Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[NH:2]1[C:6]([C:7]#[N:8])=[C:5]([C:9]#[N:10])[N:4]=[CH:3]1.[CH3:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14]Cl>C(O)C>[CH3:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][N:2]1[C:6]([C:7]#[N:8])=[C:5]([C:9]#[N:10])[N:4]=[CH:3]1
Reactant: N#Cc1nc[nH]c1C#N
Reactant: Cc1ccccc1CCl
Agent: [Na]
Solvent: CCO
Product: Cc1ccccc1Cn1cnc(C#N)c1C#N

Procedure:
3.70 g of sodium are dissolved in 375 ml of ethanol and then 14.6 g of imidazole-4,5-dinitrile and 16.5 ml of o-methylbenzyl chloride are added and the whole is heated under reflux for 8 hours. The whole is concentrated to dryness by evaporation under reduced pressure and the residue is taken up in dichloromethane, washed in succession with water and with saturated sodium chloride solution, dried over sodium sulphate and concentrated to dryness by evaporation. The crude product is purified by chromatography on silica gel with toluene/ethyl acetate (5:1) and crystallised from ethyl acetate/hexane. 1-(o-methylbenzyl)-imidazole-4,5-dinitrile having a melting point of 80°-81° is obtained.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([NH:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:9]=[CH:10][CH:11]=1)=[O:4].[Cl:19][S:20](O)(=[O:22])=[O:21]>>[Cl:19][S:20]([C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[C:2]([F:17])([F:18])[F:1])=[CH:7][C:8]=1[CH2:12][C:13]([O:15][CH3:16])=[O:14])(=[O:22])=[O:21]
Reactant: O=S(=O)(O)Cl
Reactant: COC(=O)Cc1cccc(NC(=O)C(F)(F)F)c1
Product: COC(=O)Cc1cc(NC(=O)C(F)(F)F)ccc1S(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To methyl 2-(3-(2,2,2-trifluoroacetamido)phenyl)acetate (1.0 g, 3.8 mmol) at 0° C. was added ClSO2OH (2.3 g, 19.2 mmol). Then the mixture was stirred at room temperature for 2 hr. The mixture was poured into ice water and extracted with DCM. The combined organic layer were dried and concentrated to give the crude product methyl 2-(2-(chlorosulfonyl)-5-(2,2,2-trifluoroacetamido)phenyl)acetate. The product used directly to next reaction.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1([CH2:13][OH:14])[CH2:11][OH:12])[CH2:8]2.[C:15](O)(=[O:19])[C:16]([CH3:18])=[CH2:17].C1(C)C=CC=CC=1>C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)C1C(O)=C(C(C)(C)C)C=C(C)C=1.O>[C:15]([O:14][CH2:13][C:2]1([CH2:11][OH:12])[CH:1]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]1[CH2:4]3)[CH2:8]2)(=[O:19])[C:16]([CH3:18])=[CH2:17]
Reactant: C=C(C)C(=O)O
Reactant: OCC1(CO)C2CC3CC(C2)CC1C3
Agent: Cc1cc(Cc2cc(C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(C)C(=O)OCC1(CO)C2CC3CC(C2)CC1C3
Yield: 33.4 %

Procedure:
A mixture of 100 g of 2,2-adamantane dimethanol, 48.2 g of methacrylic acid, 20 g of toluene, 25 g of acidic ion-exchange resin Amberlist-15, and 0.1 g of 2,2′-methylenebis(6-t-butyl-p-cresol) was heated at 120° C. for 6 hours while the water being formed was azeotroped off. After the reaction mixture resumed room temperature, it was filtered through Celite. The filtrate was concentrated in vacuum. 300 g of hexane was added to the concentrate for recrystallization. The crystals were recovered and dried in vacuum, obtaining 45.0 g (yield 33%) of the target compound. The spectral data of this compound were identical with those of the product in Synthesis Example 1-2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[CH2:16][O:17][CH2:18][CH2:19][OH:20])=[CH:10][CH:9]=2)[CH:2]=1.[CH2:21]=[C:22]1[O:26][C:24](=[O:25])[CH2:23]1>O1CCCC1.C(N(CC)CC)C>[C:24]([O:20][CH2:19][CH2:18][O:17][CH2:16]/[CH:15]=[CH:14]/[C:11]1[CH:12]=[CH:13][C:8]([CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:9][CH:10]=1)(=[O:25])[CH2:23][C:22]([CH3:21])=[O:26]
Reactant: OCCOC/C=C/c1ccc(Cc2cccnc2)cc1
Reactant: C=C1CC(=O)O1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)CC(=O)OCCOC/C=C/c1ccc(Cc2cccnc2)cc1
Yield: 72 %

Procedure:
In 50 ml of tetrahydrofuran was dissolved 5.4 g of 2-[(E)-3-[4-(pyridin-3-ylmethyl)phenyl]allyloxy]ethanol, and one drop of triethylamine was added to the resulting solution. To this solution was dropwise added a mixture of 1.8 g of diketene and 4 ml of tetrahydrofuran under reflux over one hour, and then the resulting mixture was subjected to reaction at the same temperature for a further 30 minutes. Subsequently, the solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: benzene:ethyl acetate (2:1 by volume)] to obtain 5.1 g (yield 72.2%) of oily 2-[(E)-3-[4-(pyridin-3-ylmethyl)phenyl]allyloxy]ethyl acetoacetate.
Reaction SMILES: C(OC(=O)[NH:5][C:6]1[C:15]([Cl:16])=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)C.[OH-].[K+]>CCO>[Cl:16][C:15]1[C:6]([NH2:5])=[CH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: CCOC(=O)Nc1cc2ccccc2cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cc2ccccc2cc1Cl
Temperature: 25 °C

Procedure:
A mixture of 2.94 g (11.77 mmol) of N-(3-chloro-2-naphthyl)carbamic acid ethyl ester, and 7.93 g (141.2 mmol) KOH in 80 mL of EtOH is heated to reflux for 7 hours under an atmosphere of nitrogen. After cooling to room temperature, the solvent is evaporated in vacuo giving a residue to which ice is added. The mixture is extracted 3 times with 30 mL of CH2Cl2. The combined organic layers are dried over Na2SO4 and the solvents evaporated to give 3-chloro-2-aminonaphthalene as a brown solid.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)C.[CH3:8][CH:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17](=[CH2:21])[C:18](=[O:20])[CH3:19])=[CH:13][CH:12]=1)[CH3:10]>CN(C)C=O>[CH3:10][CH:9]([C:11]1[CH:12]=[CH:13][C:14]([C:17]2([C:18](=[O:20])[CH3:19])[CH2:4][CH2:21]2)=[CH:15][CH:16]=1)[CH3:8]
Reactant: C[S+](C)C
Reactant: C=C(C(C)=O)c1ccc(C(C)C)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)C1(c2ccc(C(C)C)cc2)CC1
Temperature: 0 °C
Yield: 44.7 %

Procedure:
474 mg of sodium hydride (55% in paraffin oil) is introduced into 20 ml of dimethylformamide under nitrogen at 0° C., and 1.29 g of trimethylsulfonium iodide is added. After 30 minutes at this temperature, 930 mg of ketone 46 is added in drops to 4 ml of dimethylformamide. It is stirred for 1 more hour at 0° C., then quenched with sodium chloride solution, extracted with ethyl acetate, dried on sodium sulfate and concentrated by evaporation. After chromatography on silica gel with ethyl acetate/hexane, 447 mg of title compound 47 is obtained as a colorless oil.
Reaction SMILES: [CH:1]1([S:4]([NH2:7])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[H-].[Na+].[CH3:10][C:11]1([CH3:38])[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:21](O)=[O:22])[CH:18]=2)[NH:13][CH:12]1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:31]([CH3:37])([C:33](=[O:36])[NH:34][CH3:35])[CH3:32])[CH:25]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.CS(N)(=O)=O>CN(C)C=O>[CH:1]1([S:4]([NH:7][C:21]([C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH:12]([C:24]2[CH:25]=[C:26]([NH:30][C:31]([CH3:37])([CH3:32])[C:33]([NH:34][CH3:35])=[O:36])[CH:27]=[CH:28][CH:29]=2)[C:11]([CH3:38])([CH3:10])[CH2:20]3)=[O:22])(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: CNC(=O)C(C)(C)Nc1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Reactant: NS(=O)(=O)C1CC1
Agent: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Solvent: CN(C)C=O
Product: CNC(=O)C(C)(C)Nc1cccc(C2Nc3ccc(C(=O)NS(=O)(=O)C4CC4)cc3CC2(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.9 %

Procedure:
To a suspension of cyclopropanesulfonic acid amide (108 mg, 0.89 mmol) in N,N-dimethylformamide (2 mL) was added sodium hydride (36 mg, 0.89 mmol). The resulting mixture was stirred at 25° C. for 1 h. A solution of 3,3-dimethyl-2-[3-(1-methyl-1-methylcarbamoyl-ethylamino)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (50 mg, 0.127 mmol) and 1,1′-carbonyldiimidazole (41 mg, 0.253 mmol) in N,N-dimethylformamide (1.5 mL) was stirred at 70° C. for 1 h. Then the above suspension of methanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[3-(6-cyclopropanesulfonylaminocarbonyl-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-2,N-dimethyl-propionamide (5 mg, 7%) as a white solid: LC/MS m/e calcd for C26H34N4O4S (M+H)+: 499.65, observed: 499.1.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9]2[CH:13]=[C:12]([C:14]3[C:19]([O:20]CC4C=CC(OC)=CC=4)=[CH:18][CH:17]=[CH:16][C:15]=3[O:30][CH3:31])[NH:11][N:10]=2)=[N:6][CH:7]=1>CO>[Br:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9]2[CH:13]=[C:12]([C:14]3[C:15]([O:30][CH3:31])=[CH:16][CH:17]=[CH:18][C:19]=3[OH:20])[NH:11][N:10]=2)=[N:6][CH:7]=1
Reactant: COc1ccc(COc2cccc(OC)c2-c2cc(Nc3cnc(Br)cn3)n[nH]2)cc1
Solvent: CO
Product: COc1cccc(O)c1-c1cc(Nc2cnc(Br)cn2)n[nH]1
Reaction time: 2 h
Yield: 64.4 %

Procedure:
5-Bromo-N-(5-(2-methoxy-6-(4-methoxybenzyloxy)phenyl)-1H-pyrazol-3-yl)pyrazin-2-amine (3.1 g, 6.43 mmol) is dissolved in MeOH (100 mL). HCl gas is bubbled through the reaction mixture for 20 min. The mixture is stirred for 2 h and solvent is removed under reduced pressure. The residue is redissolved in 3:1 chloroform/isopropanol (100 mL) and combined with saturated NaHCO3 solution (100 mL). The layers are separated and the aqueous layer is extracted with ethyl acetate (3×50 mL). The combined organic layers are concentrated and triturated with methanol to give 1.5 g (64%) of a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:22][CH2:21]1)[N:14]=2)[C:5](O)=[O:6].[NH:29]1[CH2:34][CH2:33][CH2:32][C@@H:31]([C:35]([OH:37])=[O:36])[CH2:30]1>>[F:1][C:2]1[CH:3]=[C:4]([C:5]([N:29]2[CH2:34][CH2:33][CH2:32][C@@H:31]([C:35]([OH:37])=[O:36])[CH2:30]2)=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:21][CH2:22]1)[N:14]=2
Reactant: O=C(O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: O=C(O)[C@@H]1CCCNC1
Product: O=C(O)[C@@H]1CCCN(C(=O)c2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)C1

Procedure:
The title compound was synthesized using the procedure described in Example 105 above, with 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzoic acid (111 mg, 0.284 mmol) and (R)-piperidine-3-carboxylic acid (44 mg, 0.341 mmol). MS (ESI) m/z: Calculated: 501.2; Observed: 502.1 (M++1).
Reaction SMILES: B(Br)(Br)Br.C1([O:10][C:11]2[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][N:12]=2)CCCC1>C(Cl)Cl>[O:10]=[C:11]1[NH:12][CH:13]=[C:14]([C:15]([O:17][CH3:18])=[O:16])[CH:19]=[C:20]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1
Reactant: COC(=O)c1cnc(OC2CCCC2)c(-c2ccccn2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)c1c[nH]c(=O)c(-c2ccccn2)c1
Reaction time: 16 h
Yield: 69.5 %

Procedure:
A solution of boron tribromide (1.0 M in CH2Cl2, 10.6 mL, 10.6 mmol) was added to a solution of the nicotinate (Step 1, 1.44 g, 4.81 mmol) in 40 mL of CH2Cl2 at −10° C. The cooling bath was removed and stirring was continued at room temperature for 16 h. The reaction mixture was neutralized with saturated NaHCO3 solution and the resultant tan precipitate was filtered and washed with copious amounts of H2O to give 0.77 g (70%) of the title compound. MS m/z: 231 (M+1).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:11]=[CH:10][C:9]([S:12][C:13]3[C:14]([C:26]([NH:28][C:29]4[S:33][N:32]=[C:31]([CH3:34])[N:30]=4)=[O:27])=[N:15][C:16]([S:19][C:20]4[N:24]([CH3:25])[CH:23]=[N:22][N:21]=4)=[CH:17][CH:18]=3)=[CH:8][CH:7]=2)[CH2:2]1.[CH3:35][C:36]([CH3:38])=O>>[CH:36]([N:1]1[CH2:2][CH:3]([O:5][C:6]2[CH:11]=[CH:10][C:9]([S:12][C:13]3[C:14]([C:26]([NH:28][C:29]4[S:33][N:32]=[C:31]([CH3:34])[N:30]=4)=[O:27])=[N:15][C:16]([S:19][C:20]4[N:24]([CH3:25])[CH:23]=[N:22][N:21]=4)=[CH:17][CH:18]=3)=[CH:8][CH:7]=2)[CH2:4]1)([CH3:38])[CH3:35]
Reactant: CC(C)=O
Reactant: Cc1nsc(NC(=O)c2nc(Sc3nncn3C)ccc2Sc2ccc(OC3CNC3)cc2)n1
Product: Cc1nsc(NC(=O)c2nc(Sc3nncn3C)ccc2Sc2ccc(OC3CN(C(C)C)C3)cc2)n1

Procedure:
Starting from 3-{[4-(azetidin-3-yloxy)phenyl]thio}-N-(3-methyl-1,2,4-thiadiazol-5-yl)-6-[(4-methyl-4H-1,2,4-triazol-3-yl)thio]pyridine-2-carboxamide obtained in Example 2 (step 2) and using acetone, the entitled compound was obtained as a yellow solid in the same method as in Example 2 (step 3) or in accordance with the method or by combining it with an ordinary method.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH:13]=[CH:14][CH2:15][O-:16])[N:10]=[CH:9]2)C=CC=CC=1.[Na+].[Cl-].[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][CH3:40])=[CH:34][CH:33]=1>>[NH:8]1[CH:12]=[C:11]([CH:13]=[CH:14][CH2:15][O:16][CH2:40][CH2:39][CH2:38][C:35]2[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=2)[N:10]=[CH:9]1
Reactant: [O-]CC=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCCc1ccc(F)cc1
Agent: [Cl-]
Agent: [Na+]
Product: Fc1ccc(CCCOCC=Cc2c[nH]cn2)cc1

Procedure:
5 mmol of sodium 3-(1-triphenylmethyl-1H-imidazol-4-yl)-2-propenolate and of 3-(4-fluorophenyl)propane chloride are treated as described in Example 5.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3=[N:12][CH:13]=[C:14]([F:16])[CH:15]=[C:10]3[N:9]([CH3:17])[C:8]2=[O:18])[CH2:4]1.Cl[C:20]1[N:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1.C(N(CC)C(C)C)(C)C>CS(C)=O.O>[F:16][C:14]1[CH:15]=[C:10]2[N:9]([CH3:17])[C:8](=[O:18])[N:7]([C@H:5]3[CH2:6][C@H:3]([NH:2][C:20]4[N:29]=[CH:28][C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:21]=4)[CH2:4]3)[C:11]2=[N:12][CH:13]=1
Reactant: Cn1c(=O)n([C@H]2C[C@H](N)C2)c2ncc(F)cc21
Reactant: Clc1ncc2ccccc2n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: Cn1c(=O)n([C@H]2C[C@H](Nc3ncc4ccccc4n3)C2)c2ncc(F)cc21
Temperature: 120 °C
Reaction time: 3 h

Procedure:
3-(Trans-3-aminocyclobutyl)-6-fluoro-1-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one hydrochloride (0.105 g, 0.385 mmol), 2-chloroquinazoline (0.076 g, 0.462 mmol), and N,N-diisopropylethylamine (0.268 mL, 1.540 mmol) were mixed in DMSO (0.5 mL). The reaction mixture was warmed to 120° C. and stirred for 3 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by silica gel column chromatography eluting with EtOAc in hexanes to yield 6-fluoro-1-methyl-3-(trans-3-(quinazolin-2-ylamino)cyclobutyl)-1H-imidazo[4,5-b]pyridin-2(3h)-one (0.054 g, 0.148 mmol, 38.5% yield) as a yellow solid. M+1: 365.1. 1H NMR (400 MHz, DMSO-d) δ ppm 2.42-2.50 (m, 2 H) 3.25-3.34 (m, 2 H) 3.35 (s, 3 H) 4.63-4.74 (m, 1 H) 5.25 (quin, J=8.51 Hz, 1 H) 7.22-7.27 (m, 1 H) 7.49 (d, J=8.41 Hz, 1 H) 7.64-7.73 (m, 2 H) 7.81 (dd, J=8.02, 0.78 Hz, 1 H) 7.99 (br. d, J=6.30 Hz, 1 H) 8.05 (t, J=2.25 Hz, 1 H) 9.15 (s, 1 H).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]=2[CH:6]=[N:5]1)[CH3:3].S(=O)(=O)(O)O.C([O-])([O-])=O.[Na+].[Na+].[N+:35]([O-])([OH:37])=[O:36]>O>[CH3:1][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[N+:35]([O-:37])=[O:36])[CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]=2[CH:6]=[N:5]1)[CH3:3]
Reactant: CCOC(=O)c1cc(-c2ccccc2)nc2c1cnn2C(C)C
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cc(-c2ccccc2[N+](=O)[O-])nc2c1cnn2C(C)C
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Ethyl 1-(1-methylethyl)-6-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (120 mg, 0.388 mmol) was dissolved in concentrated nitric acid (1.7 mL) followed by addition of concentrated sulfuric acid (0.200 mL), and the reaction mixture was stirred at room temperature. After 40 min., the reaction mixture was cooled in an ice bath and with stirring was diluted with water (3 mL) and then slowly with saturated Na2CO3 (1 mL). The reaction mixture was extracted with EtOAc (2×6 mL). The combined organic layers were concentrated in vacuo and the crude product purified by silica gel chromatography (eluent: EtOAc/Hexanes, 0-70% gradient). The product, was collected as a white solid (35 mg, 26%). LCMS E-S (M+H)=355.2. 1H NMR (400 MHz, CHLOROFORM-d) 8.46 (s, 1H), 7.99 (s, 1H), 7.94 (dd, J=1.14, 7.96 Hz, 1H), 7.76-7.81 (m, 1H), 7.73 (td, J=1.26, 7.58 Hz, 1H), 7.59-7.66 (m, 1H), 5.25 (ddd, J=6.57, 6.69, 13.52 Hz, 1H), 4.51-4.59 (m, 2H), 1.61 (d, J=6.82 Hz, 6H), 1.52 (t, J=7.07 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH2:9]([O:11][C:12](=[O:26])[CH:13]([CH2:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:14](=O)[CH3:15])[CH3:10].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:9]([O:11][C:12]([C:13]1[CH:17]=[C:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:5]([C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([Br:1])[CH:3]=2)[C:14]=1[CH3:15])=[O:26])[CH3:10]
Reactant: Nc1cccc(Br)c1
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccccc2)n(-c2cccc(Br)c2)c1C

Procedure:
m-Bromoaniline (5 mmol, 0.9 g), 3-oxo-2-(2-oxo-2-phenyl-ethyl)-butyric acid ethyl ester (5 mmol, 1.2 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The named product was recrystallized from ethanol (m.p. 111° C.-112.7° C.)
Reaction SMILES: [CH:1]1[C:6]([CH:7]([CH2:12][NH2:13])[CH2:8][C:9](O)=[O:10])=[CH:5][CH:4]=[C:3]([Cl:14])[CH:2]=1.S(Cl)(Cl)=O.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:14][C:3]1[CH:4]=[CH:5][C:6]([CH:7]2[CH2:12][NH:13][C:9](=[O:10])[CH2:8]2)=[CH:1][CH:2]=1
Reactant: NCC(CC(=O)O)c1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C1CC(c2ccc(Cl)cc2)CN1
Reaction time: 0.17 h

Procedure:
To Baclofen (1.0 g, 4.7 mmol) in CH2Cl2 (20 mL) was added thionyl chloride (0.38 mL, 5.2 mmol), and the reaction was stirred for 10 minutes. Diisopropylethylamine (1.5 mL) was added, and the mixture was worked-up to give the title compound.
Reaction SMILES: C(N1C2C(=CC(S(N)(=O)=O)=CC=2)CC1)C.[C:16]1([S:22][CH2:23][C:24]([N:26]2[C:34]3[C:29](=[CH:30][C:31]([S:35]([NH2:38])(=[O:37])=[O:36])=[CH:32][CH:33]=3)[CH2:28][CH2:27]2)=O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([S:22][CH2:23][CH2:24][N:26]2[C:34]3[C:29](=[CH:30][C:31]([S:35]([NH2:38])(=[O:37])=[O:36])=[CH:32][CH:33]=3)[CH2:28][CH2:27]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NS(=O)(=O)c1ccc2c(c1)CCN2C(=O)CSc1ccccc1
Agent: CCN1CCc2cc(S(N)(=O)=O)ccc21
Product: NS(=O)(=O)c1ccc2c(c1)CCN2CCSc1ccccc1
Yield: 57 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 53, 1-(2-(phenylthio)acetyl)indoline-5-sulfonamide (Intermediate 66, 74 mg, 0.21 mmol) was converted to the title compound (40 mg, 52%) after purification using preparative HPLC. 1H NMR (DMSO-d6) δ 7.43-7.33 (m, 6H), 7.21 (t, J=7.2. Hz, 1H), 6.90 (s, 2H), 6.36 (d, J=8.4 Hz, 1H), 3.53 (t, J=8.6 Hz, 2H), 3.39 (t, J=6.8 Hz, 2H), 3.19 (t, J=6.9 Hz, 2H), 2.94 (t, J=8.6 Hz, 2H); MS(ESI+) m/z 335.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]=[C:10]1[NH:16][CH2:15][CH2:14][N:13]([CH3:17])[C:12]2[CH:18]=[CH:19][CH:20]=[CH:21][C:11]1=2)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[Cl:22]C1C=CC(C(O)=O)=C(F)C=1>>[CH2:1]([O:3][P:4]([CH:9]=[C:10]1[NH:16][CH2:15][CH2:14][N:13]([CH3:17])[C:12]2[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:11]1=2)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(C=C1NCCN(C)c2ccccc21)OCC
Reactant: O=C(O)c1ccc(Cl)cc1F
Product: CCOP(=O)(C=C1NCCN(C)c2cc(Cl)ccc21)OCC

Procedure:
(8-chloro-1-methyl-1,2,3,4-tetrahydrobenzo[e][1,4]diazepin-5-ylidenemethyl)phosphonic acid diethyl ester was prepared in an analogous fashion to (1-methyl-1,2,3,4-tetrahydrobenzo[e][1,4]diazepin-5-ylidenemethyl)phosphonic acid diethyl ester, as described in Example 1 by replacing 2-fluorobenzoic acid with 4-chloro-2-fluorobenzoic acid.
Reaction SMILES: [CH3:1][CH:2]([CH:9]=[C:10]=[C:11]([CH3:18])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[CH2:3]C(OCC)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].CC[O:27]CC>>[CH3:1][CH:2]([CH:9]=[C:10]=[C:11]([CH3:18])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[CH2:3][OH:27]
Reactant: CCOCC
Reactant: CCOC(=O)CC(C)C=C=C(C)CCC=C(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(=C=CC(C)CO)CCC=C(C)C
Reaction time: 22 h
Yield: 77 %

Procedure:
A solution of 25 mM of the ester obtained according to letter (i) above in 13 ml of anhydrous ether was added under stirring to a solution of 0.66 (17.5 mM) of LiAlH4 in 35 ml of anhydrous ether. Stirring was carried on at room temperature for 22 h, whereupon the reaction mixture was poured onto ice. After acidification with a 10% aqueous HCl solution, extraction with ether, washing with water and drying, followed by evaporation and distillation there was obtained a fraction having b.p. 130°-7°/12 Torr (yield 77%) containing 90-95% of the desired allenic alcohol in the form of a diastereoisomeric mixture.
Reaction SMILES: [F:1][C:2]([F:39])([CH3:38])[C:3]([NH:5][C@@H:6]([CH3:37])[C@@H:7]([C:27]1[CH:36]=[CH:35][C:30]2[O:31][CH2:32][CH2:33][O:34][C:29]=2[CH:28]=1)[O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([OH:23])=O)[N:13]=[CH:12]2)=[O:4].Cl.[S:41]1(=[O:48])(=[O:47])[CH2:45][CH2:44][C@H:43]([NH2:46])[CH2:42]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCCC(C)C.CCOC(C)=O.O>[F:1][C:2]([F:39])([CH3:38])[C:3]([NH:5][C@@H:6]([CH3:37])[C@H:7]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([NH:46][C@H:43]1[CH2:44][CH2:45][S:41](=[O:48])(=[O:47])[CH2:42]1)=[O:23])[N:13]=[CH:12]2)[C:27]1[CH:36]=[CH:35][C:30]2[O:31][CH2:32][CH2:33][O:34][C:29]=2[CH:28]=1)=[O:4]
Reactant: C[C@H](NC(=O)C(C)(F)F)[C@H](Oc1ccc2c(cnn2-c2cccc(C(=O)O)c2)c1)c1ccc2c(c1)OCCO2
Reactant: N[C@H]1CCS(=O)(=O)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCCC(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@H](NC(=O)C(C)(F)F)[C@H](Oc1ccc2c(cnn2-c2cccc(C(=O)N[C@H]3CCS(=O)(=O)C3)c2)c1)c1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
3-(5-((1R,2S)-2-(2,2-difluoropropanamido)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)propoxy)-1H-indazol-1-yl)benzoic acid (I4) (106 mg, 0.20 mmol), (S)-(−)-tetrahydrothiophene-3-amine-1,1-dioxide hydrochloride (I6) (40 mg, 0.23 mmol) and HBTU (95 mg, 0.25 mmol) in DMF (2 mL) was treated with DIEA (0.138 mL, 0.79 mmol). The reaction mixture was stirred at ambient temperature for 45 minutes. Water (10 mL) was added, the formed suspension was stirred for 1 hour. The solid was collected by filtration, washed with water and further purified by HPLC using an Kromasil 100-10-C18, 50×250 mm column, an 30 min gradient from 50% to 90% MeCN in water with flow=40 mL/min and UV=254 nm to collect fractions. Fractions containing the product was freeze dried, the resulting solid was dissolved in MeOH and iso-Hexane was added. The biphasic mixture was evaporated to give an solid that was suspended in iso-Hexane containing a small volume of EtOAc, the suspension was stirred at ambient temperature for 18 hours. The crystalline solid was collected by filtration, washed with iso-Hexane and dried. Yield 77 mg (59%).