Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)[CH2:4][CH2:3]1.[CH3:19][N:20]([CH3:40])[C:21]([C@@H:23]1[C@H:28]([NH:29][C:30]2[C:35]([Cl:36])=[CH:34][N:33]=[C:32]([NH2:37])[C:31]=2[NH2:38])[C@@H:27]2[CH2:39][C@H:24]1[CH:25]=[CH:26]2)=[O:22].C([O-])(=O)C.[NH4+]>>[CH3:19][N:20]([CH3:40])[C:21]([C@@H:23]1[C@H:28]([NH:29][C:30]2[C:35]([Cl:36])=[CH:34][N:33]=[C:32]3[NH:37][C:15]([C:14]4[CH:17]=[CH:18][C:11]([O:10][CH2:9][CH2:8][N:5]5[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]5)=[CH:12][CH:13]=4)=[N:38][C:31]=23)[C@@H:27]2[CH2:39][C@H:24]1[CH:25]=[CH:26]2)=[O:22]
Reactant: CN(C)C(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: CN1CCN(CCOc2ccc(C=O)cc2)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CN1CCN(CCOc2ccc(-c3nc4c(N[C@H]5[C@@H](C(=O)N(C)C)[C@@H]6C=C[C@H]5C6)c(Cl)cnc4[nH]3)cc2)CC1
Yield: 28.3 %

Procedure:
In a similar fashion to Compound LXXXVII, 4-(2-(4-methylpiperazin-1-yl)ethoxy)benzaldehyde (138 mg, 0.222 mmol), (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid dimethylamide (78.7 mg, 0.244 mmol), and Ammonium acetate (34.3 mg, 0.444 mmol) were reacted to produce 34.61 mg (28%) of the title compound. (300 MHz, DMSO-d6) 12.56 (s, 1H), 8.08 (d, J=8 Hz, 1H), 7.93 (s, 1H), 7.88 (s, 1H), 7.11 (d, J=8 Hz, 1H), 6.42 (m, 2H), 6.32 (s, 1H), 5.35 (m, 1H), 4.15 (m, 2H), 3.49 (m, 1H), 3.07 (d, J=8 Hz, 1H), 3.00 (d, J=8 Hz, 1H), 2.96-2.68 (m, 14H), 2.32 (s, 2H), 2.14 (s, 2H), 1.92 (m, 1H), 1.44 (m, 1H). MS=550 (M+H), HPLC: 1.91 min. (G Method)
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([S:18]([CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])(=[O:20])=[O:19])[CH:16]=3)[N:11]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:10]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:43]1[CH:44]=[C:45]([NH:49][CH:50]([CH:59]([CH3:61])[CH3:60])[C:51]([NH:53][CH2:54][C:55]([F:58])([F:57])[F:56])=[O:52])[CH:46]=[N:47][CH:48]=1>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>[CH3:60][CH:59]([CH3:61])[CH:50]([NH:49][C:45]1[CH:44]=[C:43]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([S:18]([CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])(=[O:19])=[O:20])[CH:16]=3)[N:11]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:34])[CH3:32])[CH:10]=2)[CH:48]=[N:47][CH:46]=1)[C:51](=[O:52])[NH:53][CH2:54][C:55]([F:58])([F:57])[F:56]
Reactant: COC(=O)CCS(=O)(=O)c1cnc2c(c1)c(B1OC(C)(C)C(C)(C)O1)cn2COCC[Si](C)(C)C
Reactant: CC(C)C(Nc1cncc(Br)c1)C(=O)NCC(F)(F)F
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: [Na+]
Product: COC(=O)CCS(=O)(=O)c1cnc2c(c1)c(-c1cncc(NC(C(=O)NCC(F)(F)F)C(C)C)c1)cn2COCC[Si](C)(C)C
Temperature: 100 °C
Yield: 50.2 %

Procedure:
To methyl 3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-ylsulfonyl)propanoate 4-1c (3.26 mmol) was added aqueous sodium carbonate (4.89 ml, 9.79 mmol), 2-[(5-bromopyridin-3-yl)amino]-3-methyl-N-(2,2,2-trifluoroethyl)butanamide (1386 mg, 3.91 mmol) and Tetrakis (188 mg, 0.163 mmol). The reaction mixture was heated at 100° C. in a sealed vessel for 1 h. The reaction was cooled, quenched with water (50 mL), and product extracted with ethyl acetate (100 mL). The organic extract was dried over sodium sulfate, filtered and concentrated to oil. The oil was chromatographed on silica (100 g) using 50-100% ethyl acetate/hexanes to give the desired product 4-1d (1.1 g).
Reaction SMILES: [CH2:1]([N:4]1[C:9](=[O:10])[CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH3:14])[N:6]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[NH:32][N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:5]1=[O:33])[CH2:2][CH3:3].CI.[C:36](=O)(O)[O-].[Na+]>CN(C=O)C>[CH3:36][N:29]1[C:28]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:19]2[CH:20]=[CH:21][C:16]([CH2:15][N:6]3[C:7]([O:11][CH2:12][CH2:13][CH3:14])=[CH:8][C:9](=[O:10])[N:4]([CH2:1][CH2:2][CH3:3])[C:5]3=[O:33])=[CH:17][CH:18]=2)=[N:32][N:31]=[N:30]1
Reactant: O=C([O-])O
Reactant: CCCOc1cc(=O)n(CCC)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCCOc1cc(=O)n(CCC)c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
A mixture of 3-propyl-6-propyloxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-2,4(1H,3H)-dione (0.1 g), methyl iodide (50 mg) and sodium bicarbonate (25 mg) in DMF (5 ml) was stirred at room temperature for 2 hours. The reaction mixture was concentrated to dryness and the residue was dissolved in CHCl3 -water. The chloroform layer was dried and evaporated in vacuo to give a syrup. The syrup was column-chromatographed on silica gel to give a colorless syrup (90 mg, 86%).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([OH:13])[CH:10]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[N:14]1([C@H:10]2[C@H:11]([OH:13])[CH2:12][NH:8][CH2:9]2)[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CC(O)C(N2CCCC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O[C@@H]1CNC[C@H]1N1CCCC1
Temperature: 0 °C
Yield: 100.5 %

Procedure:
Dissolve 4′-hydroxy-[1,3′]bipyrrolidinyl-1′-carboxylic acid tert-butyl ester (751 mg, 2.93 mmol) in dichloromethane (13 mL) and cool the mixture to 0° C. Add trifluoroacetic acid (2.5 mL, 33.1 mmol) and warm the mixture to room temperature for one hour. Remove the volatiles via reduced pressure and then purify by applying to two 10 g SCX cartridges. Wash the material with methanol then elute the material with 2N ammonia in methanol to give 460 mg (99%) of the title compound as a clear oil. 1H NMR(DMSO-d6) δ 1.60 (m, 4H), 2.31 (s, 1H), 2.41 (m, 5H), 2.53 (m, 1H), 2.81 (m, 1H), 2.93 (m, 1H), 3.94 (s, 1H).
Reaction SMILES: C([O:3][CH:4]([C@@H:6]1[C@@H:9]([S:10][CH3:11])[N:8]([C:12](=[C:17]([CH3:19])[CH3:18])[C:13]([O:15][CH3:16])=[O:14])[C:7]1=[O:20])[CH3:5])=O.C[O-].[Na+].C(O)(=O)C>CO>[OH:3][CH:4]([C@@H:6]1[C@@H:9]([S:10][CH3:11])[N:8]([C:12](=[C:17]([CH3:19])[CH3:18])[C:13]([O:15][CH3:16])=[O:14])[C:7]1=[O:20])[CH3:5]
Reactant: COC(=O)C(=C(C)C)N1C(=O)[C@H](C(C)OC=O)[C@H]1SC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)C(=C(C)C)N1C(=O)[C@H](C(C)O)[C@H]1SC
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a solution of a mixture (5:1) of methyl 2-[(3S,4R)-3-{(1RS)-1-formyloxyethyl}-4-methylthio-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (880 mg) in methanol (20 ml) was added a 4.9 M solution of sodium methoxide in methanol (0.60 ml) at 0° C. After 30 minutes, acetic acid (0.20 ml) was added and the mixture was evaporated. The residue was taken up into ethyl acetate (30 ml) and washed with a dilute aqueous sodium bicarbonate. Drying over magnesium sulfate and removal of the solvent left an oil, which was chromatographed on silica gel (25 g) eluting with 5-20% acetone in dichloromethane to give a mixture (5:1) of methyl 2-[(3S,4R)-3-{(1RS)-1-hydroxyethyl}-4-methylthio-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (742 mg).
Reaction SMILES: CO[C:3](=[O:31])[C@@H:4]([NH:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH2:5][CH2:6][NH:7][C:8](=O)[CH2:9][N:10]1[C:18]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[CH:12]=[CH:11]1.B#B>C1COCC1>[CH2:24]([O:23][C:21](=[O:22])[NH:20][C@H:4]1[CH2:5][CH2:6][N:7]([CH2:8][CH2:9][N:10]2[C:18]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=3[CH:12]=[CH:11]2)[C:3]1=[O:31])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC(=O)[C@H](CCNC(=O)Cn1ccc2cnccc21)NC(=O)OCc1ccccc1
Agent: B#B
Solvent: C1CCOC1
Product: O=C(N[C@H]1CCN(CCn2ccc3cnccc32)C1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-(S)-benzyloxycarbonylamino-4-(2-pyrrolo[3,2-c]pyridin-1-yl-acetylamino)-butyric acid methyl ester (0.51 g, 1.20 mmol) in THF (5 mL) is added diborane (5 mL, 0.500 mmol, 1 M solution in THF). The resulting mixture is stirred at room temperature for 4 hours and then concentrated in vacuo. The residue is suspended in EtOAc (10 mL), treated with 10 drops of H2O, 5 drops of 1 N NaOH and further quenched with saturated NH4Cl solution. The mixture is concentrated in vacuo to about ½ volume, partitioned between EtOAc and 10% Na2CO3 solution and the layers are separated. The aqueous layer is extracted with EtOAc. The combined organic phases are washed with saturated NaCl, dried over MgSO4, filtered and concentrated in vacuo. The crude product obtained is partially purified by column chromatography in a gradient of 2% MeOH/CH2Cl2 to 10% MeOH/CH2Cl2 to afford [2-oxo-1-(2-pyrrolo[3,2-c]pyridin-1-yl-ethyl)-pyrrolidin-3-(S)-yl]-carbamic acid benzyl ester. FAB MS, [M+H]+=379. To a solution of this crude [2-oxo-1-(2-pyrrolo[3,2-c]pyridin-1-yl-ethyl)-pyrrolidin-3-(S)-yl]-carbamic acid benzyl ester in MeOH (10 mL) and AcOH (3 mL) is added a catalytic amount of 10% palladium on activated carbon. The heterogenous mixture is stirred at room temperature under a balloon of H2 for 18 hours. The reaction mixture is filtered through a pad of Celite and washed with MeOH (3×). The crude product is concentrated in vacuo and then azeotroped with toluene to give 3-(S)-amino-1-(2-pyrrolo[3,2-c]pyridin-1-yl-ethyl)-pyrrolidin-2-one acetate as a residue (wet with excess HOAc). FAB MS, [M+H]+=245. The title compound is prepared in CH2Cl2 instead of CH3CN as described in EXAMPLE 1, Part K using the above 3-(S)-amino-1-(2-pyrrolo[3,2-c]pyridin-1-yl-ethyl)-pyrrolidin-2-one acetate in place of 7-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)-1-chloro-isoquinoline hydrochloride and 7-methoxynaphthalene-2-sulfonyl chloride as prepared in EXAMPLE 1, Part J. The crude product is partially purified by column chromatography eluting in a gradient of 3% MeOH/CH2Cl2 to 5% MeOH/CH2Cl2. The residue obtained is further purified by RP-HPLC eluting in a gradient of 10% CH3CN/H2O (0.1% TFA) to 80% CH3CN/H2O (0.1% TFA) and the appropriate product fractions are lyophilized to provide the title compound as a white solid.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH3:45])[CH2:30][CH2:31][N:32]([C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=1)[C:33](=[O:37])[CH2:34][CH2:35][CH3:36]>>[CH3:45][N:29]([CH3:28])[CH2:30][CH2:31][N:32]([C:38]1[CH:44]=[CH:43][C:41]([NH:42]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:8]3[C:7]\2=[CH:12][CH:11]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:9]=3)/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:40][CH:39]=1)[C:33](=[O:37])[CH2:34][CH2:35][CH3:36]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: CCCC(=O)N(CCN(C)C)c1ccc(N)cc1
Product: CCCC(=O)N(CCN(C)C)c1ccc(N/C(=C2\C(=O)Nc3cc(C(=O)OC)ccc32)c2ccccc2)cc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(N-(2-dimethylamino-ethyl)-N-butyryl-amino)-aniline Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C31H34N4O4
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.C(NC(C)C)(C)C.[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1>C(Cl)Cl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][N:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=2)[NH2:11])=[CH:22][CH:21]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: COc1ccc(NN)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: COc1ccc(N(N)Cc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 72 %

Procedure:
To a suspension of 4-methoxyphenylhydrazine hydrochloride (41 g, 230 mmol) in methylene chloride (1000 ml) under nitrogen were added diisopropylamine (79.8 g, 612 mmol), 4-chlorobenzylchloride (40.25 g, 250 mmol) and tetrabutylammonium bromide (22.8 g, 70 mmol). The resulting mixture was stirred at ambient temperature for 48 hours. The reaction mixture was then washed with water, and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 2.5% methanol in methylene chloride) followed by washing of the solid with 10% ethyl ether in hexane and drying in vacuo to provide 43.5 g of 1-(4-chlorobenzyl)-1-(4methoxyphenyl)hydrazine, mp. 55° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([O:23][CH3:24])=[C:14]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH:15]=2)[CH:5]=[CH:4][N:3]=1.[I-].[NH2:26][N+:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:10]3[CH:11]=[CH:12][C:13]([O:23][CH3:24])=[C:14]([NH:16][C:17](=[O:22])[C:18]([F:20])([F:21])[F:19])[CH:15]=3)=[N:26][N:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=23)[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(C#Cc2ccnc(Cl)n2)cc1NC(=O)C(F)(F)F
Reactant: N[n+]1ccccc1
Agent: [I-]
Product: COc1ccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)cc1NC(=O)C(F)(F)F
Yield: 53.5 %

Procedure:
N-[5-[(2-Chloro-4-pyrimidinyl)ethynyl]-2-(methyloxy)phenyl]-2,2,2-trifluoroacetamide (1.7 g, 4.8 mmol) was subjected to cyclization with N-aminopyridinium iodide (2.1 g, 9.6 mmol) according to the procedure of Example 56, Step E to give the desired product (1.15 g, 53%). 1H NMR (400 MHz, d6-DMSO) δ 10.82 (s, 1H), 8.88 (d, J=6.8 Hz, 1H), 8.45 (d, J=5.6 Hz, 1H), 8.39 (d, J=8.4 Hz, 1H), 7.70 (d, J=2.0 Hz, 1H), 7.64-7.60 (m, 1H), 7.57 (dd, J=8.6 and 1.8 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H), 7.21-7.18 (m, 1H), 7.11 (d, J=5.6 Hz, 1H), 3.90 (s, 3H) ppm.
Reaction SMILES: [N+:1]([C:4]1[C:9]2[CH2:10][CH:11]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[CH:12]([C:16]([O:18][CH3:19])=[O:17])[C:13](=O)[NH:14][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].C[Si](C)(C)[N-][Si](C)(C)C.[K+].P(OCC)(OCC)[O:39]CC>O1CCCC1.O=O>[N+:1]([C:4]1[C:9]2[CH2:10][CH:11]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C:12]([OH:39])([C:16]([O:18][CH3:19])=[O:17])[CH2:13][NH:14][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCOP(OCC)OCC
Reactant: COC(=O)C1C(=O)Nc2cccc([N+](=O)[O-])c2CC1c1ccc(OC)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=O
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C1(O)CNc2cccc([N+](=O)[O-])c2CC1c1ccc(OC)cc1
Yield: 166.9 %

Procedure:
6-Nitro-1,3,4,5-tetrahydro-3-(methoxycarbonyl)-4-(4-methoxyphenyl)-2H-1-benzazepin-2-one (5.05 0.014 mol) in 250 ml of tetrahydrofuran was treated with 10.9 g (0.055 mol) of potassium hexamethyldisilazide at -70° C., then with 9.6 ml (0.056 mol) of triethyl phosphite and oxygen gas at -70 to 0° C. as described in Example 1, Method II, part D. The solution became very dark on adding the base and did not lighten on passing in oxygen. Workup according to the reference procedure gave 8.7 g of a deep red oil which did not crystallize following trituration with hexane. The final yield of a deep red oil was 5.3 g.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]1=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:13]>>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]1=[S:13]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: Cn1c(=O)oc2ccccc21
Product: Cn1c(=S)oc2ccccc21
Temperature: 140 °C
Yield: 80 %

Procedure:
3-Methyl-3H-benzoxazol-2-one (2.0 g, 13.4 mmol) was treated with diphosphorus pentasulphide (4.0 g, 18 mmol). The mixture was heated to 140° C. for 2 hours with vigorous stirring. The solid was cooled and then extracted with toluene (2×50 ml). The toluene extract was evaporated in vacuo and the residue partitioned between ethyl acetate (2×10 ml) and water (20 ml). The organic phases were combined and dried over magnesium sulfate. The volatiles were removed in vacuo to provide the desired compound as a white solid (1.77 g, 80%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C:8](Cl)=[O:9])([CH3:4])([CH3:3])[CH3:2].[OH:22][CH2:23][C:24]1[CH:35]=[CH:34][C:27]([C:28]([O:30][CH2:31][CH:32]=[CH2:33])=[O:29])=[CH:26][CH:25]=1>>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C:8]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:28]([O:30][CH2:31][CH:32]=[CH2:33])=[O:29])=[CH:34][CH:35]=1)=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCOC(=O)c1ccc(CO)cc1
Reactant: CC(C)(C)c1cc(C(=O)Cl)ccc1O[Si](C)(C)C(C)(C)C
Product: C=CCOC(=O)c1ccc(COC(=O)c2ccc(O[Si](C)(C)C(C)(C)C)c(C(C)(C)C)c2)cc1

Procedure:
In a manner similar to Example 1(d), by reaction of 4.9 g (15 mmol) of 3-tert-butyl-4-(tert-butyldimethylsilyloxy)benzoyl chloride with 2.9 g (15 mmol) of allyl 4-hydroxymethylbenzoate, 4.1 g (60%) of the allyl ester are obtained in the form of a slightly yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:28]=[C:11]3[CH:12]=[C:13]([NH:16][C:17]([C:19]4[N:23]([CH3:24])[N:22]=[CH:21][C:20]=4[C:25]([OH:27])=O)=[O:18])[CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH:29]1[CH2:32][CH2:31][CH2:30]1>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:28]=[C:11]3[CH:12]=[C:13]([NH:16][C:17]([C:19]4[N:23]([CH3:24])[N:22]=[CH:21][C:20]=4[C:25]([N:29]4[CH2:32][CH2:31][CH2:30]4)=[O:27])=[O:18])[CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C1CNC1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3cccc(F)c3)nc2c1
Product: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1ccn2nc(-c3cccc(F)c3)nc2c1
Yield: 90.7 %

Procedure:
The product was prepared in the same manner as described in example 3 using 5-(2-(3-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (70 mg, 184 μmol) and azetidine (12.5 μl, 184 μmol) as starting materials. The reaction affords 4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid [2-(3-fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-amide (70 mg, 90.7%) as white solid. mp.: 232-236° C., MS: m/z=420.0 (M+H+).
Reaction SMILES: C(OC(O[CH2:8][CH3:9])CBr)C.C(O)C.C(=O)([O-])O.[Na+].[NH2:18][C:19]1[N:20]=[N:21][CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[N:24]=1>Br.O>[F:27][C:25]([F:26])([F:28])[C:23]1[CH:22]=[N:21][N:20]2[CH:8]=[CH:9][N:18]=[C:19]2[N:24]=1
Reactant: CCOC(CBr)OCC
Reactant: Nc1nncc(C(F)(F)F)n1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: FC(F)(F)c1cnn2ccnc2n1
Temperature: 60 °C
Reaction time: 20 h
Yield: 22.5 %

Procedure:
A stirred mixture of bromoacetaldehyde diethyl acetal (2.30 ml, 14.8 mmol) in concentrated hydrobromic acid (0.73 ml) and water (0.73 ml) was heated at reflux for 2 h, then poured into ethanol (25 ml). The solution was neutralised to pH 7 with solid sodium hydrogencarbonate, then filtered. To the filtrate was added 3-amino-5-trifluoromethyl-1,2,4-triazine (1.0079 g, 6.14 mmol) and the mixture was stirred at 60° C. for 20 h, then 80° C. for 23 h. The mixture was evaporated in vacuo, and the residue was purified by flash chromatography (silica gel, 35-50% EtOAc/isohexane) to give 0.2593 g (22%) of the title compound: 1H NMR (360 MHz, CDCl3) δ 8.20 (1H, d, J 0.8 Hz), 8.30 (1H, d, J 0.9 Hz), 8.73 (1H, s).
Reaction SMILES: Br[C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[C:18]([O-:21])(=[S:20])[CH3:19].[K+]>CN(C)C=O>[C:18]([S:20][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4])(=[O:21])[CH3:19]
Reactant: CC(C)(Br)C(=O)O
Reactant: CC([O-])=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC(C)(C)C(=O)O
Temperature: -45 °C
Reaction time: 22 h
Yield: 82 %

Procedure:
Dimethylformamide (DMF), 100 ml was poured into a 4 l indented 3 neck round bottom flask equipped with a nitrogen bubbler and an overhead stirrer (glass shaft, teflon paddle). The hot 2-bromo-2-methylpropionic acid was then added to the flask through a powder funnel. The flask and the funnel were rinsed with 4×100 ml portions of DMF and were added to the reaction flask. A thermometer was placed in the third neck and the stirred solution was cooled under an atmosphere of nitrogen to -45° C. by placing it in a methanol/water 50:50 dry ice bath. The thermometer was removed and potassium carbonate 250.21 g (1.810 mol, 100 M%) was added through a powder funnel over a 5 minute period. The reaction mixture warmed to -40° C. but there was no apparent reaction and the carbonate did not dissolve. The soluton was diluted with 200 ml DMF and potassium thioacetate 407.10 g (3.564 mol, 196.9 M%) was added through a powder funnel over a 5 minute period. The powder funnel was rinsed with 300 ml DMF which was added to the reaction solution which had warmed to -30° C. The reaction was allowed to slowly warm up as the dry ice was consumed. When the reaction temperature reached -10° C. the reaction began to bubble. The reaction was allowed to warm slowly to room temperature and was stirred under nitrogen for 22 hours. Water, 2 1, and 500 ml concentrated hydrochloric acid were mixed and cooled to 9° C. in an ice bath. The tan colored reaction mixture was slowly poured into the stirred acid solution over a 25 minute period. The reaction flask was washed with 2×100 ml portions of deionized water which was added to the acid solution (10° C., pH 1.5). The acid solution was poured into a 4 l separatory funnel and was extracted sequentially with 3×500 ml and 1×250 ml ethyl acetate. Each organic extract was washed with a separate 100 ml portion of saturated sodium chloride solution. The organic extracts were combined and dried over 400 g of anhydrous sodium sulfate. The solution was filtered through a fluted filter paper into a 2,000 ml round bottom flask and the solvent was removed in two portions under reduced pressure on the rotary evaporator. The sodium sulfate was washed with 3×100 ml portions of ethyl acetate which were filtered into the 2,000 ml round bottom. After all the solvent was removed, the rotary evaporator was connected to the high-vacuum pump and the water bath was heated to 100° C. The product was removed after 1.5 hour to afford 241.07 g of the crude brown oily product which crystallized on cooling. The crystalline mass was placed under high vacuum at 22° C. for 16 hours to afford 240.51 g (82% yield) of the crude crystalline 2-acetylthio-2-methylpropanoic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:11].Br[CH2:13][CH:14]([CH3:16])[CH3:15]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[N:6]=[C:5]2[I:11]
Reactant: CC(C)CBr
Reactant: Fc1ccc2[nH]nc(I)c2c1
Product: CC(C)Cn1nc(I)c2cc(F)ccc21
Yield: 70 %

Procedure:
The title compound was prepared in 70% yield from 5-fluoro-3-iodo-indazole and 1-bromo-2-methylpropane according to the general procedure for Preparation 10A. The minor isomer was not isolated or characterized. 1H NMR (400 MHz, CDCl3): δ 0.92 (6H, d, J=6.8 Hz), 2.30-2.37 (1H, m), 4.16 (2H, d, J=7.2 Hz), 7.11 (1H, dd, J=2.4, 8.8 Hz), 7.19 (1H, td, J=2.4, 8.8 Hz), 7.32 (1H, dd, J=4.0, 8.8 Hz).
Reaction SMILES: [OH:1][CH:2]([C:15]1[CH:16]=[C:17]([Si:20]([CH3:23])([CH3:22])[CH3:21])[O:18][CH:19]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[H-].[Na+].I[CH3:27]>O1CCCC1.C(OCC)C>[CH3:27][O:1][CH:2]([C:15]1[CH:16]=[C:17]([Si:20]([CH3:23])([CH3:22])[CH3:21])[O:18][CH:19]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCC(O)c1coc([Si](C)(C)C)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCCCCCCCC(OC)c1coc([Si](C)(C)C)c1

Procedure:
A mixture of 4-(1-hydroxytridecyl)-2-trimethylsilylfuran (318.5 mg, 0.9 mmol), sodium hydride (60% dispersion in oil; 150 mg, 3.8 mmol) and iodomethane (0.29 ml, 4.7 mmol) in tetrahydrofuran (7 ml) was refluxed for 16 hours. On cooling, the mixture was diluted with ethyl ether (20 ml), quenched with methanol (2 ml) and washed with water. Evaporation of the dried (magnesium sulfate) organic phase gave a deep yellow oil, identified as 4-(1-methoxytridecyl)-2-trimethylsilyfuran.