Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1.Cl[C:17]1[N:22]=[C:21]2[N:23]([C:26]([O:28][CH3:29])=[O:27])[CH:24]=[CH:25][C:20]2=[CH:19][CH:18]=1>O1CCOCC1.Cl[Pd]Cl.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:1][C:17]1[N:22]=[C:21]2[N:23]([C:26]([O:28][CH3:29])=[O:27])[CH:24]=[CH:25][C:20]2=[CH:19][CH:18]=1
Reactant: COC(=O)n1ccc2ccc(Cl)nc21
Reactant: O=C([O-])[O-]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CB1OB(C)OB(C)O1
Solvent: C1COCCO1
Product: COC(=O)n1ccc2ccc(C)nc21
Temperature: 110 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
Potassium carbonate (5.03 g), trimethyl boroxin (3.18 ml) and bis(diphenylphosphino)ferrocene dichloropalladium(II) (666 mg) were added to a solution of methyl 6-chloro-1H-pyrrolo[2,3-b]pyridin-1-carboxylate (1.92 g) in 1,4-dioxane (140 ml) and the mixture was stirred at 110° C. for 4 hours under argon atmosphere. The reaction mixture was cooled to room temperature, insoluble materials were filtered and the filtrate was concentrated in vacuo. The residue was diluted with ethyl acetate, washed with water and saturated brine successively, dried over magnesium sulfate and concentrated in vacuo. The resulted residue was purified with a silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=4/1 to 3/7) to give methyl 6-methyl-1H-pyrrolo[2,3-b]pyridin-1-carboxylate (1.30 g) as a brown powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=[C:10]([C:20](O)=[O:21])[N:9]=2)=[CH:4][CH:3]=1.Cl.[F:24][C:25]([F:34])([F:33])[C:26]1[N:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=1>>[F:34][C:25]([F:24])([F:33])[C:26]1[N:30]=[C:29]([CH2:31][NH:32][C:20]([C:10]2[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:13]([O:14][CH2:15][C:16]([F:18])([F:19])[F:17])=[CH:12][N:11]=2)=[O:21])[O:28][N:27]=1
Reactant: NCc1nc(C(F)(F)F)no1
Reactant: O=C(O)c1ncc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)n1
Agent: Cl
Product: O=C(NCc1nc(C(F)(F)F)no1)c1ncc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyrimidine-2-carboxylic acid (example W) and C-(3-trifluoromethyl-[1,2,4]oxadiazol-5-yl)-methylamine hydrochloride (CAS registry No. 944905-93-5; example AK) as starting materials; LC-MS (UV peak area/ESI) 100%, 482.0446 (M+H)+.
Reaction SMILES: Br.C([N:9]1[C:13]2=[C:14]([N+:29]([O-:31])=[O:30])[C:15]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][C:22]=3[F:28])=[C:16]([CH3:19])[C:17](=[O:18])[N:12]2[CH2:11][CH2:10]1)C1C=CC=CC=1.C(OC(=O)C)C>C(O)(=O)C>[Br:27][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:15]2[C:14]([N+:29]([O-:31])=[O:30])=[C:13]3[NH:9][CH2:10][CH2:11][N:12]3[C:17](=[O:18])[C:16]=2[CH3:19])=[C:22]([F:28])[CH:23]=1
Reactant: Cc1c(Nc2ccc(Br)cc2F)c([N+](=O)[O-])c2n(c1=O)CCN2Cc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1c(Nc2ccc(Br)cc2F)c([N+](=O)[O-])c2n(c1=O)CCN2
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.9 %

Procedure:
HBr in acetic acid (20 mL) was added to 1-benzyl-7-(4-bromo-2-fluoro-phenylamino)-6-methyl-8-nitro-2,3-dihydro-1H-imidazo[1,2-a]pyridin-5-one (I-1f: 1.4 g) and the resulting mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC (100% ethylacetate). The reaction mixture was partitioned between ice water and ethyl acetate. The organic layer was concentrated to afford the crude product. Purification by column chromatography on silica gel (65% ethylacetate in hexane) afforded 600 mg of the product (54.5% yield).
Reaction SMILES: [C:1]([CH:3]([OH:12])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)#[N:2].C1C=CC=CC=1.C(O)C>Cl>[C:1]([C@@H:3]([OH:12])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)#[N:2]
Reactant: N#CC(O)CCc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: c1ccccc1
Product: N#C[C@@H](O)CCc1ccccc1

Procedure:
α-Cyano-3-phenylpropyl alcohol wad hydrolyzed in concentrated hydrochloric acid (0.5 ml) at room temperature for 3 days with stirring to convert it to 1-hydroxy-4-phenyl butyric acid which was isolated by crystallization from benzene. [α]D20 =7.02° (ethanol, c=0.968).
Reaction SMILES: [CH:1]1([C:5]2[NH:13][C:12]3[C:11](=[O:14])[NH:10]/[C:9](=[N:15]\[NH2:16])/[N:8]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:7]=3[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[C:22](OCC)(OCC)(OCC)[CH3:23]>>[CH:1]1([C:5]2[NH:13][C:12]3[C:11](=[O:14])[N:10]4[C:22]([CH3:23])=[N:16][N:15]=[C:9]4[N:8]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:7]=3[N:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: CCCCCn1/c(=N/N)[nH]c(=O)c2[nH]c(C3CCC3)nc21
Reactant: CCOC(C)(OCC)OCC
Product: CCCCCn1c2nc(C3CCC3)[nH]c2c(=O)n2c(C)nnc12
Temperature: 100 °C
Reaction time: 8 h
Yield: 10.6 %

Procedure:
(2E)-8-cyclobutyl-3-pentyl-3,7-dihydro-1H-purine-2,6-dione 2-hydrazone (100 mg, 0.0003 mol) was mixed with triethyl orthoacetate (10 mL, 0.05 mol) and then stirred at 100° C. overnight. After cooling to room temperature, the mixture was concentrated and purified by preparative LCMS to yield the desired product (10 mg, 9.2%). 1HNMR (300 MHz, CD3OD): δ 4.35 (m, 2H), 3.72 (m, 1H), 2.84 (s, 3H), 2.44 (m, 4H), 2.05 (m, 2H), 1.90 (m, 2H), 1.40 (m, 4H), 0.92 (m, 3H). LCMS calculated for C16H23N6O (M+H): 315.2. found: 315.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[OH-].[K+].Cl.[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29]Cl>CS(C)=O>[ClH:22].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:29][CH2:28][N:27]([CH3:31])[CH3:26])[C:12]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc([C@@H]2Sc3cc(Cl)ccc3NC(=O)[C@@H]2O)cc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1ccc([C@@H]2Sc3cc(Cl)ccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 149.9 %

Procedure:
A mixture of 6.72 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 2.58 g of potassium hydroxide and 90 ml of dimethylsulfoxide is stirred at room temperature for one hour. Then, 3.16 g of 2-(dimethylamino)ethyl chloride hydrochloride are added to the mixture, and said mixture is stirred at room temperature for 16 hours. The reaction mixture is poured into ice-water, and the precipitated crystals are collected by filtration and washed with water. The crystals are dissolved in concentrated hydrochloric acid, and the solution is washed with ethyl acetate and then alkalized with potassium carbonate. Then, the solution is extracted with chloroform. The extract is washed with water, dried and then evaporated to remove solvent. The residue is converted to its hydrochloride and then recrystallized from ethanol. 6.65 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride are thereby obtained. Recrystallization of the product from a mixture of chloroform, ethanol and ether gives crystals (prisms) melting at 136°-139° C.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13](=[O:41])[NH:14][CH2:15][CH2:16][CH2:17][NH:18][CH:19]([C:23]1[N:28]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:27](=[O:36])[C:26]2=[C:37]([Cl:40])[CH:38]=[CH:39][N:25]2[N:24]=1)[CH:20]1[CH2:22][CH2:21]1)([CH3:11])([CH3:10])[CH3:9].[CH3:42][C:43]1[CH:51]=[CH:50][C:46]([C:47](Cl)=[O:48])=[CH:45][CH:44]=1>C(Cl)Cl>[C:8]([O:12][C:13](=[O:41])[NH:14][CH2:15][CH2:16][CH2:17][N:18]([CH:19]([C:23]1[N:28]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:27](=[O:36])[C:26]2=[C:37]([Cl:40])[CH:38]=[CH:39][N:25]2[N:24]=1)[CH:20]1[CH2:21][CH2:22]1)[C:47](=[O:48])[C:46]1[CH:50]=[CH:51][C:43]([CH3:42])=[CH:44][CH:45]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)NCCCNC(c1nn2ccc(Cl)c2c(=O)n1Cc1ccccc1)C1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(=O)N(CCCNC(=O)OC(C)(C)C)C(c2nn3ccc(Cl)c3c(=O)n2Cc2ccccc2)C2CC2)cc1
Reaction time: 1.5 h
Yield: 98 %

Procedure:
Triethylamine (0.425 mL, 3.05 mmol) was added to a 0° C. solution of (3-{[(3-benzyl-5-chloro-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-cyclopropyl-methyl]-amino}-propyl)-carbamic acid tert-butyl ester (0.74 g, 1.52 mmol) and 4-methylbenzoyl chloride (0.403 mL, 3.05 mmol) in CH2Cl2 (10 mL) and was stirred at 0° for 1.5 h. The reaction mixture was quenched with 1 N HCl (30 mL) and extracted with CHCl3 (3×50 mL). The combined organic extracts were washed with saturated NaHCO3 (1×100 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 3/1 hexane/EtOAc to afford the title compound (0.90 g, 98%) as a solid: MS (ESI+) 604 (M++H); HRMS (ESI+) calculated: 604.2691 (M++H). found: 604.2702 (M++H).
Reaction SMILES: C(#N)C.[CH2:4]([O:6][C:7]([N:9]1[CH2:15][CH:14]([NH:16]CC2C=CC(OC)=CC=2)[C:13]2=[N:26][C:27]([C:31]3[CH:36]=[CH:35][N:34]=[CH:33][N:32]=3)=[CH:28][C:29](=[O:30])[N:12]2[CH2:11][CH2:10]1)=[O:8])[CH3:5].O.[N+]([O-])([O-])=O.[Ce].[NH4+]>>[CH2:4]([O:6][C:7]([N:9]1[CH2:15][CH:14]([NH2:16])[C:13]2=[N:26][C:27]([C:31]3[CH:36]=[CH:35][N:34]=[CH:33][N:32]=3)=[CH:28][C:29](=[O:30])[N:12]2[CH2:11][CH2:10]1)=[O:8])[CH3:5]
Reactant: CCOC(=O)N1CCn2c(nc(-c3ccncn3)cc2=O)C(NCc2ccc(OC)cc2)C1
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)N1CCn2c(nc(-c3ccncn3)cc2=O)C(N)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.3 %

Procedure:
To a solution of 10.75 g (23.86 mmol) of 9-(4-methoxy-benzylamino)-4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-1,4a,7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester acetonitrile/water (160/80 mL) was added 26.16 g (47.73 mmol) of ammonium cerium nitrate. The reaction was stirred at room temperature for 2 hours. 13.08 g (23.86 mmol) of ammonium cerium nitrate was added and the reaction was stirred at room temperature for 0.5 hours. After an acido-basic work-up and extraction with dichloromethane, the organic phase was washed with a saturated solution of sodium chloride, dried over sodium sulfate and concentrated to afford 5.15 g (65%) of a powder.
Reaction SMILES: Cl.[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]([CH3:20])[C:13]([NH:15][CH2:16][CH2:17][CH2:18][NH2:19])=[O:14])=[CH:8][CH:7]=1)[CH:3]([CH3:5])[CH3:4].CS[C:23]1[NH:24][CH2:25][CH2:26][N:27]=1>>[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]([CH3:20])[C:13]([NH:15][CH2:16][CH2:17][CH2:18][NH:19][C:23]2[NH:27][CH2:26][CH2:25][N:24]=2)=[O:14])=[CH:8][CH:7]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)Cc1ccc([C@@H](C)C(=O)NCCCN)cc1
Reactant: CSC1=NCCN1
Agent: Cl
Product: CC(C)Cc1ccc([C@@H](C)C(=O)NCCCNC2=NCCN2)cc1

Procedure:
The (R)2-[(4-isobutylphenyl)-N-3-(aminopropyl)propionamide hydrochloride (see example 5) is converted in the free amine and treated with 2-methylthio-2-imidazoline iodohydrate (commercial reactant) according to the above cited Bodanszky procedure (J. Am. Chem. Soc., 86, 4452, 1964) to give (R)2-(4′-isobutylphenyl)-N-[3-(imidazolin-2-yl)aminopropyl]propionamide
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][Si](C)(C)C)[CH:5]=[CH:4][N:3]=1.I[C:15]1[NH:19][C:18]([CH3:20])=[N:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:16]2[N:17]=[C:18]([CH3:20])[NH:19][CH:15]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ncc(I)[nH]1
Reactant: Cc1cc(C#C[Si](C)(C)C)ccn1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
2-Methyl-4-trimethylsilanylethynyl-pyridine (12 g, 74 mmol) and 5-iodo-2-methyl-1H-imidazole (13.24 g, 64 mmol, synthesis: Cliff and Pyne, Synthesis 681–682 (1994) were dissolved in 75 mL dry THF and 20 mL dry DMF. This mixture was evacuated and backfilled with argon several times to remove oxygen from the solution. Solution 2: Triphenylphosphine (223 mg, 0.85 mmol), bis(triphenylphosphine)-palladium(II)chloride (1.79 g, 2.55 mmol), copper(I)iodide (81 mg, 0.43 mmol) and triethyl amine (8.87 mL, 64 mmol) were dissolved in 75 mL dry THF. This mixture was also evacuated and backfilled with argon several times to remove oxygen from the solution. Solution 2 was heated to 40° C. and solution 1 was added dropwise. The reaction mixture was heated to 60° C. and tetrabutylammonium fluoride solution (1M in THF, 55 mL, 55 mmol) was added dropwise during 45 min. The reaction was than stirred at RT overnight. The solvent was evaporated. The residue was taken up in 200 mL water and extracted three times with ethyl acetate (200 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude product was purified by chromatography on silica gel (methylene chloride/methanol 95:5) and recrystallized from a mixture of methylene chloride and ethyl acetate. The desired product was obtained as a light brown solid (7.44 g, 59%).
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:12][C:13]([F:18])([F:17])[CH2:14][CH2:15][OH:16]>>[Cl:1][C:2]1[C:3]([O:16][CH2:15][CH2:14][C:13]([F:18])([F:17])[F:12])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Reactant: OCCC(F)(F)F
Product: O=C(O)c1cnc(OCCC(F)(F)F)c(Cl)c1
Yield: 66 %

Procedure:
The title compound is prepared in 66% yield (6.48 g, white solid) from 5,6-dichloronicotinic acid (7.00 g, 36.5 mmol) and 3,3,3-trifluoropropan-1-ol (8.32 g, 72.9 mmol) in a similar manner to Step-1 of Amine-1.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([OH:14])=O)[CH:7]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.ClC(OC)=O.[NH2:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([CH2:40][CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])(=[O:39])=[O:38])=[CH:33][CH:32]=1>C(Cl)Cl.O>[CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([S:37]([CH2:40][CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])(=[O:39])=[O:38])=[CH:33][CH:32]=3)=[O:14])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CCCN(CC1CC1)c1cc(C(=O)O)ncn1
Reactant: CCOC(=O)CCCS(=O)(=O)c1ccc(N)cc1
Agent: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(S(=O)(=O)CCCC(=O)OCC)cc2)ncn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A cooled (0° C.) solution of 6-((cyclopropylmethyl)(propyl)amino)pyrimidine-4-carboxylic acid (Intermediate 21, 100 mg; 0.43 mmol) in DCM (5 ml) was treated with triethylamine (0.1 ml; 0.72 mmol) and methyl chloroformate (0.060 ml; 0.78 mmol). After stirring at 0° C. for 30 minutes, ethyl 4-(4-aminophenylsulfonyl)butanoate (Intermediate 48, 125 mg; 0.46 mmol) was added. After stirring at 0° C. for 5 minutes and RT for 1 hour water was added and the mixture passed through a hydrophobic frit. The solvent was removed in vacuo and the residue purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give ethyl 4-(4-(6-((cyclopropylmethyl)(propyl)amino)pyrimidine-4-carboxamido)phenylsulfonyl)butanoate. The intermediate was redissolved in ethanol (3 ml) and treated with 10% sodium hydroxide solution (2 ml). After stirring at RT for 18 hours the mixture was acidified to pH 3 with dilute HCl and EtOAc added. The organic phase was removed in vacuo and the aqueous phase extracted with EtOAc. The combined organic extracts were passed through a hydrophobic frit and the solvent removed in vacuo. The residue was triturated with diisopropyl ether and allowed to dry to give the title compound as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[C:5]([C:10]#[N:11])=[C:6]([CH3:9])[C:7]=1I.[CH2:21]([O:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(OCC)(=O)C.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>[CH2:21]([O:28][C:29]1[CH:34]=[C:33]([C:7]2[C:6]([CH3:9])=[C:5]([C:10]#[N:11])[C:4]([NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[C:3]([O:19][CH3:20])[C:2]=2[Br:1])[CH:32]=[CH:31][CH:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1c(Br)c(I)c(C)c(C#N)c1NC(=O)C(C)(C)C
Reactant: OB(O)c1cccc(OCc2ccccc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COc1c(Br)c(-c2cccc(OCc3ccccc3)c2)c(C)c(C#N)c1NC(=O)C(C)(C)C
Temperature: 95 °C
Reaction time: 4 h
Yield: 54.9 %

Procedure:
N-(3-Bromo-6-cyano-4-iodo-2-methoxy-5-methylphenyl)-2,2-dimethylpropionamide (I-6) (1.02 g, 2.26 mmol), 3-benzyloxybenzeneboronic acid (541 mg, 2.37 mmol), tripotassium phosphate (74-85%, 1.30 g, 4.52 mmol) and tetrakis(triphenylphosphine)palladium(0) (261 mg, 0.226 mmol) were added to a 50-ml eggplant-type flask, followed by purging with nitrogen. N,N-Dimethylformamide (20 ml) was injected into it with a syringe, followed by stirring at 95° C. for 4 hours. After cooling, the reaction liquid was diluted with ethyl acetate, successively washed with saturated brine (×3), 1 N hydrochloric acid, saturated brine, an aqueous saturated sodium hydrogencarbonate solution and saturated brine, dried on anhydrous magnesium sulfate, then the solvent was concentrated under reduced pressure to obtain a pale brown residue. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=6:1) to obtain the entitled compound (630 mg, 55%) as a pale brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1.[F:22][C:23](=[CH2:27])[C:24](O)=[O:25].C(OP(ON1C(=O)C2C=CC=CC=2N=N1)(OCC)=O)C.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[F:22][C:23](=[CH2:27])[C:24]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1)=[O:25]
Reactant: CCOC(=O)c1c[nH]c2ncnc(-c3cccc(N)c3)c12
Reactant: C=C(F)C(=O)O
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: C=C(F)C(=O)Nc1cccc(-c2ncnc3[nH]cc(C(=O)OCC)c23)c1
Temperature: 50 °C

Procedure:
Ethyl 4-(3-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (0.028 g, 0.10 mmol), 2-fluoroacrylic acid (0.013 g, 0.15 mmol), 3-[(diethoxyphosphoryl)oxy]-1,2,3-benzotriazin-4(3H)-one (0.060 g, 0.20 mmol), and DIPEA (0.070 mL, 0.40 mmol) were suspended in DMA (1.0 mL) in a sealed tube. The reaction mixture was purged with argon and the reaction flask was capped and heated to 50° C. for 12 hours. The completed reaction was passed through a syringe filter, and was directly purified by reverse phase HPLC using an acetonitrile gradient in water with 0.1% NH4OH modifier to afford ethyl 4-{3-[(2-fluoroacryloyl)amino]phenyl}-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate. LRMS (ESI) calc'd for C18H16FN4O3 [M+H]+: 355, found 355. 1H NMR (600 MHz, DMSO-D6) δ 12.99 (s, 1H), 10.44 (s, 1H), 8.91 (s, 1H), 8.32 (s, 1H), 8.09 (t, J=1.8 Hz, 1H), 7.87 (ddd, J=1.1, 2.1, 8.0 Hz, 1H), 7.45 (t, J=7.8 Hz, 1H), 7.40 (dt, J=1.3, 7.7 Hz, 1H), 5.72 (dd, J=3.6, 47.6 Hz, 1H), 5.44 (dd, J=3.7, 15.6 Hz, 1H), 3.85 (q, J=7.1 Hz, 2H), 0.84 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>>[C:10]([N:2]1[CH:3]=[C:4]2[C:9]([CH:8]=[CH:7][CH:6]=[CH:5]2)=[N:1]1)(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc2[nH]ncc2c1
Product: CC(=O)n1cc2ccccc2n1
Yield: 96 %

Procedure:
Indazole (3.5 g, 29.6 mmol) and acetic anhydride (35 ml) were heated at 60° C. under nitrogen for 3 h. Excess acetic anhydride was evaporated and the remaining oily residue partitioned between 3% aqueous NaHCO3 (20 ml) and EtOAc (30 ml). The organic layer was separated, dried (MgSO4) and evaporated to provide the title product (4.5 g, 96%); 1HNMR (400 MHz, CDCl3) δ: 2.80 (s, 3H), 7.37 (t, 1H), 7.58 (t, 1H), 7.75 (d, 1H), 8.46 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH:6]=O)[CH2:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=1[CH:16]([O:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:17][NH2:18].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=1[CH:16]([O:19][Si:20]([CH2:21][CH3:22])([CH2:25][CH3:26])[CH2:23][CH3:24])[CH2:17][NH:18][CH2:6][C:2]1([CH3:1])[CH2:3][CH2:4][CH2:5]1
Reactant: CC1(C=O)CCC1
Reactant: CC[Si](CC)(CC)OC(CN)c1c(Cl)cccc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC[Si](CC)(CC)OC(CNCC1(C)CCC1)c1c(Cl)cccc1Cl
Reaction time: 0.75 h
Yield: 56.7 %

Procedure:
To a mixture of 1-methylcyclobutanecarbaldehyde (38.3 mg, 0.390 mmol) in DCM (2.0 ml) was added 2-(2,6-dichlorophenyl)-2-((triethylsilyl)oxy)ethanamine (125 mg, 0.390 mmol) followed by NaBH(OAc)3 (124 mg, 0.585 mmol). After 45 min, this was quenched with sat. aq. NaHCO3. The layers were separated. The aqueous layer was extracted with DCM. The combined organic layers were concentrated and then purified by prep TLC eluted with 5% MeOH/DCM to provide 2-(2,6-dichlorophenyl)-N-((1-methylcyclobutyl)methyl)-2-((triethylsilyl)oxy)ethanamine (89 mg, 0.221 mmol, 56.7% yield). 1H NMR (500 MHz, CDCl3) δ 7.18-7.22 (m, 2H), 6.98-7.10 (m, 1H), 5.57 (br. s., 1H), 3.30 (t, J=10.70 Hz, 1H), 2.74 (br. s., 1H), 2.60 (br. s., 1H), 2.51 (d, J=10.03 Hz, 1H), 1.68-1.89 (m, 4H), 1.60 (br. s., 2H), 1.47 (br. s., 1H), 1.03-1.14 (m, 3H), 0.76-0.84 (m, 9H), 0.41-0.54 (m, 6H); LCMS (ESI) m/z 402.4 (M+H)+.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[CH:6]1([OH:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.N1C=CC=CC=1.Cl.N1C=CC=CC=1>C1C=CC=CC=1>[C:2](=[O:3])([O:14][CH:6]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[O:4][CH3:5]
Reactant: COC(=O)Cl
Reactant: OC1CCCCCCC1
Agent: Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: COC(=O)OC1CCCCCCC1
Reaction time: 12 h

Procedure:
18.9 gm of methyl chloroformate were added drop-by-drop under agitation to a solution of 25.6 gm of cyclooctanol and 15.8 gm of absolute pyridine in 150 ml of dry benzene under external cooling at 0° to 5° C. After the methyl chloroformate had been added, agitation was continued for 12 hours at room temperature. Then, the benzene phase was drawn off from the precipitated pyridine hydrochloride, and washed with diluted hydrochloric acid, sodium hydroxide solution and water, and dried. After the solvent had been distilled off, the raw ester was distilled in vacuo by means of a Vigreux column. A colorless liquid was obtained which had a herbal, very natural and complex fragrance which is distinguished by a strong and long-clinging flowery jasmine scent.
Reaction SMILES: CS[CH:3]1[C:11]2[C:6](=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:18]>[Ni].O.O1CCCC1>[C:12]1([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:6]=2[NH:5][C:4](=[O:18])[CH2:3]3)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CSC1C(=O)Nc2c(-c3ccccc3)cccc21
Agent: [Ni]
Solvent: C1CCOC1
Solvent: O
Product: O=C1Cc2cccc(-c3ccccc3)c2N1

Procedure:
A stirred solution of 21.5 g. (0.084 mole) of 3-methylthio-7-phenylindolin-2-one in 400 ml. of tetrahydrofuran was treated portionwise with 110 g. of a commercial Raney nickel/water slurry over a 3 hr. period. The mixture was filtered through Celite and the filtrate was concentrated to a gummy residue. The residue was recrystallized from cyclohexane-benzene to yield 7.6 g. (43%) of product as tan needles, m.p. 167°-169° C.