Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C@@H:12]([NH:16]C(=O)OC(C)(C)C)[CH2:13][O:14][CH3:15])=[CH:6][C:5]=1[NH:24][C:25]1[S:29][N:28]=[C:27]([CH3:30])[CH:26]=1)(=[O:3])[NH2:2].[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32]>C(Cl)Cl>[NH2:16][C@@H:12]([CH2:13][O:14][CH3:15])[CH2:11][NH:10][C:7]1[CH:8]=[CH:9][C:4]([C:1]([NH2:2])=[O:3])=[C:5]([NH:24][C:25]2[S:29][N:28]=[C:27]([CH3:30])[CH:26]=2)[CH:6]=1.[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32]
Reactant: COC[C@@H](CNc1ccc(C(N)=O)c(Nc2cc(C)ns2)c1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC[C@H](N)CNc1ccc(C(N)=O)c(Nc2cc(C)ns2)c1

Procedure:
The above product from step 3 was added TFA in DCM (1:1, 2 mL), 30 min later, the solution was concentrated under vacuum and was purified by preparative HPLC to give (R)-4-(2-amino-3-methoxypropylamino)-2-(3-methylisothiazol-5-ylamino)benzamide as TFA salt. MS 336.2 (M+H); UV 293.8 nm.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([CH3:11])=[N:9][N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[C:31]([CH2:35][C:36]#[N:37])[CH:32]=[CH:33][CH:34]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.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>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:8]2[C:5]3=[N:6][CH:7]=[C:2]([C:29]4[CH:30]=[C:31]([CH2:35][C:36]#[N:37])[CH:32]=[CH:33][CH:34]=4)[CH:3]=[C:4]3[C:10]([CH3:11])=[N:9]2)=[CH:14][CH:15]=1
Reactant: CC1(C)OB(c2cccc(CC#N)c2)OC1(C)C
Reactant: COc1ccc(Cn2nc(C)c3cc(Br)cnc32)cc1
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: [Cs+]
Solvent: COCCOC
Product: COc1ccc(Cn2nc(C)c3cc(-c4cccc(CC#N)c4)cnc32)cc1
Temperature: 80 °C

Procedure:
The starting material 5-bromo-1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine (7) (136 mg, 0.41 mmol, 1 eq) and 2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetonitrile (156) (100 mg, 0.41 mmol, 1 eq) in DME (10 mL) was degassed and purged under argon atmosphere for 10 min. To this reaction mixture was charged Cs2CO3 (260 mg, 0.82 mmol, 2 eq) followed by addition of Pd(PPh3)4 (15 mg, 0.03 mmol), degassing and purging under argon for additional 10 min. The reaction mixture was heated at 80° C. for 12 h in a sealed tube. After completion of the reaction, the solvents were removed and reaction mixtures were extracted into EtOAc, dried over Na2SO4 and the solvents distilled off. The crude material was submitted for flash column purification using 20% EtOAc in hexane to obtain off-white solid compound 2-(3-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)acetonitrile 157.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][N:15]=1)[C:12]1[N:8]([CH:9]=[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:11]=1)[CH2:7][CH2:6][O:5]2.[CH3:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[CH:29]1[CH2:33][CH2:32][CH2:31][NH:30]1>CN1C(=O)CCC1>[CH3:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]1[C@@H:29]1[CH2:33][CH2:32][CH2:31][N:30]1[C:2]1[N:15]=[CH:14][C:13]2[C:12]3[N:8]([CH:9]=[C:10]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)[N:11]=3)[CH2:7][CH2:6][O:5][C:4]=2[CH:3]=1
Reactant: CN1CCCCC1C1CCCN1
Reactant: Clc1cc2c(cn1)-c1nc(-c3ccccn3)cn1CCO2
Solvent: CN1CCCC1=O
Product: CN1CCCC[C@H]1[C@@H]1CCCN1c1cc2c(cn1)-c1nc(-c3ccccn3)cn1CCO2
Temperature: 150 °C
Reaction time: 24 h

Procedure:
A mixture of 12-chloro-4-(pyridin-2-yl)-9-oxa-3,6,13-triazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene (300 mg, 1.00 mmol), TEA (0.5 mL), and 1-methyl-2-(pyrrolidin-2-yl)piperidine (507 mg, 3.01 mmol) in NMP (0.5 mL) was stirred at 150° C. for 24 h under nitrogen atmosphere. After cooling down, the resultant mixture was purified directly by reverse phase Combiflash eluting with 0-50% gradient of CH3CN in 0.5% NH4HCO3 to give diastereomeric 111: 15 mg of diasteromer A and 12 mg diasteromer B (48% total yield). Diasteromer A: LCMS (ESI): RT=4.48 min, m/z: 431.3 [M+H+]. 1H-NMR (500 MHz, DMSO-d6): δ 9.14 (s, 1H), 8.50 (d, J=4.5 Hz, 1H), 7.96 (d, J=7.5 Hz, 1H), 7.83-7.79 (m, 2H), 7.22-7.19 (m, 1H), 6.05 (s, 1H), 4.52-4.45 (m, 4H), 4.11 (s, 1H), 3.45-3.34 (m, 2H), 2.78 (s, 1H), 2.17 (s, 3H), 2.11-2.01 (m, 2H), 1.95-1.85 (m, 4H), 1.70 (s, 1H), 1.50-1.35 (m, 3H), 1.30-1.19 (m, 2H). Diasteromer B: LCMS (ESI): RT=4.75 min, m/z: 431.3 [M+H+]. 1H-NMR (500 MHz, DMSO-d6): δ 9.15 (s, 1H), 8.50 (d, J=4.0 Hz, 1H), 7.96 (d, J=8.2 Hz, 1H), 7.83-7.78 (m, 2H), 7.22-7.19 (m, 1H), 5.98 (s, 1H), 4.52-4.45 (m, 5H), 3.42 (s, 2H), 2.77 (s, 1H), 2.29 (s, 3H), 2.16-2.13 (m, 2H), 2.00-1.88 (m, 4H), 1.64 (s, 1H), 1.50-1.25 (m, 3H), 1.20-0.90 (m, 2H)
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](O)=[O:14])=[CH:8][CH:7]=1)=[O:4]>O1CCCC1.C(OCC)(=O)C>[OH:14][CH2:13][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][C:3]([O:2][CH3:1])=[O:4])=[CH:7][CH:8]=1
Reactant: COC(=O)Cc1ccc(CC(=O)O)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(CCO)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Borane-tetrahydrofuran complex (40 ml of a 1.0 molar solution in tetrahydrofuran) was added, dropwise over 10 minutes, to a solution of 4-(methoxycarbonylmethyl)phenylacetic acid (see U.S. Pat. No. 3,341,531) (7.7 g) in tetrahydrofuran (100 ml) at 0°. The mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction was quenched by the addition of 2M hydrochloric acid (50 ml) then concentrated in vacuo. The residue was partitioned between dichloromethane (200 ml) and 2M hydrochloric acid (100 ml), the layers separated, and the aqueous layer extracted with dichloromethane (2×50 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give an oil which was dissolved in ethyl acetate (100 ml) and the solution extracted with saturated aqueous sodium bicarbonate (2×100 ml). The aqueous extracts were combined, acidified with 2M hydrochloric acid (pH5) and extracted with dichloromethane (2×100 ml). The combined dichloromethane extracts were dried (MgSO4 ) and concentrated in vacuo to give the title compound as an oil, yield 2.7 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23](Cl)[N:22]=3)=[O:20])=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:28]([F:31])([F:30])[F:29].C(O)=[O:33].O.C(=O)(O)[O-].[Na+]>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:33])[N:22]=3)=[O:20])=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:28]([F:29])([F:30])[F:31]
Reactant: O=C(c1cccc(Cl)n1)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(c1cccc(O)n1)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A 2 dram vial was charged with 4-chloro-N-[5-chloro-2-(6-chloro-pyridine-2-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide (65 mg, 0.127 mmol), formic acid (2.0 mL) and water (0.50 mL). The heterogeneous solution was warmed to 110° C. and stirred overnight. The following day, the resultant mixture was neutralized with saturated aqueous sodium bicarbonate, diluted with EtOAc, and the organic layer washed with saturated sodium bicarbonate. The combined organics were dried with sodium sulfate, concentrated in vacuo, and purified via automated silica gel chromatography to afford the desired hydroxypyridine: MS (ES) (M+H)+ expected 492.0, found 491.9.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Br:9][C:10]1[CH:11]=[C:12]([C:21]([OH:23])=[O:22])[S:13][C:14]=1[C:15]1[N:19]([CH3:20])[N:18]=[CH:17][CH:16]=1>O1CCCC1>[Br:9][C:10]1[CH:11]=[C:12]([C:21]([OH:23])=[O:22])[S:13][C:14]=1[C:15]1[N:19]([CH3:20])[N:18]=[CH:17][C:16]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1nccc1-c1sc(C(=O)O)cc1Br
Solvent: C1CCOC1
Product: Cn1ncc(Cl)c1-c1sc(C(=O)O)cc1Br
Temperature: 70 °C
Yield: 0.1 %

Procedure:
N-chlorosuccinimide (NCS) (299 mg, 2.194 mmol) was added in portions to a 30 mL sealed tube reactor containing 4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (503 mg, 1.23 mmol) in tetrahydrofuran (THF) (6 mL) at room temperature. The mixture was heated to 70° C. for 2 hours. Upon completion, the reaction mixture was partitioned between CHCl3 and H2O, the organic layer dried with Na2SO4, solvents removed by vacuum distillation affording the title compound (0.54 mg, quant.) which was used without further purification. LC-MS (ES) m/z=321 (M+H)+
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][CH:6]([CH3:13])[CH2:7][CH2:8][CH2:9][C:10](Cl)=[O:11].[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22]>[N+](C1C=CC=CC=1)([O-])=O>[F:14][C:15]1[CH:20]=[C:19]([C:10](=[O:11])[CH2:9][CH2:8][CH2:7][CH:6]([CH3:13])[CH3:5])[CH:18]=[CH:17][C:16]=1[O:21][CH3:22]
Reactant: COc1ccccc1F
Reactant: CC(C)CCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc(C(=O)CCCC(C)C)cc1F
Temperature: 0 °C

Procedure:
14 ml of nitrobenzene are cooled in an ice-bath and then mixed in succession with 3.8 g of AlCl3 and 3.7 g of 5-methyl-hexanoyl chloride in 5 ml of nitrobenzene. The mixture is stirred and then treated with 2.7 ml of 2-fluoro-anisole. The solution is stirred overnight, then poured into ice-water and extracted with methylene chloride. The extracts are washed with water and 10% aqueous NaCl solution, and thereafter dried and concentrated and recrystallized using pentane. 5.31 g of 1-(3-fluoro-4-methoxy-phenyl)-5-methyl-hexan-1-one, MS: m/e 238 (M+), are obtained.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([C@@H:5](/[CH:7]=[CH:8]/[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[OH:6])[NH2:4].[C:22]([NH:25][CH2:26][C:27](O)=[O:28])(=[O:24])[CH3:23].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[C:22]([NH:25][CH2:26][C:27]([NH:4][C@H:3]([C@@H:5](/[CH:7]=[CH:8]/[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[OH:6])[CH2:2][OH:1])=[O:28])(=[O:24])[CH3:23]
Reactant: CCCCCCCCCCCCC/C=C/[C@@H](O)[C@@H](N)CO
Reactant: CC(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCC/C=C/[C@@H](O)[C@H](CO)NC(=O)CNC(C)=O

Procedure:
5.0 gr of sphingosine (16.70 mM), prepared according to Example 4, 2.1 gr of N-acetylglycine (18.37 mM) and 3.8 gr of dicyclohexylcarbodiimide (18.40 mM) are left to react in 150 cc of chloroform, under warm conditions overnight. The reaction mixture is placed in a freezer to precipitate. The urea is filtered, and the chloroform solution is washed with H2O. The raw material is purified by chromatography using a mixture of CH2Cl2 /ethyl acetate/CH3OH, 70:30:10 v/v/v.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH:16]1([C:19]2[CH:24]=[CH:23][C:22]([CH:25]=[CH2:26])=[CH:21][N:20]=2)[CH2:18][CH2:17]1.[OH-].[K+]>CN1C(=O)CCC1>[CH:16]1([C:19]2[N:20]=[CH:21][C:22]([CH2:25][CH2:26][N:6]3[C:7]4[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=4[C:4]4[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]3=4)=[CH:23][CH:24]=2)[CH2:18][CH2:17]1
Reactant: C=Cc1ccc(C2CC2)nc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C3CC3)nc2)CCN(C)C1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole, 2-cyclopropyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:15]([OH:17])=O)[S:10][C:11]=2[CH2:12][CH2:13][CH3:14])=[C:5]([CH3:18])[CH:4]=[N:3]1.[NH2:19][C@@H:20]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]([F:43])([F:42])[F:41])[CH2:21][N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:15]([NH:19][C@@H:20]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]([F:43])([F:41])[F:42])[CH2:21][N:22]3[C:30](=[O:31])[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]3=[O:32])=[O:17])[S:10][C:11]=2[CH2:12][CH2:13][CH3:14])=[C:5]([CH3:18])[CH:4]=[N:3]1
Reactant: CCCc1sc(C(=O)O)cc1-c1c(C)cnn1C
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCc1sc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1c(C)cnn1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.3 %

Procedure:
To a solution of 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylic acid (180 mg, 0.68 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (262 mg, 0.68 mmol)[prepared in Preparation 6] and diisopropylethylamine (0.59 ml, 3.40 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (350 mg, 0.75 mmol) in one portion. The solution stirred at 25° C. for 2 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding 4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-propyl-2-thiophenecarboxamide (243 mg, 0.41 mmol, 60% yield) as a yellow oil: LCMS (ES) m/e 595 (M+H)+.
Reaction SMILES: [Si:1]([C:8]1[C:9]([CH:21]=O)=[CH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([N:18]([CH3:20])[CH3:19])=[CH:13][CH:12]=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:23](#[N:27])[CH2:24][C:25]#[N:26].N1CCCCC1>CCO>[CH3:19][N:18]([CH3:20])[C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH:21]=[C:24]([C:23]#[N:27])[C:25]#[N:26])[C:8]([Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:17]2
Reactant: N#CCC#N
Reactant: CN(C)c1ccc2cc(C=O)c([Si](C)(C)C(C)(C)C)cc2c1
Solvent: CCO
Solvent: C1CCNCC1
Product: CN(C)c1ccc2cc(C=C(C#N)C#N)c([Si](C)(C)C(C)(C)C)cc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.1 %

Procedure:
415.7 mg (1.2616 mmol) of the compound 14 was dissolved in 9 mL of EtOH, and then added with 83.4 mg (1.2616 mmol) of malononitrile and 1 mL (12.616 mmol) of piperidine, and stirred for 3 hours at room temperature. When the reaction was completed, EtOH was removed by vacuum-distillating, and then the mixture was separated and purified by a column chromatography (eluent: EtOAc/n-hexane(v/v)=¼) without an additional extraction process to obtain 333.4 mg (70%) of an orange solid compound 15. 1H NMR (CDCl3, 300 MHz, 293K): δ 8.70(s, 1H), 8.24(s, 1H), 7.70-7.67(d, 1H), 7.02-6.98(dd, 1H), 6.88(s, 1H), 6.60-6.59(d, 1H), 3.14(s, 6H), 1.05(s, 9H), 0.31(s, 6H). 13C NMR(CDCl3, 75 MHz, 293K): δ 154.13, 152.53, 151.30, 140.20, 131.43, 131.09, 121.46, 119.27, 115.40, 114.88, 114.30, 111.78, 103.41, 40.29, 25.79, 18.38, −4.23. HRMS: m/z calcd. for C22H27N3OSi 377.1923 found 377.1923.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][N:15](C(OCC)=O)[CH2:14][C@@H:13]1[O:23][CH2:24][CH2:25][CH3:26])=[O:10].[OH-].[K+].O.NN.O>C(O)CO>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][NH:15][CH2:14][C@@H:13]1[O:23][CH2:24][CH2:25][CH3:26])=[O:10]
Reactant: CCCO[C@H]1CN(C(=O)OCC)CC[C@H]1NC(=O)c1[nH]c(C)c(Cl)c1Cl
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: CCCO[C@H]1CNCC[C@H]1NC(=O)c1[nH]c(C)c(Cl)c1Cl
Temperature: 25 °C
Yield: 0.1 %

Procedure:
A solution of ethyl (3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-propoxypiperidine-1-carboxylate (Intermediate 77, 3.3 g, 8.12 mmol) potassium hydroxide (4.55 g, 81.2 mmol), and hydrazine hydrate (4.06 g, 81.2 mmol) in ethylene glycol (100 mL) was stirred for 60 h at 120° C. The reaction mixture was cooled to room temperature and poured into water (300 mL) and extracted with ethyl acetate (2×300 mL). The combined organic extracts were dried over anhydrous sodium sulphate, filtered, and concentrated under vacuum to afford 3,4-dichloro-5-methyl-N-[(3S,4R)-3-propoxypiperidin-4-yl]-1H-pyrrole-2-carboxamide 1.5 mg, (62.5%) as solid.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[C:23]([F:30])=[CH:22][C:21]=1/[CH:31]=[CH:32]/[C:33](O)=[O:34]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:33](=[O:34])/[CH:32]=[CH:31]/[C:21]3[CH:22]=[C:23]([F:30])[C:24]([C:26]([F:27])([F:29])[F:28])=[CH:25][C:20]=3[F:19])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)/C=C/c1cc(F)c(C(F)(F)F)cc1F
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)/C=C/c3cc(F)c(C(F)(F)F)cc3F)cn2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(2,5-difluoro-4-trifluoromethyl-phenyl)-acrylic acid. LC-MS-conditions 01b: tR=0.97 min; [M+H]+=440.1.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])=[CH:14][C:13]=1[OH:24].[C:25]([O-])([O-])=O.[K+].[K+].IC>CCO>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:21]([CH3:22])[CH3:23])(=[O:19])=[O:20])=[CH:14][C:13]=1[O:24][CH3:25]
Reactant: O=C([O-])[O-]
Reactant: CN(C)S(=O)(=O)c1ccc(N2C(=O)c3ccccc3C2=O)c(O)c1
Agent: [K+]
Solvent: CI
Solvent: CCO
Product: COc1cc(S(=O)(=O)N(C)C)ccc1N1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 57.8 %

Procedure:
A suspension of 4-(1,3-dioxoisoindolin-2-yl)-3-hydroxy-N,N-dimethylbenzenesulfonamide (Preparation 106, 83 mg, 0.240 mmol), K2CO3 (50 mg, 0.359 mmol) and iodomethane (0.1 mL, 1.60 mmol) in EtOH (4 mL) was stirred at 100° C. under microwave irradiation for 60 minutes. When cooled, the resulting crystals (50 mg, 58%) obtained were filtered, washed with EtOH and dried to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4](I)[C:3]=1[O:11][CH2:12][C:13]([F:16])([F:15])[F:14].[Cl:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][C:23]=1[CH3:24]>>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([C:20]2[CH:21]=[CH:22][C:23]([CH3:24])=[C:18]([Cl:17])[CH:19]=2)[C:3]=1[O:11][CH2:12][C:13]([F:16])([F:15])[F:14]
Reactant: OCc1cc(I)c(OCC(F)(F)F)c(Cl)n1
Reactant: Cc1ccc(B(O)O)cc1Cl
Product: Cc1ccc(-c2cc(CO)nc(Cl)c2OCC(F)(F)F)cc1Cl

Procedure:
The title compound was synthesized in analogy to Example B using [4-iodo-6-chloro-5-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl]-methanol (example A) and B-(3-chloro-4-methylphenyl)-boronic acid, (CAN 175883-63-3) as starting materials; LC-MS (UV peak area/ESI) 100%, 366.0269 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([O:8][C:9]2[CH:22]=[CH:21][C:12]3[N:13]=[C:14]([NH:16][C:17](=[O:20])[O:18][CH3:19])[S:15][C:11]=3[CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.Cl[Sn]Cl>CN(C=O)C>[NH2:1][C:4]1[CH:24]=[CH:23][C:7]([O:8][C:9]2[CH:22]=[CH:21][C:12]3[N:13]=[C:14]([NH:16][C:17](=[O:20])[O:18][CH3:19])[S:15][C:11]=3[CH:10]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)Nc1nc2ccc(Oc3ccc([N+](=O)[O-])cc3)cc2s1
Agent: Cl[Sn]Cl
Solvent: CN(C)C=O
Product: COC(=O)Nc1nc2ccc(Oc3ccc(N)cc3)cc2s1
Temperature: 25 °C
Reaction time: 96 h
Yield: 43.9 %

Procedure:
To a solution of methyl (6-(4-nitrophenoxy)benzthiazole-2-yl)carbamate (Intermediate 10E-172.7 mg, 0.5 mmol) in DMF (5 mL) was added SnCl2 (474.0 mg, 2.5 mmol) and stirred at room temperature for 4 days. The mixture was extracted with ethyl acetate, and the organic layer was washed with NaHCO3aq. and dried over Na2SO4 then evaporated to remove solvent. The residue dissolved in small amount of DMF was charged on SCX column chromatography then washed with MeOH then eluted with NH3—MeOH to give the title compound (69.2 mg, 44%): MS m/e 316 (M+1).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[C:10]([O:14][C:15]([N:17]1[CH2:29][C@@H:28]([CH3:30])[N:27]2[C@H:19]([CH2:20][C:21]3[C:26]2=[N:25][C:24]([CH2:31]OCCO)=[CH:23][CH:22]=3)[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>ClCCl>[C:10]([O:14][C:15]([N:17]1[CH2:29][C@@H:28]([CH3:30])[N:27]2[C@H:19]([CH2:20][C:21]3[C:26]2=[N:25][C:24]([CH2:31][F:7])=[CH:23][CH:22]=3)[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(COCCO)nc3N21
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(CF)nc3N21
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.7 %

Procedure:
A solution of 82.0 μl (0.11 g, 0.63 mmol) diethylaminosulphur trifluoride in 2 ml dichloromethane was cooled to −78 deg C. and treated with a solution of 0.20 g (0.63 mmol) (4R,9aR)-6-(2-hydroxy-ethoxymethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (Example 15, intermediate b) in 2 ml dichloromethane. The cooling bath was removed and the reaction stirred for 1 h at room temperature. The solution was extracted with 10% aqueous sodium bicarbonate solution, washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel (0.032–0.063 mm) with ethyl acetate:n-hexane (1:2) as eluant to afford the desired compound as a colorless oil (51.7%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]#[CH:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.I[C:12]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:13]=1[NH2:14]>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>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][C:12]2[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:13]=2[NH2:14])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: C#Cc1cc(C)cc(C)c1
Reactant: Nc1ccc([N+](=O)[O-])cc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: Cc1cc(C)cc(C#Cc2cc([N+](=O)[O-])ccc2N)c1
Temperature: 25 °C

Procedure:
To a solution of 3,5-dimethylphenylethyne (156 mg in 7 mL of dry, nitrogen saturated triethylamine) was added 2-iodo-4-nitroaniline (264 mg, prepared essentially as described in: Toth, I. Helv. Chim. Acta, 1971, 54, 1486.) followed by tetrakis(triphenylphosphine)palladium (23 mg) and cuprous bromide (10 mg) and the mixture heated to reflux on an oil bath. After 2 hours the mixture was cooled to room temperature, concentrated in vacuo and purified by flash chromatography on silica gel (hexane:methylene chloride:ethyl acetate, 15:8:1) to give the title compound (256 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10]C)=[O:9])=[C:4]([NH:14][C:15](OCC)=O)[CH:3]=1.Br.BrC[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:24]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:6]([CH2:7][C:8]([OH:10])=[O:9])=[C:15]([C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)=[O:24])[NH:14]2)=[CH:12][CH:13]=1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1/C=C/C(=O)OC
Reactant: O=C(CBr)c1ccccn1
Agent: Br
Product: O=C(O)Cc1c(C(=O)c2ccccn2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound were prepared according the procedure described in step 2 of Example 31 from methyl trans-4-chloro-2-(ethoxycarbonylamino)cinnamate (Example 31, step 1) and 2-bromoacetylpyridine hydrobromide (H. McKennis et al., J. Org. Chem., 1963, 387.).