Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][OH:9])[N:5]=[CH:4][C:3]=1[C:10]#[N:11].[C:12]1([C:18](Cl)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[NH2:1][C:2]1[N:6]([CH2:7][CH2:8][O:9][C:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:5]=[CH:4][C:3]=1[C:10]#[N:11]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#Cc1cnn(CCO)c1N
Solvent: c1ccncc1
Product: N#Cc1cnn(CCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c1N
Temperature: 60 °C
Reaction time: 6 h
Yield: 98 %

Procedure:
To a suspension of 5-amino-1-(2-hydroxyethyl)pyrazole-4-carbonitrile (10 g, 65.7 mmol) and pyridine (100 ml) was added triphenylmethyl chloride (22.3 g, 78.9 mmol) at room temperature. After stirring at 60° C. for 6 hours, the reaction mixture was concentrated in vacuo. To the residue were added tetrahydrofuran and brine, and the separated organic layer was washed with brine. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was triturated with ethyl acetate to give 5-amino-1-[2-(trityloxy)ethyl]pyrazole-4-carbonitrile (25.4 g) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13]C(=O)C3C=CC=CC=3)=[N:9]2)[CH2:4][O:3]1.O.[OH-].[Na+]>CO>[CH3:1][C:2]1([CH3:22])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH2:13])=[N:9]2)[CH2:4][O:3]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(NC(=O)c3ccccc3)n2)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-[1-((R)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-benzamide (150 mg, 0.5 mmol) was dissolved in methanol (2 ml), and water (1 ml) was added in one portion. The mixture was stirred at room temperature for 30 minutes. NaOH (120 mg, 3 mmol) was added. The mixture was stirred at reflux for 18 h. UPLC indicated the conversion was ˜20%, so the mixture was agitated for another 20 h. The conversation was still ˜40%. Another portion of NaOH (120 mg, 3 mmol) was added into the mixture. The mixture was agitated at reflux for another 20 h. The conversation was ˜70%. No further workup.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([C:18]2[C:19]3[C:20](=[N:24][O:25][C:26]=3[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:33])[CH:21]=[N:22][N:23]=2)[N:9]=[N:8]1.C(#N)C>[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Mo].O>[NH2:24][C:20]1[C:19]([C:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])=[O:25])=[C:18]([C:10]2[N:9]=[N:8][N:7]([CH2:6][C:5]3[CH:34]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:36]=[C:3]([C:2]([F:41])([F:1])[F:42])[CH:4]=3)[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:23]=[N:22][CH:21]=1
Reactant: FC(F)(F)c1cc(Cn2nnc(-c3nncc4noc(-c5ccccc5Cl)c34)c2-c2ccccc2)cc(C(F)(F)F)c1
Agent: [Mo]
Agent: [C-]#[O+]
Solvent: CC#N
Solvent: O
Product: Nc1cnnc(-c2nnn(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2-c2ccccc2)c1C(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.4 %

Procedure:
Combine 4-[1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazol-4-yl]-3-(2-chloro-phenyl)-isoxazolo[3,4-d]pyridazine (79 mg, 0.1314 mmol), acetonitrile (2.5 mL), water (131 μL), and molybdenum hexacarbonyl (17.4 mg, 0.066 mmol), and heat to 73° C. After 4 hours, cool to RT. Pour the mixture through a plug of Celite® (1 cm) and silica gel (2 cm). Concentrate the dark liquid to 1.5 mL and apply to a 2 mm chromatotron plate with CH2Cl2 and EtOAc and elute with a EtOAc/hexanes gradient to provide 70 mg of a pink solid. Exact Mass 602.1: mass spectrum (IS): m/z=603.0 (M+1), 601.0 (M−1). 1H NMR (250 MHz, CDCl3) 8.62 (s, 1H), 7.75 (s, 1H), 7.45-7.32 (m, 3H), 7.28-7.10 (m, 3H), 7.00-6.80 (m, 3H), 6.10 (s, 2H).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH3:9])=[C:6]([CH3:10])[N:5]=[C:4]([NH2:11])[N:3]=1.[CH2:12]([NH2:17])[CH2:13][CH2:14][CH2:15][CH3:16]>O1CCOCC1>[NH2:11][C:4]1[N:3]=[C:2]([NH:17][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:7]([CH2:8][CH3:9])=[C:6]([CH3:10])[N:5]=1
Reactant: CCc1c(C)nc(N)nc1Cl
Reactant: CCCCCN
Solvent: C1COCCO1
Product: CCCCCNc1nc(N)nc(C)c1CC
Reaction time: 17 h
Yield: 58.1 %

Procedure:
A mixture of 4-chloro-5-ethyl-6-methylpyrimidine-2-ylamine (400 mg, 33 mmol), amylamine (1.35 ml) and dioxane (5 ml) was kept at 95-100° C. for 17 hours. The procedure according to pro-treatment of Example 23 was carried out to give the object compound (301 mg, 58.1%).
Reaction SMILES: ClC(OCC)=O.N1C=CC=C1.[C:12]([O:16][C:17]([N:19]1[CH:23]([C:24]2[C:28]([NH2:29])=[C:27]([C:30]#[N:31])[N:26](C(OCC)=O)[CH:25]=2)[CH:22]2[O:37][C:38]([CH3:41])([CH3:40])[O:39][CH:21]2[CH:20]1[CH2:42][S:43][CH3:44])=[O:18])([CH3:15])([CH3:14])[CH3:13].N12CCCN=C1CCCCC2>>[C:12]([O:16][C:17]([N:19]1[CH:23]([C:24]2[C:28]([NH2:29])=[C:27]([C:30]#[N:31])[NH:26][CH:25]=2)[CH:22]2[O:37][C:38]([CH3:41])([CH3:40])[O:39][CH:21]2[CH:20]1[CH2:42][S:43][CH3:44])=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CCOC(=O)n1cc(C2C3OC(C)(C)OC3C(CSC)N2C(=O)OC(C)(C)C)c(N)c1C#N
Agent: CCOC(=O)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1cc[nH]c1
Product: CSCC1C2OC(C)(C)OC2C(c2c[nH]c(C#N)c2N)N1C(=O)OC(C)(C)C

Procedure:
The corresponding cyanomethylamino compound is then obtained by reaction, for example, with amino acctonitrile. This intermediate is then converted to the ester form by reaction with an esterification agent such as ethyl chloroformate. This intermediate is then cyclized to the corresponding pyrrol compound, 4-(4-amino-5-cyano-1-ethoxycarbonyl-1H-pyrrol-3-yl)-2,2-dimethyl-6-methylsulfanylmethyl-tetrahydro-[1,3]dioxolo[4,5-c]pyrrole-5-carboxylic acid tert-butyl ester using, for example, 1,8-diazabicyclo[5.4.0]undec-7-ene. This compound was then converted to the corresponding amino derivative by removal of the ethoxycarbonyl substituent to produce 4-(4-amino-5-cyano-1H-pyrrol-3-yl)-2,2-dimethyl-6-methylsulfanylmethyl-tetrahydro-[1,3]dioxolo[4,5-c]pyrrole-5-carboxylic acid tert-butyl ester. This compound, in turn was then reacted with formamidine acetate to form the target compound.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([O:20]CC4C=CC=CC=4)=[C:16]([F:19])[CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.[Pd]>[F:19][C:16]1[CH:17]=[C:18]2[C:13]([CH:12]=[CH:11][N:10]2[S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])=[CH:14][C:15]=1[OH:20]
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(OCc3ccccc3)c(F)cc21
Agent: [Pd]
Solvent: CCO
Product: O=S(=O)(c1ccccc1)n1ccc2cc(O)c(F)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
Pd/C 10 wt. % (250 mg, 0.236 mmol was added to a solution of N-benzenesulfonyl-5-benzyloxy-6-fluoroindole (Intermediate 27, 250 mg, 6.55 mmol) in ethanol (100 mL). The reaction mixture was stirred under an atmosphere of hydrogen (1 atm) at room temperature for 2 hours, filtered and evaporated. The crude material was purified by flash chromatography on silica gel using 0.5% MeOH/DCM as the eluent to give the title compound (1.79 g) as a white solid. MS m/z 292 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[N:4]([C:12]1[CH:17]=[CH:16][C:15](B2OC(C)(C)C(C)(C)O2)=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11].Br[C:32]1[CH:37]=[N:36][C:35]([Br:38])=[CH:34][N:33]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C.[Cl-].[Na+].O>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>[Br:38][C:35]1[N:36]=[CH:37][C:32]([C:15]2[CH:14]=[CH:13][C:12]([N:4]([C:3]3[CH:27]=[CH:28][CH:29]=[CH:30][C:2]=3[CH3:1])[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[CH3:11])=[CH:17][CH:16]=2)=[N:33][CH:34]=1
Reactant: Cc1ccccc1N(c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)c1ccccc1C
Reactant: Brc1cnc(Br)cn1
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: [Cl-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccccc1N(c1ccc(-c2cnc(Br)cn2)cc1)c1ccccc1C
Temperature: 80 °C
Yield: 53 %

Procedure:
2-methyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-(o-tolyl)aniline (Compound 12) (3.3 g, 8.3 mmol), 2,5-dibromopyrazine (4.27 g, 16 mmol), Pd(PPh3)4 (0.46 g, 0.4 mmol), K2CO3 (2.21 g, 16 mmol) in dioxane/water (100 mL/16 mL), was degassed and heated at about 80° C. overnight. The resulting mixture was worked up with ethyl acetate/brine, dried over Na2SO4, loaded on silica gel, purified by flash column using eluents of hexanes to hexanes/dichloromethane 9:1 to 6:1 to 4:1). The desired fraction was collected, and a yellow solid (Compound 13) was obtained after removal of solvents (1.9 g, in 53% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]#[C:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1[NH2:10])=[O:4].[N:17]1([CH:22]2[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]2)[CH:21]=[CH:20][N:19]=[N:18]1.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]#[C:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1[NH:10][CH:25]1[CH2:24][CH2:23][CH:22]([N:17]2[CH:21]=[CH:20][N:19]=[N:18]2)[CH2:27][CH2:26]1)=[O:4]
Reactant: O=C1CCC(n2ccnn2)CC1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1NC1CCC(n2ccnn2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-amino-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (example 9) (0.387 g, 1.6 mmol) and 4-[1,2,3]triazol-1-yl-cyclohexanone (0.27 g, 1.6 mmol) in dry THF is added dibutyltin dichloride (0.024 g, 0.080 mmol) followed by phenylsilane (0.276 ml, 2.2 mmol). The mixture is stirred overnight at room temperature. Solvent is evaporated under reduced pressure, and the residue is diluted with ethyl acetate. The organic layer is washed with water and brine, dried with sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel using gradient 50-100% ethyl acetate in hexane to afford 5-(3,3-dimethyl-but-1-ynyl)-3-(4-[1,2,3]triazol-1-yl-cyclohexylamino)-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[Cl:10][C:11]1[N:12]=[CH:13][C:14]2[CH2:20][NH:19][CH2:18][CH2:17][C:15]=2[N:16]=1.C(N(CC)CC)C>C1COCC1>[Cl:10][C:11]1[N:12]=[CH:13][C:14]2[CH2:20][N:19]([C:1]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)=[O:8])[CH2:18][CH2:17][C:15]=2[N:16]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: Clc1ncc2c(n1)CCNC2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(c1cccnc1)N1CCc2nc(Cl)ncc2C1
Temperature: 25 °C
Yield: 87.9 %

Procedure:
A solution of nicotinoyl chloride (0.230 g, 1.62 mmol) in anhydrous THF (1.5 mL) was treated with 2-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (0.250 g, 1.47 mmol) and triethylamine (0.3 g, 3.0 mmol) and subsequently allowed to stir at room temperature. After 4 hours the reaction was quenched with deionized H2O (10 mL). Following dilution with EtOAc (10 mL) the reaction mixture was washed twice with brine and once with saturated Na2HCO3(aq). The combined aqueous layers were then washed once with EtOAc. The combined organic layers were dried over anhydrous Na2SO4(s), filtered and then concentrated in vacuo. Purification over silica using a Methanol/CHCl3 gradient afforded the desired product in 87.9% yield (0.356 g, 1.3 mmol).
Reaction SMILES: [C:1]([S:14](F)(=[O:16])=[O:15])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[O-]S([O-])=O.[Na+:22].[Na+].C([O-])(O)=O.[Na+].FC(F)(S([O-])(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.[Na+]>CCO>[F:3][C:1]([F:2])([S:14]([O-:16])=[O:15])[C:4]([F:5])([F:6])[C:7]([F:9])([F:8])[C:10]([F:13])([F:12])[F:11].[Na+:22]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: O=C([O-])O
Agent: O=S(=O)([O-])C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: O=S([O-])[O-]
Solvent: CCO
Product: O=S([O-])C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 60 °C
Yield: 65 %

Procedure:
A three necked 500 ml reaction flask, equipped with a reflux condenser, a stirrer, a thermometer and a heating mantle was charged with 30.2 g of C4F9SO2F (0.1 moles), 15.1 g Na2SO3 (0.12 moles), 16.8 g NaHCO3 (0.2 moles), 50 g EtOH and 50 g DI-water. The reaction mixture was degassed 3 times using nitrogen and aspirator vacuum. The mixture was then heated to 60° C. under a nitrogen atmosphere for 16 hours. A slightly yellow reaction mixture with a pH of 6.5 was obtained. EtOH was stripped off under reduced pressure using an aspirator vacuum (20 torr and temperature between 60-85° C.) and the temperature was kept below 110° C. in order to avoid thermal decomposition of the sulfinate product. 19F analysis indicated a yield of 65% sodium perfluorobutyl sulfinate and 25% sodium perfluorobutyl sulfonate.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8][CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:6]1)(=[O:3])[CH3:2].[BH4-].[Na+].C[OH:25]>>[C:1]([NH:4][CH:5]1[CH:11]([OH:25])[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8][CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CO
Reactant: CC(=O)NC1Cc2ccccc2OC(c2ccccc2)C1
Agent: [BH4-]
Agent: [Na+]
Product: CC(=O)NC1CC(c2ccccc2)Oc2ccccc2C1O
Reaction time: 5 h
Yield: 28 %

Procedure:
797 mg (2.70 m moles) of 4-acetamido-2-phenyl-2,3,4,5-tetrahydro-1-benzoxepin (compound R3a of Reference Example) was dissolved in 50% methanol, 411 mg (10.8 m moles) of sodium borohydride was added to the solution at -50° C. to -20° C., and the whole was stirred for 5 hours. The reaction mixture was concentrated, and ice water was added to the concentrate. The mixture was extracted with methylene chloride, and the extract was washed with water and dried with anhydrous magnesium sulfate. After filtrating off the magnesium sulfate, the filtrate was concentrated to obtain a residue, which was then applied to a silica gel column, and eluted with a mixture of methylene chloride/methanol (98:2) to obtain stereoisomers R4a (22.5 mg; yield 28.0%) and R4b (485 mg; yield 60.4%) of the desired compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]2[CH2:14][CH2:15][NH2:16])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[NH:24]1[CH:28]=[C:27]([CH2:29][C:30](Cl)=[O:31])[N:26]=[CH:25]1>C(Cl)(Cl)Cl.O>[CH3:2][O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]2[CH2:14][CH2:15][NH:16][C:30](=[O:31])[CH2:29][C:27]2[N:26]=[CH:25][NH:24][CH:28]=2)=[CH:6][CH:5]=1
Reactant: COc1ccc2cccc(CCN)c2c1
Reactant: O=C(Cl)Cc1c[nH]cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1ccc2cccc(CCNC(=O)Cc3c[nH]cn3)c2c1
Temperature: 25 °C

Procedure:
0.01 mol of 2-(7-methoxynaphth-1-yl)ethylamine hydrochloride is dissolved in 60 ml of a chloroform/water mixture, and 0.025 mol of potassium carbonate is added under magnetic agitation. The mixture is cooled, and 0.012 mol of 4-imidazoleacetyl chloride hydrochloride is added dropwise. The agitation is maintained for 30 minutes at room temperature and the chloroform phase is evaporated to dryness. The residue is then recrystallized.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:14]([CH3:15])[C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][C:18]=1[Cl:26])=[O:5])C.[OH-].[Na+].Cl>>[Cl:26][C:18]1[CH:19]=[C:20]([CH:23]([CH3:25])[CH3:24])[CH:21]=[CH:22][C:17]=1[NH:16][C:7]1[C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:13]=2[N:14]([CH3:15])[C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1c(Nc2ccc(C(C)C)cc2Cl)c2cnccc2n1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)c1ccc(Nc2c(C(=O)O)n(C)c3ccncc23)c(Cl)c1
Temperature: 25 °C
Yield: 103.2 %

Procedure:
A solution of 3-(2-chloro-4-isopropyl-phenylamino)-1-methyl-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (230 mg, 0.62 mmol) and 1M NaOH (0.74 ml, 7.4 mmol) in IMS (5 ml) was heated at 60° C. for 3 hours. The reaction mixture was cooled to ambient temperature then acidified to pH 5 using 1M HCl. The fine yellow suspension was filtered to provide the title compound as a yellow solid (220 mg, 100%). LCMS (method B): RT=2.53 min, M+H+=344.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][C:10]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[C:20]2[C:11]=1[O:12][C:13]1[C:14]([CH2:30][C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:32])=[C:15]([O:28][CH3:29])[CH:16]=[CH:17][C:18]=1[C:19]2([CH3:27])[CH3:26].[CH2:41]([O:48][C:49]([NH:51][C@H:52]([C:54](O)=[O:55])[CH3:53])=[O:50])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(=O)(O)[O-].[Na+]>>[CH2:41]([O:48][C:49]([NH:51][C@H:52]([C:54]([NH:8][CH2:9][C:10]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[C:20]2[C:11]=1[O:12][C:13]1[C:14]([CH2:30][C:31]([O:33][CH2:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)=[O:32])=[C:15]([O:28][CH3:29])[CH:16]=[CH:17][C:18]=1[C:19]2([CH3:27])[CH3:26])=[O:55])[CH3:53])=[O:50])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COc1ccc2c(c1CN)Oc1c(ccc(OC)c1CC(=O)OCc1ccccc1)C2(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1CNC(=O)[C@H](C)NC(=O)OCc1ccccc1)Oc1c(ccc(OC)c1CC(=O)OCc1ccccc1)C2(C)C
Temperature: 25 °C
Reaction time: 36 h
Yield: 81.1 %

Procedure:
A solution of 0.35 g of benzyl 5-aminomethyl-3,6-dimethoxy-9,9-dimethylxanthene-4-acetate trifluoroacetate in 70 ml of acetonitrite was cooled to 0° and treated with 0.15 g of N-benzyloxycarbonyl-L-alanine. A total of 0.36 9 of O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate and 0.17 g of sodium bicarbonate were added in several portions. The reaction mixture was stirred for a total of 36 hours and thereby warmed to room temperature, whereupon it was diluted with ice-water and extracted with methylene chloride. The organic phase was washed with water, dried over magnesium sulphate and concentrated. The residue was chromatographed several times over silica gel in chloroform/methanol, whereby 0.33 g of benzyl 5-[(N-benzyloxycarbonyl-L-alanyl)aminomethyl]-3,6-dimethoxy-9,9-dimethylxanthene-4-acetate was obtained as a colourless foam; IR 1728, 1673, 1605, 1494 cm-1.
Reaction SMILES: [OH:1][C@H:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][C:4](OC)=[O:5].O.[NH2:15][NH2:16]>CO>[OH:1][C@H:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][C:4]([NH:15][NH2:16])=[O:5]
Reactant: NN
Reactant: COC(=O)C[C@H](O)c1ccccc1
Solvent: O
Solvent: CO
Product: NNC(=O)C[C@H](O)c1ccccc1
Temperature: 70 °C
Yield: 74 %

Procedure:
In a 1 liter four-necked flask were charged 200 g (1.11 mol) of methyl (S)-3-hydroxy-3-phenylpropionate (optical purity: 87%e.e.), 77.8 g (1.56 mol) of hydrazine monohydrate, and 400 ml of methanol, and the mixture was heated at 70° C. for 3 hours. The reaction mixture was cooled to 5° C. with ice-water, followed by filtration. The collected crystals were dissolved in 4.7 liter of methanol while hot and cooled to 5° C. The crystals thus precipitated were collected by filtration and dried to give 148 g (74%) of the title compound. Melting point: 179.5° C. Optical purity: >99.9%e.e.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:5]([OH:7])=[O:6].N([O-])=[O:16].[Na+].S(=O)(=O)(O)O>Cl.C(O)(=O)C>[OH:16][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:5]([OH:7])=[O:6]
Reactant: O=N[O-]
Reactant: COC(=O)c1ccc(C(=O)O)cc1N
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1ccc(C(=O)O)cc1O
Reaction time: 0.5 h
Yield: 53 %

Procedure:
To 3-amino-4-methoxycarbonylbenzoic acid (1.95 g, 10 mmol) suspended in 3 M hydrochloric acid (12.5 mL) and acetic acid (20 mL), an aqueous solution (20 mL) of sodium nitrite (0.69 g, 10 mmol) was added at −10° C., and the resulting solution was stirred for 30 minutes. The solution was added to 10% aqueous sulfuric acid (30 mL) at 0° C., and the resulting reaction mixture was heated with reflux for 1 hour. The desired product was extracted with ethyl acetate, and the extract was dried over magnesium sulfate and purified by silica gel column chromatography to give 1.04 g of the desired product as a white solid (yield 53%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[CH3:11][C:12]1[CH:20]=[C:19]2[C:15]([CH:16]=[CH:17][NH:18]2)=[CH:14][CH:13]=1.[OH-].[Na+]>O>[CH3:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16]([CH:8]=[O:9])=[CH:17][NH:18]2)=[CH:14][CH:13]=1
Reactant: Cc1ccc2cc[nH]c2c1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc2c(C=O)c[nH]c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Phosphorus oxychoride (3.2 ml, 34.3 mmol) was added dropwise to dimethyl formamide (26 ml) over ten minutes at ~5° C. To this solution was added a dimethyl formamide (32 ml) solution of 6-methylindole (3.307 g, 25.2 mmol) over 10 minutes. The mixture was slowly warmed to ambient temperature, then heated to 50° C. for four hours. The mixture was cooled to ambient temperature, then poured onto ice (500 g). The aqueous solution was left to stand for 16 hours. Sodium hydroxide (6.0 g) was dissolved in water (22 ml) and added dropwise to the brown solution. The resultant yellow precipitate was boiled and filtered hot. It was left to cool to room temperature, then to 5° C. The precipitate was filtered off and washed with water (800 ml), dried at the pump, then further dried in vacuo at 50° C. for 16 hours to yield a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[CH:14][N:13]([CH3:16])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[CH3:17][N:18]([CH3:50])[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[C:25](=[O:29])[N:24]([C:30]1[CH:40]=[CH:39][CH:38]=[C:37](B3OC(C)(C)C(C)(C)O3)[C:31]=1[CH2:32][O:33]C(=O)C)[CH:23]=[CH:22]2.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Li+]>COCCOC.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>[CH3:17][N:18]([CH3:50])[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[C:25](=[O:29])[N:24]([C:30]1[CH:40]=[CH:39][CH:38]=[C:37]([C:2]3[CH:3]=[C:4]([NH:10][C:11]4[CH:15]=[CH:14][N:13]([CH3:16])[N:12]=4)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=3)[C:31]=1[CH2:32][OH:33])[CH:23]=[CH:22]2
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1ccc2cc(N(C)C)ccc2c1=O
Reactant: Cn1ccc(Nc2cc(Br)cn(C)c2=O)n1
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: [Li+]
Solvent: O
Solvent: COCCOC
Product: CN(C)c1ccc2c(=O)n(-c3cccc(-c4cc(Nc5ccn(C)n5)c(=O)n(C)c4)c3CO)ccc2c1
Reaction time: 3 h
Yield: 44.1 %

Procedure:
5-Bromo-1-methyl-3-(1-methyl-1H-pyrazol-3-ylamino)-1H-pyridin-2-one (47 mg, 0.17 mmol), Acetic acid 2-(6-dimethylamino-1-oxo-1H-isoquinolin-2-yl)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl ester (77 mg, 0.17 mmol), tetrakis(triphenylphosphine)palladium(0) (19 mg, 0.016 mmol), and sodium carbonate (53 mg, 0.50 mmol) were dissolved in 2 mL 1,2-dimethoxyethane and 1 mL water. This was microwaved at 120° C. for 30 minutes. This was partitioned between ethylacetate and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. This was dissolved in 3 mL tetrahydrofuran, 1.5 mL methanol, and 1.5 mL water. 1M aq. Lithium hydroxide solution (0.5 mL, 0.5 mmol) was added. This stirred for 3 hours. This was partitioned between ethylacetate and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by preparative TLC (elution with 5% methanol/dichloromethane) to yield 6-Dimethylamino-2-{2-hydroxymethyl-3-[1-methyl-5-(1-methyl-1H-pyrazol-3-ylamino)-6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}-2H-isoquinolin-1-one (37 mg, 0.075 mmol). MS (ESI) 497.1 (M+H)+.