Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].C1(S([NH2:11])(=O)=O)C=CC=CC=1.[C:12]1([N:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19](Cl)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[C:12]1([N:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19](=[O:20])[NH2:11])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Reactant: NS(=O)(=O)c1ccccc1
Agent: [Na]
Solvent: Cc1ccccc1
Product: NC(=O)N(c1ccccc1)c1ccccc1

Procedure:
6.5 g of sodium salt of 4-(β-<2-methoxy-5-chlorobenzamido>-ethyl)-benzenesulfonamide were refluxed for 3 hours with 3.9 g of diphenylcarbamic acid chloride in 60 ml of toluene. The crude N-[4-(β-<2-methoxy-5-chlorobenzamido>-ethyl)-benzenesulfonyl]-N',N'-diphenyl-urea obtained was suction-filtered, suspended in dioxane and, after addition of 1 g of acetic acid and 1.6 g of cyclopentyl-amine, the substance was refluxed for 11/2 hours. After acidification with dilute hydrochloric acid the precipitate was separated by suction-filtration and treated with 0.5 %-ammonia. The aqueous alkaline solution was acidified and the crystals were re-crystallized from methanol. N-[4-(β-<2-methoxy-5-chloro-benzamido>-ethyl)-benzenesulfonyl] -N'-cyclopentyl-urea was obtained having a melting point of 182° - 184°C.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[C:22]([CH2:23][CH2:24][C:13]=34)=[CH:21][C:20]([CH:25]=[O:26])=[CH:19][CH:18]=5)[C:8]=2[C:27]([F:30])([F:29])[F:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:31][Mg]Br>C1COCC1>[C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[C:22]([CH2:23][CH2:24][C:13]=34)=[CH:21][C:20]([CH:25]([OH:26])[CH3:31])=[CH:19][CH:18]=5)[C:8]=2[C:27]([F:28])([F:29])[F:30])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)c1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
To 3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (Preparation 88A, 0.425 g, 1.036 mmol) in THF (5 mL), cooled to −50° C. was added methylmagnesium bromide (3.0M in diethyl ether) (0.380 mL, 1.139 mmol) over a period of 2 min. The contents were allowed to come to room temperature over a period of 30 min. The reaction mixture was re-cooled to −50° C. and 0.15 mL of methylmagnesium bromide was added and the contents allowed to come to room temperature over a period of 10 min. The reaction mixture was quenched by the slow addition of sat. aq ammonium chloride (3 mL) and extracted into EtOAc (2×15 mL). The EtOAc layer was dried over sodium sulfate and concentrated to yield 1-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)ethanol (0.44 g, 1.032 mmol, 100% yield) as a tan colored solid. LC/MS M+1=427.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[F:22][C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=1[C:30]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:31]=1[CH2:32][C:33](=[O:39])[NH:34]2>>[F:22][C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=1[C:30]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:31]=1[C:32](=[CH:20][C:3]1[NH:4][C:5]3[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]4[CH2:14][CH2:15][O:16][CH2:17][CH2:18]4)[C:7](=[O:19])[C:6]=3[C:2]=1[CH3:1])[C:33](=[O:39])[NH:34]2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2F)N1
Product: Cc1c(C=C2C(=O)Nc3cccc(-c4cccc(F)c4F)c32)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Yield: 33.3 %

Procedure:
The title compound was prepared under the same conditions as described in Example 13 with 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-(2,3-difluoro-phenyl)-1,3-dihydro-indol-2-one (prepared according to WO2002055517) as starting materials to give 2-[4-(2,3-difluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-3-methyl-5-(2-morpholin-4-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (30 mg, 33.3%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.C(N(CC)CC)C.Br.[Br:18][CH2:19][CH2:20][CH2:21][NH2:22]>C(#N)C>[Br:18][CH2:19][CH2:20][CH2:21][NH:22][C:6]1[CH:5]=[C:4]([Cl:9])[N:3]=[C:2]([Cl:1])[N:7]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: NCCCBr
Agent: Br
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Clc1cc(NCCCBr)nc(Cl)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 30.3 %

Procedure:
A solution of 2,4,6-trichloropyrimidine (100 g, 545 mmol) in acetonitrile (2000 mL) was added triethylamine (166 g, 1636 mmol) at 0° C., The reaction mixture was stirred for 5 min at rt, then 3-bromopropan-1-amine hydrobromide (119 g, 545 mmol) was added portionwise. The reaction mixture was stirred for 1 h at rt, and filtered to provide a clear solution. Purification via FC afforded the title compound as a white solid (47 g, 30% yield).
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[C:7]([C:11]([O:13]CC)=[O:12])[NH:8]2)=[CH:4][CH:3]=1.O.O.O.[OH-].[Li+]>O1CCCC1.O>[C:18]([CH2:17][CH2:16][C:6]1[C:5]2[C:9](=[CH:10][C:2]([I:1])=[CH:3][CH:4]=2)[NH:8][C:7]=1[C:11]([OH:13])=[O:12])([OH:20])=[O:19]
Reactant: CCOC(=O)CCc1c(C(=O)OCC)[nH]c2cc(I)ccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCc1c(C(=O)O)[nH]c2cc(I)ccc12
Temperature: 25 °C
Yield: 95 %

Procedure:
Ethyl 6-iodo-3-(3-ethoxy-3-oxopropyl)-1H-indole-2-carboxylate (4.15 g, 10 mmol) was dissolved in 25 ml tetrahydrofurane (THF) with stirring at rt. Then a solution of 1.26 g of lithium hydroxide trihydrate (3 equiv.) in 25 ml water was added and the resulting mixture was let to stir at rt for 24 h. After completion of the reaction THF was removed under reduced pressure and the pH was adjusted to 4-5, and the product was extracted with diethyl ether (3×30 ml). The organic layers were dried over magnesium sulfate, filtered, and evaporated to dryness to yield a light-beige-colored solid in 95-100% yield. mp. 230-232° C. 1H-NMR (DMSO-d6) δ 2.49 (m, 2H, 2′-H); 3.22 (m, 2H, 1′-H); 7.31 (dd, 1H, J=1.8 Hz, 5-H); 7.50 (d, 1H, J=8.5 Hz, 4-H); 7.74 (d, 1H, J=1.8 Hz, 7-H); 11.52 (s, 1H, NH); 12.53 (b, 2H, 2CO2H). 13C-NMR (DMSO-d6) δ 19.9 (C2′); 35.2 (C1′); 89.6 (C-6); 121.0 (C-7); 121.6 (C-3); 122.7 (C-4); 124.6 (C-2); 126.5 (C-3a); 127.9 (C-5); 137.3 (C-7a); 163.0 (2′-CO2H); 174.0 (2-CO2H). LC-MS (m/z): 377 [M-NH4+]+, 360 [M]+, 358 [M]−. Purity (LC-MS): 98%.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13]([O:17][CH3:18])(=[O:16])[C:14]#[CH:15].CN1CCOCC1>C(#N)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][CH:15]=[CH:14][C:13]([O:17][CH3:18])=[O:16])=[O:9])=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: C#CC(=O)OC
Solvent: CN1CCOCC1
Solvent: CC#N
Product: COC(=O)C=COC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
4-Nitrobenzoic acid (10 g, 59.8 mmol) and methyl propargylate (5.5 g, 65.8 mmol) were dissolved in acetonitrile (100 ml), N-methylmorpholine (3 g, 30 mmol) was added, and the mixture was stirred overnight at 40° C. The reaction mixture was concentrated under reduced pressure, and the residue was washed with ether to give the title compound (12.6 g, 50.2 mmol, 83.9%).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:19]([NH:21][CH2:22][C:23]([NH:25][C@H:26]([C:34]([NH:36][NH:37][C:38]([CH3:40])=[O:39])=[O:35])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:24])=[O:20])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[Cl:14])=[O:9].[CH3:48][C:49]([O:52][C:53]([NH:55][C@H:56]([C:65]([O:67]CC1C=CC([N+]([O-])=O)=CC=1)=O)[CH2:57][C:58]1[CH:63]=[CH:62][C:61]([OH:64])=[CH:60][CH:59]=1)=[O:54])([CH3:51])[CH3:50]>>[NH:55]([C:53]([O:52][C:49]([CH3:48])([CH3:50])[CH3:51])=[O:54])[C@H:56]([C:65]([NH:1][C@@H:2]([C:19]([NH:21][CH2:22][C:23]([NH:25][C@H:26]([C:34]([NH:36][NH:37][C:38]([CH3:40])=[O:39])=[O:35])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:24])=[O:20])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[Cl:14])=[O:9])=[O:67])[CH2:57][C:58]1[CH:59]=[CH:60][C:61]([OH:64])=[CH:62][CH:63]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)NNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H](CCCCNC(=O)OCc1ccccc1Cl)NC(=O)OC(C)(C)C
Product: CC(=O)NNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H](CCCCNC(=O)OCc1ccccc1Cl)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Yield: 81.7 %

Procedure:
Using BOC-(D)-Lys(Cl-Z)-Gly-Phe-NHNH-COCH3 (0.70 g) and BOC-Tyr-ONB (0.50 g), the desired compound (0.71 g) is obtained in a similar manner to(V) of Example 26. m.p. 196°-198° C., [α]D23 -2.0°(c=0.47, DMF), Rf1 =0.46
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[CH2:10][CH3:11]>>[C:2]1([CH:1]([OH:8])[CH:10]([CH3:11])[C:9]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)CC
Product: CCOC(=O)C(C)C(O)c1ccccc1
Temperature: -78 °C
Reaction time: 0 h
Yield: 72 %

Procedure:
50 mmol (5.10 ml) of benzaldehyde are added at -78° C. to the manganous enolate of ethyl propionate, prepared as indicated above. After stirring for 10 seconds at -78° C., the reaction medium is hydrolyzed by the dropwise addition of a saturated solution of (NH4)2SO4. After decantation, filtration on hyflo-supercel and evaporation of the solvents under vacuum, ethyl 3-phenyl-3-hydroxy-2-methylpropionate is isolated by low pressure liquid chromatography on 15 μm silica gel using cyclohexane/ethyle acetate (90/10) as the eluent. Yield=72%. Erythro/threo=61/39.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]([C:12]2[NH:13][C:14](=[O:27])[C:15]3[C:16](=[C:18]([CH2:25][CH3:26])[N:19]([CH2:21][CH2:22][O:23][CH3:24])[N:20]=3)[N:17]=2)=[CH:10][C:9](I)=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[K+].[K+].B(O)(O)[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=1>O1CCOCC1.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>[CH2:1]([O:5][C:6]1[C:11]([C:12]2[NH:13][C:14](=[O:27])[C:15]3[C:16](=[C:18]([CH2:25][CH3:26])[N:19]([CH2:21][CH2:22][O:23][CH3:24])[N:20]=3)[N:17]=2)=[CH:10][C:9]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=2)=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CCCCOc1ncc(I)cc1-c1nc2c(CC)n(CCOC)nc2c(=O)[nH]1
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
Product: CCCCOc1ncc(-c2cccc(C(F)(F)F)c2)cc1-c1nc2c(CC)n(CCOC)nc2c(=O)[nH]1
Yield: 70 %

Procedure:
5-(2-Butoxy-5-iodo-3-pyridinyl)-3-ethyl-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (Example 1) (140 mg, 0.28 mmol), K2CO3 (78 mg, 0.56 mmol) and 3-trifluoromethylboronic acid (60 mg, 0.34 mmol) were stirred together in aqueous dioxan under a nitrogen atmosphere. The mixture was immersed in a pre-heated oil bath at 120° C. for a few minutes and Pd(PPh3)4 (34 mg, 0.028 mmol) was added. The mixture was heated at reflux for 2 h and then cooled. The cooled mixture was concentrated and partitioned between ethyl acetate and water. This was then filtered through an Arbocel® pad to remove the palladium residues and the organic layer separated, washed with sodium bicarbonate solution then brine, dried (MgSO4) and concentrated. Recrystallisation from ethyl acetate gave the title compound (101 mg, 70%).
Reaction SMILES: [C:1]([CH2:6][C:7]([S:9][CH2:10][CH3:11])=[S:8])(OCC)=[O:2].C[O-].[Na+].Cl[CH2:16][C:17]#[N:18]>CO>[C:17]([C:16]1[S:8][C:7]([S:9][CH2:10][CH3:11])=[CH:6][C:1]=1[OH:2])#[N:18]
Reactant: N#CCCl
Reactant: CCOC(=O)CC(=S)SCC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCSc1cc(O)c(C#N)s1
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 52.4 %

Procedure:
192 g of ethyl α-carbethoxy-dithioacetate [Ber., Vol. 100 (1967), p. 1420] were added at 20° C. to a solution of 70 g of sodium methylate in one liter of methanol and after stirring for 5 minutes at 20° C., 76 g of chloroacetonitrile were added thereto. The mixture was stirred for 1 hour at 45° C. and 2 hours at 20° C. and after the addition of a solution of 70 g of sodium methylate in 500 ml of methanol, the mixture was stirred for 4 hours at 20° C. The mixture was evaporated to dryness under reduced pressure and the residue was dissolved in water. Toluene was added to the aqueous phase which was then acidified by addition of concentrated hydrochloric acid and the organic phase was rapidly separated by decanting. The organic phase was iced and vacuum filtered and the recovered crystals were dried to obtain 97 g of 2-cyano-3 -hydroxy-5-ethylthio-thiophene melting at 105° C. A microanalytically pure sample after crystallization from benzene melted at 105° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][C:22]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:24]=3[CH2:25][C@H:14]12>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:13]3[CH2:18][CH2:17][CH2:16][C@@H:15]4[C:19]5[CH:20]=[CH:21][C:22]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:24]=5[CH2:25][C@H:14]34)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Product: CS(=O)(=O)Nc1ccc2c(c1)C[C@H]1[C@@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1
Yield: 7 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and N-(cis-2,3,4,4a,9,9a-Hexahydro-1H-indeno[2,1-b]pyridin-7-yl)-methanesulfonamide following a procedure analogous to that described in Example 1. Yield: 7% of theory; LC (method 1): tR=2.07 min; Mass spectrum (ESI+): m/z=411 [m+H]+.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]#[C:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[CH:14]=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH:19]1[CH2:24][CH2:23][S:22][CH2:21][CH2:20]1>>[N:19]1([CH2:14][C:13]2[CH:12]=[C:11]([C:10]#[C:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[CH:18]=[CH:17][CH:16]=2)[CH2:24][CH2:23][S:22][CH2:21][CH2:20]1
Reactant: O=Cc1cccc(C#CCCN2CCOCC2)c1
Reactant: C1CSCCN1
Product: C(#Cc1cccc(CN2CCSCC2)c1)CCN1CCOCC1

Procedure:
May be prepared analogously to Example 15 using the product of Example 10 and thiomorpholine.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([S:11][CH3:12])=[N:9][CH:10]=[C:5]2[C:4](=O)[NH:3]1.P(Cl)(Cl)([Cl:16])=O.[OH-].[NH4+]>>[Cl:16][C:4]1[C:5]2[C:6](=[N:7][C:8]([S:11][CH3:12])=[N:9][CH:10]=2)[N:2]([CH3:1])[N:3]=1
Reactant: CSc1ncc2c(=O)[nH]n(C)c2n1
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Product: CSc1ncc2c(Cl)nn(C)c2n1
Temperature: 0 °C
Yield: 61 %

Procedure:
1-Methyl-6-methylsulfanyl-1,2-dihydro-pyrazolo[3,4-d]pyrimidin-3-one (2.0 g, 0.01 mol) was heated with phosphorus oxychloride (8 mL) in a sealed tube at 140° C. for 6 hours. The reaction mixture was then poured into ice-water and basified with ammonium hydroxide. The formed product was isolated by filtration. The crude product was recrystalized from a 1:1 ethanol-water mixture to give 1.3 g (61%) of pure 3-chloro-1-methyl-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine; LC/MS (m/e)=215.0 (MH+), Rt=1.94 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10]([CH3:15])=[C:9]2[C:16]([O:18]C)=[O:17])=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10]([CH3:15])=[C:9]2[C:16]([OH:18])=[O:17])=[CH:6][CH:7]=1
Reactant: COC(=O)C1=C(C)NC(=O)CC1c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1=C(C(=O)O)C(c2ccc(F)cc2)CC(=O)N1
Temperature: 60 °C
Reaction time: 16 h
Yield: 67.6 %

Procedure:
The product from Step 1 (0.200 g, 0.76 mmol, 1.00 equiv) was dissolved in MeOH (3 mL). Following addition of 2.5N NaOH (1 mL), the reaction mixture was heated to 60° C. for 6 hours, then stirred at room temperature for an additional 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed again with 1N NaOH. The aqueous phases were combined and acidified to pH˜1 with 5N HCl, and extracted twice with ethyl acetate. The combined organic extracts were washed with satd NaCl, dried over Na2SO4, and filtered. The filtrate was concentrated en vacuo and azeotroped several times with hexanes to afford 128 mg (67%) of the acid as an off-white solid. MS (ES+) m/e 250 [M+H]+.
Reaction SMILES: [C:1]([C:3]([C:10]#[N:11])=[C:4]([CH3:9])[CH:5]=[CH:6]OC)#[N:2].S(=O)(=O)(O)[OH:13]>O>[C:1]([C:3]1[C:10](=[O:13])[NH:11][CH:6]=[CH:5][C:4]=1[CH3:9])#[N:2]
Reactant: O=S(=O)(O)O
Reactant: COC=CC(C)=C(C#N)C#N
Solvent: O
Product: Cc1cc[nH]c(=O)c1C#N
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 90.6 %

Procedure:
The mixture of 4,4-dicyano-3-methyl-3-butenal dimethyl acetatal (1) and 1, 1-dicyano-4-methoxy-2-methyl-1,3-butadiene (2) produced by the preceding step was added to a stirred solution of concentrated sulfuric acid (1 09.8 g, 1.12 moles) at a rate so that the reaction contents did not exceed 30° C. The reaction mixture was then heated to 50° C. and held at that temperature for 1.5 hours. The reaction mixture was cooled to ambient temperature followed by the addition of water (150 mL). The product was filtered from the reaction mixture, washed with water (20 mL) and dried in a vacuum oven at 70° C. and full vacuum for 12 hours to give 40.7 g of 3-cyano-4-methyl-2-pyridone (3).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH3:11].F[B-](F)(F)F.[CH2:17]([O+](CC)CC)[CH3:18].[OH-].[Na+]>C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[C:5]([CH3:11])[N:6]([CH2:17][CH3:18])[N:7]=2)[CH:3]=1
Reactant: Cc1n[nH]c2ccc(Br)cc12
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCn1nc2ccc(Br)cc2c1C
Reaction time: 8 h

Procedure:
To a solution of 5-bromo-3-methyl-1H-indazole (8.44 g) in ethyl acetate (100 ml) was added dropwise triethyloxonium tetrafluoroborate (1 M dichloromethane solution, 60 ml) at room temperature, and the mixture was stirred at the same temperature overnight. To the reaction mixture was added a 1 M aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to give the title compound (1.3 g).
Reaction SMILES: [Na].N.[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([OH:20])=[C:8]([C:10]([CH2:18][CH3:19])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[OH:11])[CH:9]=1.Cl[CH:22](Cl)[C:23]([O-:25])=[O:24].[K+]>C1(C)C=CC=CC=1.O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[O:20][CH:22]([C:23]([OH:25])=[O:24])[O:11][C:10]([CH2:18][CH3:19])([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]=2[CH:9]=1
Reactant: O=C([O-])C(Cl)Cl
Reactant: CCC(O)(c1ccccc1)c1cc(Cl)ccc1O
Agent: N
Agent: [K+]
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: O
Product: CCC1(c2ccccc2)OC(C(=O)O)Oc2ccc(Cl)cc21
Reaction time: 1.5 h
Yield: 84.9 %

Procedure:
4.8 g of sodium were added in small amounts to a stirred mixture of 250 ml of condensed liquid ammonia and 100 mg of ferric nitrate and then a solution of 26.2 g of 5-chloro-α-ethyl-2-hydroxy-α-phenyl-benzene-methanol [prepared by Step A of Example 23 using ethyl bromide] with a melting point of 85° C. in 200 ml of anhydrous toluene was added thereto at 28°-30° C. over 90 minutes. The temperature was raised to disengage the ammonia and the mixture was then refluxed for 3 hours. 100 ml of toluene was added thereto followed by addition of 18 g of potassium dichloroacetate at 50° C. The mixture was refluxed overnight and 9 g of potassium dichloroacetate were added thereto. The mixture was refluxed for 2 more hours and was cooled and poured into water. The organic phase was decanted and the aqueous phase was acidified and extracted with ether. The ether extracts were washed 3 times with 500 ml of water and was extracted 3 times with 300 ml of sodium bicarbonate solution. The combined aqueous phases were washed twice with 500 ml of ether, were acidified with concentrated hydrochloric acid and extracted 3 times with 500 ml of ether. The ether extracts were washed with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure to obtain 27 g of raw 6-chloro-4-ethyl-4-phenyl-[4H]-1,3-benzodioxin-2-carboxylic acid. (mixture of two racemates diastereoisomers).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([NH:13][C:14]([C:16]1[C:20]2=[N:21][C:22]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([F:34])=[CH:31][CH:32]=4)[NH:27][N:26]=3)=[CH:23][N:24]=[C:19]2[N:18]([C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:17]=1)=[O:15])([CH3:12])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[CH2:55][CH2:56][CH2:57][S:58]([CH3:61])(=[O:60])=[O:59].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Si:1]([O:8][CH2:9][C:10]([NH:13][C:14]([C:16]1[C:20]2=[N:21][C:22]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([F:34])=[CH:31][CH:32]=4)[N:27]([CH2:55][CH2:56][CH2:57][S:58]([CH3:61])(=[O:60])=[O:59])[N:26]=3)=[CH:23][N:24]=[C:19]2[N:18]([C:35]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:17]=1)=[O:15])([CH3:11])[CH3:12])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3n[nH]c4cc(F)ccc34)nc12
Reactant: CS(=O)(=O)CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3nn(CCCS(C)(=O)=O)c4cc(F)ccc34)nc12
Temperature: 40 °C
Yield: 75.3 %

Procedure:
To a mixture of N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-(6-fluoro-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (40 mg, 0.055 mmol) in DMF (3 mL) was added 1-chloro-3-(methylsulfonyl)propane (13 mg, 0.083 mmol) followed by K2CO3 (23 mg, 0.165 mmol). The mixture was heated at 40° C. for 16 h, then cooled, poured into water and filtered to give N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-(6-fluoro-1-(3-(methylsulfonyl)propyl)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (35 mg, 76%). The crude material was used directly in the next step without purification. LCMS: 845.2 [M+H]+.