol) and 3-methoxybenzaldehyde (34) (0.9 g, 6.5 mmol) were used to afford 51 (0.8 g, 46.8%) as pale yellow needles.
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[CH:30]1[C:35]2=[C:36]3[C:45](=[CH:46][CH:47]=[C:34]2[C:33](B(O)O)=[CH:32][CH:31]=1)[CH:44]=[C:43]1[C:38]([CH:39]=[CH:40][CH:41]=[CH:42]1)=[CH:37]3.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.O1CCOCC1>[C:24]1([C:33]2[C:34]3=[CH:47][CH:46]=[C:45]4[C:36]([CH:37]=[C:38]5[C:43]([CH:42]=[CH:41][CH:40]=[CH:39]5)=[CH:44]4)=[C:35]3[CH:30]=[CH:31][CH:32]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: OB(O)c1cccc2c1ccc1cc3ccccc3cc12
Reactant: Brc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: c1ccc(-c2cccc3c2ccc2cc4ccccc4cc23)cc1

Procedure:
913 mg (3 mmol) of tri-o-tolylphosphine and then 112 mg (0.5 mmol) of palladium(II) acetate are added to a well-stirred suspension of 7.8 g (50 mmol) of bromobenzene, 15.0 g (55 mmol) of benz[a]anthracene-4-boronic acid and 25.5 g (120 mmol) of tripotassium phosphate in a mixture of 300 ml of toluene, 100 ml of dioxane and 400 ml of water, and the mixture is subsequently heated under reflux for 16 h. After cooling, the precipitated solid is filtered off with suction, washed three times with 50 ml of toluene, three times with 50 ml of ethanol:water (1:1, v:v), three times with 100 ml of ethanol and finally dried.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:11](=[O:12])[CH:10]2[C:5](=[C:6]3[N:16]=[C:15]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:14]=[C:7]3[C:8](=[O:13])[CH2:9]2)[CH:4]=[N:3]1.[ClH:25].[O:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][Cl:34])[CH2:28][CH2:27]1>>[ClH:34].[ClH:25].[CH3:1][C:2]1([CH3:24])[C:11](=[O:12])[CH:10]2[C:5](=[C:6]3[N:16]=[C:15]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:14]=[C:7]3[C:8](=[O:13])[CH:9]2[CH2:33][CH2:32][N:29]2[CH2:30][CH2:31][O:26][CH2:27][CH2:28]2)[CH:4]=[N:3]1
Reactant: CC1(C)N=CC2=C3N=C(Cc4ccccc4)N=C3C(=O)CC2C1=O
Reactant: ClCCN1CCOCC1
Agent: Cl
Product: CC1(C)N=CC2=C3N=C(Cc4ccccc4)N=C3C(=O)C(CCN3CCOCC3)C2C1=O

Procedure:
Prepared analogous to Example 23 from 1.6 gm of 7,7-dimethyl-2-benzyl-5H,7H-imidazo[4,5-h]isoquinoline-4,6-dione and 1.2 gm of 2-morpholino-ethyl chloride hydrochloride.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@@H:29]4[CH2:33][CH2:32][NH:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@@H:29]4[CH2:33][CH2:32][N:31]([C:34](=[O:37])[CH2:35][CH3:36])[CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)N[C@@H]1CCNC1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-N-[(3R)-pyrrolidin-3-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f4) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:25])[CH:6]([CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[C:21]([O:20][C:18]([NH:17][CH2:16][CH:6]([CH2:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:5]([OH:25])=[O:4])=[O:19])([CH3:23])([CH3:24])[CH3:22]
Reactant: COC(=O)C(CNC(=O)OC(C)(C)C)CNC(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(CNC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Aqueous 2N sodium hydroxide (2.48 mL, 4.96 mmol) was added to a stirring solution of the methyl ester 13 (0.41 g, 1.24 mmol) in THF (7.5 mL) and the mixture was stirred at rt. for 24 h. Water (15 mL) was added and the solution was acidified with 5% aqueous citric acid. The mixture was extracted with CHCl3 (3×25 mL) and the combined organic extracts were washed with brine (30 mL), dried (Na2SO4), and evaporated in vacuo to leave the acid 14 as a viscous, colourless oil (280 mg).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].[NH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:27]3[CH2:28][CH2:29][CH:24]([CH2:23][NH2:22])[CH2:25][CH2:26]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: NCC1CCNCC1
Product: NCC1CCN(C(=O)Oc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)CC1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 4-aminomethylpiperidine. The crude product was purified by preparative HPLC (Method C) (32%, off-white crystals). HPLC-MS m/z=396.1 (M+1), Rt: 2.65 min. purity: 86%.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:12].[CH2:13]([O:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[Cl:27])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C=O)C.CCOCC.CCOC(C)=O.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>[CH2:13]([O:20][C:21]1[CH:22]=[C:23]([C:2]2[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=2[OH:12])[CH:24]=[CH:25][C:26]=1[Cl:27])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccc(O)c(Br)n1
Reactant: OB(O)c1ccc(Cl)c(OCc2ccccc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)c1ccc(O)c(-c2ccc(Cl)c(OCc3ccccc3)c2)n1
Temperature: 90 °C
Reaction time: 10 h

Procedure:
Stir a solution of 37 g (163 mmol) of methyl 6-bromo-5-hydroxy-2-pyridine carboxylate and 51 g (196 mmol) of [3-(benzyloxy)-4-chlorophenyl]boronic acid in 300 mL of anhydrous DMF for 15 min while bubbling with argon, then add 63.8 g (196 mmol) of anhydrous caesium carbonate and 5 g (4.33 mmol) of Pd(PPh3)4. Stir the reaction mixture for 10 h at 90° C. under argon, cool to RT, then distribute in 1 L of ether/EtOAc 1:1 mixture and 1 L of a 0.5N aqueous HCl solution. Extract the aqueous phase again with 500 mL of EtOAc/ether 1:1 mixture. Combine the organic phases and wash with 4×500 mL of water. After drying over Na2SO4 and concentration under reduced pressure, take up the precipitate with 500 mL of a 7:3 mixture of pentane/DCM, filter and wash with pentane. We thus obtain 32 g of methyl 6-[3-(benzyloxy)-4-chlorophenyl]-5-hydroxypyridine-2-carboxylate in the form of yellow ochre powder.
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12]O)=[C:10]([CH2:14][CH3:15])[C:9]2[C:4](=[CH:5][C:6]([F:18])=[C:7]([O:16][CH3:17])[CH:8]=2)[N:3]=1.[CH2:19]([C:21]1([OH:34])[C:31]2[CH:30]=[CH:29][NH:28][C:27](=[O:32])[C:26]=2[CH2:25][O:24][C:23](=[O:33])[CH2:22]1)[CH3:20]>>[CH2:19]([C:21]1([OH:34])[C:31]2[CH:30]=[C:29]3[N:28]([CH2:12][C:11]4[C:2]3=[N:3][C:4]3[CH:5]=[C:6]([F:18])[C:7]([O:16][CH3:17])=[CH:8][C:9]=3[C:10]=4[CH2:14][CH3:15])[C:27](=[O:32])[C:26]=2[CH2:25][O:24][C:23](=[O:33])[CH2:22]1)[CH3:20]
Reactant: CCc1c(CO)c(Cl)nc2cc(F)c(OC)cc12
Reactant: CCC1(O)CC(=O)OCc2c1cc[nH]c2=O
Product: CCc1c2c(nc3cc(F)c(OC)cc13)-c1cc3c(c(=O)n1C2)COC(=O)CC3(O)CC

Procedure:
(2-chloro-4-ethyl-7-fluoro-6-methoxy-3-quinolinyl)methanol is coupled with compound (M) as described in Stage 11.j. of Example 11. The resultant coupled product is cyclized according to the procedure described in Stage 11.k. A yellow solid is obtained, m.p. >275° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]/[CH:9]=[CH:10]\[CH2:11]O)=[CH:4][CH:3]=1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O-:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1.[CH2:24]([N:31]1[CH:35]=[CH:34][N:33]=[CH:32]1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>C(#N)C>[CH3:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([O-:23])(=[O:22])=[O:21])=[CH:18][CH:19]=1.[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]/[CH:9]=[CH:10]\[CH2:11][N+:33]2[CH:34]=[CH:35][N:31]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:32]=2)=[CH:4][CH:3]=1
Reactant: CCCCCCCn1ccnc1
Reactant: OC/C=C\Cc1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CC#N
Product: CCCCCCCn1cc[n+](C/C=C\Cc2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Add 3.37 g (0.01 mole) of (Z)-4-(4-chlorophenyl)-2-buten-1-ol 4-methylbenzenesulfonate (ester) and 1.50 g (0.009 mole) of 1-heptyl-1H-imidazole in 40 ml of acetonitrile and stir at room temperature for two days. Evaporate the acetonitrile and triturate the residue with hexanes and ethyl acetate to yield a solid. Recrystallize from ethyl acetate to provide the title compound.
Reaction SMILES: C([O:9][CH:10]1[CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH3:23])[C:13]=2[CH2:12][CH2:11]1)(=O)C1C=CC=CC=1.[OH-].[K+].OC1CC2C3C(=CC=C(C)C=3)NC=2CC1>>[OH:9][CH:10]1[CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH3:23])[C:13]=2[CH2:12][CH2:11]1
Reactant: Cn1c2c(c3ccccc31)CC(OC(=O)c1ccccc1)CC2
Agent: Cc1ccc2[nH]c3c(c2c1)CC(O)CC3
Agent: [K+]
Agent: [OH-]
Product: Cn1c2c(c3ccccc31)CC(O)CC2

Procedure:
The 3-hydroxy-9-methyl-1,2,3,4-tetrahydrocarbazole was prepared by hydrolysis of 9.1 g. of 3-benzoyloxy-9-methyl-1,2,3,4-tetrahydrocarbazole and 1.95 g. of potassium hydroxide in 100 ml. of 50% ethaol using the procedure described in Example 21 for the preparation of 3-hydroxy-6-methyl-1,2,3,4-tetrahydrocarbazole. There was thus otained 48 g. of 3l -hydroxy-9-methyl-1,2,3,4-tetrahydrocarbazole which melted at 104°-106°C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH2:5][CH:6]([C:29]1[CH:38]=[N:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[N:14]=1)[CH3:2].C=O.[C:42](O)(=O)C.[BH3-]C#N.[Na+]>CO>[CH2:1]([O:3][C:4](=[O:39])[CH2:5][CH:6]([C:29]1[CH:38]=[N:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N:19]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[CH3:42])[N:14]=1)[CH3:2]
Reactant: CC(=O)O
Reactant: CCOC(=O)CC(CCCCCCc1cccc(NCc2ccc(OC)cc2)n1)c1cnc2ccccc2n1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)CC(CCCCCCc1cccc(N(C)Cc2ccc(OC)cc2)n1)c1cnc2ccccc2n1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 99.2 %

Procedure:
To a solution of 22-5 (0.130 g, 0.246 mmol) in methanol (5 mL) was added paraformaldehyde (0.07 g) and acetic acid (0.071 mL, 1.23 mmol). After stirring at 50° C. for 15 minutes, NaCNBH3 (0.020 g, 0.32 mmol) was added. After stirring 2 hours the solution was concentrated in vacuo. The residue was dissolved in CHCl3 (125 mL) and washed with saturated NaHCO3, dried, and concentrated to afford 22-6 (0.132 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]#[C:13]Cl)=[CH:7][CH:6]=1.[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C)C=O.O>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]#[C:13][N:16]=[N+:17]=[N-:18])=[CH:7][CH:6]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)Cc1ccc(CC#CCl)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1ccc(CC#CN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 97.1 %

Procedure:
4-(3-Chloroprop-2-ynyl)phenylacetic acid methyl ester (5.3 g, 0.023M) was dissolved in dry dimethylformamide (30 ml) with sodium azide (1.7 g, 1.1 molar equivalents) and stirred at room temperature for 14 h. The reaction mixture was diluted with water (200 ml) and washed with dichloromethane (2×150 ml). The combined organic layers were washed with water (2×100 ml) and brine (1×100 ml) then dried (Na2SO4), filtered and concentrated in vacuo to give a residue which was purified by passage down a silica gel column, using as eluents 20% dichloromethane in hexane and finally neat dichloromethane, to give the required product (5.3 g) as a colourless oil. δ (360 MHz, CDCl3) 3.63 (2H, s, CH2CO2CH3), 3.70 (3H, s, CH2CO2CH3), 4.14 (2H, s, CH2N3), 7.24 (2H, d, J=8.4 Hz, ArH), 7.42 (2H, d, J=8.4 Hz, ArH); m/e 229 (M+).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[F:10].[F:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[C:16]([CH:18]=[O:19])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O.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>[F:10][C:3]1[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=1[C:14]1[CH:13]=[C:12]([F:11])[CH:17]=[C:16]([CH:18]=[O:19])[CH:15]=1
Reactant: O=Cc1cc(F)cc(B(O)O)c1
Reactant: COc1ccc(F)c(Br)c1
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: C1COCCO1
Solvent: O
Product: COc1ccc(F)c(-c2cc(F)cc(C=O)c2)c1
Temperature: 90 °C
Yield: 28.6 %

Procedure:
To a RBF was added 2-bromo-1-fluoro-4-methoxybenzene (1.850 mL, 9.02 mmol, Oakwood), 3-fluoro-5-formylphenylboronic acid (1667 mg, 9.93 mmol, Combi-blocks), tetrakis(triphenylphosphine)palladium (521 mg, 0.451 mmol) and potassium carbonate (3741 mg, 27.1 mmol). A condenser and septum was attached and 1,4-dioxane (24.100 mL) and water (6.03 mL) were added. The mixture was heated at 90° C. for 2 h, at which time the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2×50 mL). The organic extract was washed with brine (20 mL) and dried over MgSO4. The solution was filtered and concentrated. The residue was absorbed onto a plug of silica gel and purified by chromatography through a 50 g silica column, eluting with a gradient of 0% to 30% EtOAc in Heptane, to provide 2′,5-difluoro-5′-methoxy-[1,1′-biphenyl]-3-carbaldehyde (640 mg, 2.58 mmol, 28.6% yield) as white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.01-10.14 (m, 1H), 8.01 (q, J=1.56 Hz, 1H), 7.82 (tdd, J=1.41, 2.59, 9.76 Hz, 1H), 7.67-7.78 (m, 1H), 7.32 (dd, J=9.65, 10.42 Hz, 1H), 7.18 (dd, J=3.23, 6.46 Hz, 1H), 7.05 (td, J=3.57, 9.00 Hz, 1H) 3.83 (s, 3H).
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH:20]3C(OC3C=CC=CC=3)=O)=[N:11]2)(=O)=O)C=CC=CC=1.[OH-].[K+].Cl>C(O)C>[N:19]1([C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][N:11]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1
Reactant: O=C(Oc1ccccc1)C1CNCCN1c1nn(S(=O)(=O)c2ccccc2)c2ccccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: c1ccc2c(N3CCNCC3)n[nH]c2c1
Temperature: 25 °C
Yield: 94.9 %

Procedure:
To a suspension of 1-benzenesulfonyl-3(3-phenoxycarbonyl-4piperazinyl)-1H-indazole (31.3 g, 67.7 mmol) in ethanol (500 ml) was added 50% KOH (aq.) (100 g of KOH in 100 g H2O) at room temperature. The reaction mixture was warmed to reflux for 6.5 hours and cooled to room temperature. After adjusting the pH to about two using HCl (con., 120 ml), the volatiles were removed under reduced pressure. The remaining residue was diluted with water and removed via filtration. The aqueous filtrate was washed with EtOAc and basified to pH=8 using 50% NaOH (aq.). The product was extracted into 10:1 dichloromethane/isopropylalcohol. The combined organics were dried (MgSO4), filtered, and concentrated to give 13.0 g of desired 3-piperazin-1-yl-1H-indazole as a brown solid which was used without further purification.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:9])[CH2:6][CH2:7][NH2:8])[CH3:3].[C:10]1(=O)[CH2:13][CH2:12][CH2:11]1.C([O-])(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:2]([O:4][C:5](=[O:9])[CH2:6][CH2:7][NH:8][CH:10]1[CH2:13][CH2:12][CH2:11]1)[CH3:3]
Reactant: O=C1CCC1
Reactant: CCOC(=O)CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)CCNC1CCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 18.3 %

Procedure:
To a solution of 10.4 g (0.067 mole) of beta-alanine ethyl ester hydrochloride and 5.0 g (0.071 mole) of cyclobutanone in 200 mL of dichloromethane was added 6.1 g (0.074 mole) of sodium acetate and 21.5 g (0.101 mole) of sodium triacetoxyborohydride. The mixture was stirred at room temperature for 24 hours and then quenched by the addition of 200 mL of aqueous sodium bicarbonate. After 20 minutes, the organic layer was separated and the aqueous layer was extracted with twice with 50 mL of dichloromethane. The combined organic layers dried over anhydrous magnesium sulfate, filtered, and concentrated. Purification of the residue by silica gel chromatography, eluting with hexanes-ethyl acetate (20:80) gave 2.1 g of 3-cyclobutylamino-propanoic acid ethyl ester.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])[C:4]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25].Cl.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH:31]1[C:36]([OH:38])=[O:37].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:27]([O:26][C:24]([C:4]1[CH:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]=1[CH2:2][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH:31]1[C:36]([OH:38])=[O:37])=[O:25])[CH3:28]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccccc1C(F)(F)F
Reactant: O=C(O)C1COCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2nccs2)=NC1c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 50 %

Procedure:
A mixture of ethyl 6-(bromomethyl)-2-(thiazol-2-yl)-4-(2-(trifluoromethyl)phenyl)-1,4-dihydropyrimidine-5-carboxylate (3.8 g, 8 mmol), morpholine-3-carboxylic acid hydrochloride (2.62 g, 16 mmol) and potassium carbonate (4.2 g, 30 mmol) in ethanol (130 mL) was stirred at 25° C. for 12 hours. The resulting mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (V/V)=30/1) to give the title compound as a yellow solid (2.1 g, 50%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:19])/[CH:7]=[C:8](\[CH3:18])/[CH2:9]P(OCC)(OCC)=O)[CH3:4].[Br:20]/[C:21](=[C:24](/[C:26]1[CH:35]=[CH:34][C:33]2[C:32]([CH3:37])([CH3:36])[CH2:31][CH2:30][C:29]([CH3:39])([CH3:38])[C:28]=2[CH:27]=1)\[CH3:25])/[CH:22]=O>C1COCC1>[CH2:3]([O:5][C:6](=[O:19])/[CH:7]=[C:8](\[CH3:18])/[CH:9]=[CH:22]/[C:21](/[Br:20])=[C:24](\[C:26]1[CH:35]=[CH:34][C:33]2[C:32]([CH3:37])([CH3:36])[CH2:31][CH2:30][C:29]([CH3:39])([CH3:38])[C:28]=2[CH:27]=1)/[CH3:25])[CH3:4]
Reactant: C/C(=C(\Br)C=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: CCOC(=O)/C=C(\C)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(C)/C=C/C(Br)=C(/C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reaction time: 1 h
Yield: 38.1 %

Procedure:
290 mg of NaH (50% in mineral oil) was suspended in 8 ml of abs. THF and treated at 0° C. with 1.69 g of 4-(diethoxyphosphinyl)-3-methyl-crotonic acid ethyl ester. When the development of H2 had ceased (1/2 hour at 0° C.), 1.04 g of (E)-2-bromo-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-but-2-enal, dissolved in 8 ml of abs. THF, was added and stirring continued for 3/4 hour at 0° C. and for 1 hour at room temperature. The reaction mixture was then quenched with crashed ice and extracted with EtOEt. Twice washing with brine, drying over Na2SO4 and evaporation of the solvent afforded the crude product which was purified by flash chromatography (silica gel, hexane/AcOEt=98:2) to give 527 mg of (2E,4E,6E)-6-bromo-3-methyl-7-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-octa-2,4,6-trienoic acid ethyl ester as yellow crystals of m.p. 97°-98.5° C.
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.COC(=O)C1C=CC(OC[C:36]2[C:37]([C:42]3[CH:47]=CC=C(F)C=3)=[N:38][O:39][C:40]=2C)=NC=1.NC1CCOCC1>>[CH3:17][C:16]1[O:15][N:14]=[C:13]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[C:12]=1[CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([NH:38][CH:37]2[CH2:42][CH2:47][O:39][CH2:40][CH2:36]2)=[O:24])=[CH:5][N:6]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3cccnc3)noc2C)nc1
Reactant: COC(=O)c1ccc(OCc2c(-c3cccc(F)c3)noc2C)nc1
Agent: NC1CCOCC1
Product: Cc1onc(-c2cccnc2)c1COc1ccc(C(=O)NC2CCOCC2)cn1
Yield: 83 %

Procedure:
As described for example 89, 6-(5-methyl-3-pyridin-3-yl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (130 mg, 0.4 mmol), instead of 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester, using 4-aminotetrahydropyran instead of 2,2,2-trifluoroethylamine, was converted to the title compound (117 mg, 83%) which was obtained as an off white solid. MS: m/e=395.1 [M+H]+.
Reaction SMILES: C(OC(=O)[N:7]([C:29]1[CH:34]=[CH:33][C:32]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[CH:31][CH:30]=1)[C:8]1[C:9]2[N:10]([N:26]=[CH:27][N:28]=2)[C:11]([C:14]2[CH:25]=[CH:24][C:17]3[C:18](=[O:23])[NH:19][S:20](=[O:22])(=[O:21])[C:16]=3[CH:15]=2)=[CH:12][N:13]=1)(C)(C)C>Cl.O1CCOCC1>[N:35]1([C:32]2[CH:33]=[CH:34][C:29]([NH:7][C:8]3[C:9]4[N:10]([N:26]=[CH:27][N:28]=4)[C:11]([C:14]4[CH:25]=[CH:24][C:17]5[C:18](=[O:23])[NH:19][S:20](=[O:22])(=[O:21])[C:16]=5[CH:15]=4)=[CH:12][N:13]=3)=[CH:30][CH:31]=2)[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1
Reactant: CC(C)(C)OC(=O)N(c1ccc(N2CCOCC2)cc1)c1ncc(-c2ccc3c(c2)S(=O)(=O)NC3=O)n2ncnc12
Agent: Cl
Solvent: C1COCCO1
Product: O=C1NS(=O)(=O)c2cc(-c3cnc(Nc4ccc(N5CCOCC5)cc4)c4ncnn34)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.7 %

Procedure:
A suspension of (4-morpholin-4-yl-phenyl)-[5-(1,1,3-trioxo-2,3-dihydro-1H-1 λ6-benzo[d]isothiazol-6-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl]-carbamic acid tert-butyl ester (100 mg, 0.173 mmol) in 4M HCl (2.5 mL) in dioxane is stirred at room temperature for 2 hours. The solvent is removed under vacuum and the residue is triturated with DCM, diethyl ether and petroleum ether to afford the title compound (84 mg, 100%). 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 3.25 (4H, m), 3.85 (4H, m), 7.20 (2H, d), 7.88 (2H, d), 8.16 (1H, d), 8.24 (1H, s), 8.58 (1H, d), 8.82 (2H, s), 8.96 (1H, s), 10.31 (1H, s). LCMS: Rt 2.31 min (95.7%), m/z (APCI) 478 (M+H)+.