Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[C@@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:21]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:23])[CH3:22])[C@@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)[C@@H]1C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1C(=O)O
Reaction time: 16 h
Yield: 95.4 %

Procedure:
To (2R,3S)-1-(tert-butoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid (4.812 g, 20.81 mmol) in DMF (30 mL) at 0° C. was added tert-butylchlorodimethylsilane (9.409 g, 62.43 mmol) and triethylamine (10.53 g, 104.0 mmol). The cold bath was removed and the reaction mixture was stirred for 16 hours. The mixture was diluted with EtOAc (50 mL) and 10% NaOH (30 mL), and the phases were separated. The organic phase was washed with 10% NaOH. The combined aqueous phases were acidified with concentrated HCl until pH=2. The aqueous phase was extracted with DCM. The combined organic phases were dried (Na2SO4) and concentrated under reduced pressure to give the crude product 6.86 g).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:16][CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21]>O>[Br:16][CH2:17][CH2:18][CH2:19][C:20]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:21]
Reactant: OCc1ccccc1
Reactant: O=C(Cl)CCCBr
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(CCCBr)OCc1ccccc1
Yield: 36.7 %

Procedure:
Benzyl alcohol (28 mL, 270 mmol) and triethylamine (3.8 mL, 27 mmol) were combined and stirred over an ice bath, under nitrogen (N2). 4-Bromobutyryl chloride (1) (3.1 mL, 27 mmol) was added in a dropwise fashion, then the reaction was stirred an additional 30 minutes. The completed reaction was poured into 250 mL H2O and extracted with Et2O (3×200 mL). The ether extracts were combined, dried over MgSO4, and solvent removed in vacuo. Resulting crude product was purified by column chromatography, eluting with EtOAc/Hex (10/90) to afford 2.55 g (37%) of the desired benzyl 4-bromobutyrate (2a). 1H NMR (200 MHz, CDCl3) d 7.4 (s, 5H), 5.2 (s, 2H), 3.4 (t, 2H), 2.6 (t, 2H), 2.2 (p, 2H); mass spec (DCl, NH3) (M+NH4)+ 275.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:14][CH3:15])[CH:8]=[CH:9][C:10]=2[O:12][CH3:13])[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[CH:27]=[C:26]2[C:22]([CH:23]=[N:24][NH:25]2)=[CH:21][CH:20]=1.C(OC(O)C)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[NH:25]1[C:26]2[C:22](=[CH:21][CH:20]=[C:19]([NH:18][C:2]3[C:11]4[C:6](=[C:7]([O:14][CH3:15])[CH:8]=[CH:9][C:10]=4[O:12][CH3:13])[N:5]=[CH:4][C:3]=3[C:16]#[N:17])[CH:27]=2)[CH:23]=[N:24]1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: COc1ccc(OC)c2c(Cl)c(C#N)cnc12
Agent: CCOC(C)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(OC)c2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc12
Yield: 91.9 %

Procedure:
A mixture of 0.148 g of 4-chloro-5,8-dimethoxy-quinolin-3-carbonitrile, 0.093 g of 6-aminoindazole, and 5 ml of ethoxyethanol was stirred under nitrogen, at reflux temperature for 30 minutes. The mixture was cooled and added to 50 ml of water. To this mixture was added sodium carbonate to pH 9. The product was collected, washed with water, dried, and washed with 10 ml of hexanes-ethyl acetate (4:1) to give 0.189 g of 4-(1H-indazol-6-ylamino)-5,8-dimethoxy-quinoline-3-carbonitrile as a solid, mp 302-305° C.; mass spectrum (EI, m/e): M 345.1223.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[O:16]=[C:17]1[C:22]2=[CH:23][NH:24][C:25]([CH:26]=O)=[C:21]2[CH2:20][CH2:19][NH:18]1.N1CCCCC1>C(O)C>[CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:26][C:25]1[NH:24][CH:23]=[C:22]2[C:21]=1[CH2:20][CH2:19][NH:18][C:17]2=[O:16])(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1[nH]cc2c1CCNC2=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CNS(=O)(=O)c1ccc2c(c1)C(=Cc1[nH]cc3c1CCNC3=O)C(=O)N2
Temperature: 80 °C
Yield: 44.8 %

Procedure:
A mixture of 2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid methylamide (66 mg, 0.3 mmol), 4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridine-1-carbaldehyde (50 mg, 0.3 mmol) and 0.1 mL of piperidine in ethanol (1 mL) was heated in a sealed tube at 80° C. for 4 hours. The precipitate was collected by vacuum filtration, washed with cold ethanol and dried to give 50 mg (45%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:13]=1)[C:7](N(OC)C)=[O:8].[CH3:14][Mg+].[Br-]>C1COCC1>[Br:1][C:2]1[CH:13]=[C:6]([C:7](=[O:8])[CH3:14])[CH:5]=[N:4][CH:3]=1
Reactant: CON(C)C(=O)c1cncc(Br)c1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=O)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
To a solution of 5-bromo-N-methoxy-N-methyl-nicotinamide (2.08 g, 8.5 mmol) in THF (20 mL) was added MeMgBr (1.52 g, 12.75 mmol) at −78° C. After the addition, the reaction mixture was stirred at room temperature for 2 hours before quenching with water. After extraction with EtOAC, the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was then purified by flash column chromatography to afford the title compound (1.5 g, 88%).
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([OH:15])=[CH:6][CH:7]=[C:8]2[CH:13]=[O:14])[CH3:2].S(Cl)([Cl:19])(=O)=O.O>C1C=CC=CC=1>[Cl:19][C:6]1[CH:7]=[C:8]([CH:13]=[O:14])[C:9]2[C:4]([C:5]=1[OH:15])=[C:3]([CH2:1][CH3:2])[CH:12]=[CH:11][CH:10]=2
Reactant: CCc1cccc2c(C=O)ccc(O)c12
Reactant: O=S(=O)(Cl)Cl
Solvent: O
Solvent: c1ccccc1
Product: CCc1cccc2c(C=O)cc(Cl)c(O)c12

Procedure:
0.81 g of 5-ethyl-4-hydroxy-1-naphthalenecarbaldehyde and 0.49 ml of sulfuryl chloride were heated in 30 ml of benzene under reflux for 30 minutes. The reaction solution was returned to room temperature and poured into water, followed by extraction with ethyl acetate. The resultant organic phase was washed with a saturated saline solution and dried with anhydrous magnesium sulfate, followed by concentration under reduced pressure. The resultant crystals were washed with isopropyl ether to obtain 0.8 g of the captioned compound as yellowish brown crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:44]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:42]=[CH:41][C:9]=2[O:10][C:11]2[C:16]([Cl:17])=[CH:15][C:14]([S:18]([N:21](CC3C=CC(OC)=CC=3OC)[C:22]3[N:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=3)(=[O:20])=[O:19])=[C:13]([F:40])[CH:12]=2)[CH:5]=[CH:4][N:3]=1.Cl.[CH3:50][C:51]1[CH:56]=[CH:55][C:54]([S:57]([OH:60])(=[O:59])=[O:58])=[CH:53][CH:52]=1>O1CCOCC1.CO>[CH3:50][C:51]1[CH:52]=[CH:53][C:54]([S:57]([OH:60])(=[O:59])=[O:58])=[CH:55][CH:56]=1.[NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:44]=[C:43]([C:45]([F:47])([F:48])[F:46])[CH:42]=[CH:41][C:9]=2[O:10][C:11]2[C:16]([Cl:17])=[CH:15][C:14]([S:18]([NH:21][C:22]3[N:23]=[CH:24][C:25]([F:28])=[CH:26][N:27]=3)(=[O:20])=[O:19])=[C:13]([F:40])[CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(CN(c2ncc(F)cn2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(C(F)(F)F)cc3-c3ccnc(N)c3)cc2F)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Nc1cc(-c2cc(C(F)(F)F)ccc2Oc2cc(F)c(S(=O)(=O)Nc3ncc(F)cn3)cc2Cl)ccn1
Reaction time: 18 h

Procedure:
4-[2-(2-Aminopyridin-4-yl)-4-(trifluoromethyl)phenoxy]-5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(5-fluoropyrimidin-2-yl)benzenesulfonamide (Preparation 20, 2.24 g, 3.16 mmol) was dissolved in 1,4-dioxane (6.0 mL) and a 4.0 M solution of hydrogen chloride in 1,4-dioxane (4.0 mL, 16 mmol) was added. The reaction mixture was stirred for 18 hours then concentrated in vacuo. The residue was partitioned between water and dichloromethane. A large amount of undissolved solid was present. The aqueous phase was adjusted to pH10 with 1N aqueous sodium hydroxide solution, then back to pH3 with citric acid. The mixture was filtered and the solid was set aside. The organic phase was collected and combined with the solid and the solvent removed in vacuo. The residue was purified by silica gel column chromatography (0 to 10% methanol in dichloromethane gradient elution). The resulting residue was then slurried in methanol before 1 equivalent of 4-methylbenzenesulfonic acid was added and the mixture concentrated in vacuo. The residue was dissolved in a minimum amount of hot methanol and filtered while hot. The filtrate was diluted with tert-butyl methyl ether. Crystals formed on standing which were collected by filtration and washed with tert-butyl methyl ether to afford the title compound as a white solid (1.48 g containing 0.5 mol % tert-butyl methyl ether). The solid was dissolved in a minimum amount of boiling methanol, then water was added slowly. Fine crystals formed which were collected by filtration and rinsed with water to afford the title compound as a white powder (1.45 g).
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.[C:12]([N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)(=[O:16])/[CH:13]=[CH:14]/[CH3:15].[OH-]>>[CH:7](=[CH:15]/[CH:14]=[CH:13]/[C:12]([N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16])[C:6]1[CH:1]=[CH:2][C:3]2[O:11][CH2:10][O:9][C:4]=2[CH:5]=1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: C/C=C/C(=O)N1CCCCC1
Agent: [OH-]
Product: O=C(/C=C/C=Cc1ccc2c(c1)OCO2)N1CCCCC1

Procedure:
1 mol of piperonal is reacted with 1.1 mols of crotonic acid piperidide in the presence of 0.09 mol of a hydroxide, indicated in Table 2 below, under the reaction conditions described in Example 1 to give piperonylidenecrotonic acid piperidide. The yields obtained are likewise indicated in Table 2.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][OH:11])[CH2:2][CH2:3][CH3:4].[H-].[Na+].Cl[C:15]1[C:16]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[N:17][S:18][N:19]=1.O>O1CCCC1>[CH2:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][C:15]1[C:16]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[N:17][S:18][N:19]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOCCO
Reactant: Clc1nsnc1-c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCOCCOCCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(2-butoxyethoxy)ethanol (1.46 g, 9 mmol) and sodium hydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[N:16]=[N:17][C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:21]([N+:27]([O-:29])=[O:28])=[CH:20][C:19]=1Cl)[N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])(=[O:3])[CH3:2].[C-:31]#[N:32].[Na+].O>C(CCSCCC#N)#N>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[N:16]=[N:17][C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:21]([N+:27]([O-:29])=[O:28])=[CH:20][C:19]=1[C:31]#[N:32])[N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])(=[O:3])[CH3:2]
Reactant: CCN(CC)c1ccc(N=Nc2c(Cl)cc([N+](=O)[O-])cc2[N+](=O)[O-])c(NC(C)=O)c1
Reactant: [C-]#N
Agent: N#CCCSCCC#N
Agent: [Na+]
Solvent: O
Product: CCN(CC)c1ccc(N=Nc2c(C#N)cc([N+](=O)[O-])cc2[N+](=O)[O-])c(NC(C)=O)c1
Temperature: 132.5 °C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
7.175 parts of cuprous bromide are dissolved in 350 parts of bis-(β-cyanoethyl) sulfide. 43.45 parts of 3-acetamido-4-(2'-chloro-4',6'-dinitrophenylazo)-N,N-diethylaniline are introduced, and the mass is brought to 130° C. During 1 hour 30 minutes, in an open reactor, a solution of 6.35 parts of sodium cyanide in 20 parts of water is added to the mixture and the mixture is stirred for 4 hours at 130-135° C. The product formed is separated as in Example 1; 35.12 parts of 3-acetamido-4-(2'-cyano-4', 6'-dinitrophenylazo)-N,N-diethylaniline are obtained. The yield is 82.5%.
Reaction SMILES: [CH2:1]([N:4]([C@H:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1)[C:5](=[O:11])[C:6]([CH3:10])([CH3:9])[CH2:7][Cl:8])[CH:2]=[CH2:3].I[C:22]1[CH:23]=[C:24]2[CH2:39][C@@:29]3([C:37]4[C:32](=[N:33][CH:34]=[CH:35][CH:36]=4)[NH:31][C:30]3=[O:38])[CH2:28][C:25]2=[N:26][CH:27]=1.C1(CNCC2CCCCC2)CCCCC1>CN(C=O)C.[Pd].C(P(CCCC)CCCC)CCC.C(P(CCCC)CCCC)CCC>[Cl:8][CH2:7][C:6]([CH3:10])([CH3:9])[C:5]([N:4]([C@H:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1)[CH2:1]/[CH:2]=[CH:3]/[C:22]1[CH:23]=[C:24]2[CH2:39][C@@:29]3([C:37]4[C:32](=[N:33][CH:34]=[CH:35][CH:36]=4)[NH:31][C:30]3=[O:38])[CH2:28][C:25]2=[N:26][CH:27]=1)=[O:11]
Reactant: O=C1Nc2ncccc2[C@@]12Cc1cc(I)cnc1C2
Reactant: C=CCN(C(=O)C(C)(C)CCl)[C@@H]1CCc2ccccc21
Agent: [Pd]
Agent: C1CCC(CNCC2CCCCC2)CC1
Agent: CCCCP(CCCC)CCCC
Solvent: CN(C)C=O
Product: CC(C)(CCl)C(=O)N(C/C=C/c1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21)[C@@H]1CCc2ccccc21
Temperature: 120 °C

Procedure:
To a degassed solution of N-allyl-3-chloro-N-[(1R)-2,3-dihydro-1H-inden-1-yl]-2,2-dimethylpropanamide (110. mg, 0.377 mmol, prepared in Step B), (6S)-3-iodo-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (137 mg, 0.377 mmol, Intermediate 7) and N,N-dicyclohexylmethylamine (81.0 mg, 0.415 mmol) in DMF (3.77 mL) was added bis-(tri-1-butylphosphine) palladium(0) (57.8 mg, 0.113 mmol). This solution was once again degassed, before being sealed and heated in a microwave at 120° C. for 20 minutes. The reaction mixture was then diluted with DCM and washed twice with half-saturated brine. The organics were dried over sodium sulfate, filtered, and concentrated in vacuo to provide a residue. The residue was then applied to a silica gel column for purification, eluting with a gradient of 1-7% MeOH in DCM to provide the title compound. MS: m/z=527 (M+1).
Reaction SMILES: [H-].[Na+].[NH2:3][CH2:4][CH2:5][SH:6].[CH2:7](Cl)/[CH:8]=[C:9](/[CH2:11][CH2:12][CH2:13][C@@H:14]([CH2:16][CH2:17][CH2:18][C@@H:19]([CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH3:20])[CH3:15])\[CH3:10].O>O1CCCC1.C1OCCOCCOCCOCCOCCOC1>[CH3:10][C:9]([CH2:11][CH2:12][CH2:13][CH:14]([CH3:15])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:20])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:8][CH2:7][S:6][CH2:5][CH2:4][NH2:3]
Reactant: C/C(=C\CCl)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Reactant: NCCS
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=CCSCCN)CCCC(C)CCCC(C)CCCC(C)C
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
Under an atmosphere of argon, sodium hydride (9.60 g, 240 mmol, 60% dispersion in mineral oil) was added to a solution of 2-aminoethanethiol (15.3 g, 200 mmol) in 200 ml of tetrahydrofuran and the mixture was stirred at 20° C. for 30 minutes. To the reaction mixture, 18-crown-6 (50 mg, 0.190 mmol) was added and then a solution of phytyl chloride (1-chloro-3,7,11,15-tetramethyl-2-hexadecaene) [55.0 g, 175 mmol, prepared as described in Item a) given above] in 200 ml of tetrahydrofuran was added in dropwise for an hour at below 10° C. After stirring at 20°-30° C. for 24 hours, water was added to the reaction mixture until forming did not occur. The solvent was evaporated in vacuo to dryness and the remaining residue was extracted with ethyl ether. The ether layer was washed twice with water and an aqueous solution saturated with sodium chloride, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to dryness. The remaining residue was chromatographed on silica gel, eluting with CH2Cl2 /MeOH (10:1) to afford 50.9 g (81.8%) of the desired compound, as a pale brown oil.
Reaction SMILES: [OH-].[Na+].C1COCC1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])=[O:22])=[N:19][CH:20]=2)=[C:11]([CH2:31][NH:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=3)=[CH:35][CH:34]=2)[CH:10]=1>CO>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([NH:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:22])=[N:19][CH:20]=2)=[C:11]([CH2:31][NH:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=3)=[CH:35][CH:34]=2)[CH:10]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2ccc(Cl)cc2CNc2ccc(-c3ccc(Cl)cc3)cc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCNC(=O)c1ccc(-c2ccc(Cl)cc2CNc2ccc(-c3ccc(Cl)cc3)cc2)cn1
Temperature: 25 °C

Procedure:
A 3M aqueous solution of NaOH (0.08 mL, 0.25 mmol) was added to a THF (1 mL) and MeOH (0.5 mL) solution of ethyl 3-(5-(4-chloro-2-(((4′-chloro-[1,1′-biphenyl]-4-yl)amino)methyl)phenyl)picolinamido)propanoate (45 mg, 0.08 mmol) and the homogeneous mixture was stirred at room temperature. After 3 h the resulting mixture was concentrated in vacuo, suspended in water, and acidified with 2 M HCl. The resulting precipitate was filtered off and dried in vacuo to yield the title compound.
Reaction SMILES: Br[C:2]1[C:7]2[CH2:8][C@@H:9]([CH3:11])[O:10][C:6]=2[C:5]([NH2:12])=[CH:4][C:3]=1[CH3:13].[N:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=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>[CH3:11][C@@H:9]1[CH2:8][C:7]2[C:2]([C:17]3[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=3)=[C:3]([CH3:13])[CH:4]=[C:5]([NH2:12])[C:6]=2[O:10]1
Reactant: Cc1cc(N)c2c(c1Br)C[C@@H](C)O2
Reactant: OB(O)c1ccncc1
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: O
Solvent: CN(C)C=O
Product: Cc1cc(N)c2c(c1-c1ccncc1)C[C@@H](C)O2
Temperature: 135 °C
Reaction time: 1 h

Procedure:
The mixture of (R)-4-bromo-2,5-dimethyl-2,3-dihydrobenzofuran-7-amine (3g) (1.0 g, 4.3 mmol), pyridin-4-ylboronic acid (1.08 g, 8.77 mmol), Cs2CO3 (3.56 g, 10.9 mmol), Pd(PPh3)4 (0.506 g, 0.438 mmol) and water (9 mL) in DMF (44 mL) was stirred at 135° C. under N2 for 1 h. It was cooled to ambient temperature, poured into water (50 mL), extracted with EtOAc (150 mL, washed with water, brine, dried and concentrated. The residue was purified by column chromatography on silica gel eluting with hexanes/EtOAc (20:1 to 5:1 to 1:1) to give the title compound (3h) as a solid. MS-ESI (m/z): 241 (M+1)+.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:18][N:6]2[CH2:7][CH2:8][N:9]([C:11]3[N:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=3)[CH2:10][C@@H:5]2[CH2:4]1.[F:19][C:20]1[CH:25]=[CH:24][C:23](O)=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[F:19][C:20]1[CH:25]=[CH:24][C:23]([O:1][CH2:2][C@@H:3]2[CH2:18][N:6]3[CH2:7][CH2:8][N:9]([C:11]4[N:12]=[CH:13][C:14]([F:17])=[CH:15][N:16]=4)[CH2:10][C@@H:5]3[CH2:4]2)=[CH:22][CH:21]=1
Reactant: Oc1ccc(F)cc1
Reactant: OC[C@H]1C[C@H]2CN(c3ncc(F)cn3)CCN2C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1ccc(OC[C@H]2C[C@H]3CN(c4ncc(F)cn4)CCN3C2)cc1
Yield: 53.9 %

Procedure:
A solution of 0.25 g (0.99 mmol) of (7S,8aS)-7-hydroxymethyl-2-(5-fluoropyrimidin-2-yl)-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine (Preparation 13), 0.167 g (1.49 mmol) of 4-fluorophenol, 0.31 g (1.19 mmol) of triphenylphosphine and 0.19 mL (1.2 mmol) of diethyl azodicarboxylate (DEAD) in 10 mL of dry THF was stirred at ambient temperature for 16 h. The solvent was evaporated, the residue was dissolved in chloroform and washed with 1M sodium hydroxide. The organic phase was dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with 1:1 hexane:ethyl acetate and a second chromatography with 3:1 hexane:ethyl acetate gave 0.185 g (54%) of the title compound. mp (.HCl) 207.5°-208° C. 13C NMR (base, CDCl3) δ 31.7, 35.2, 43.8, 49.1, 51.4, 56.6, 62.3, 72.5, 115.5, 115.6, 115.9, 144.9, 145.2, 149.9, 153.2, 155.1, 155.6, 158.8, 158.9. m/z (MH+) 347.
Reaction SMILES: [C:1]([C:3]1[C:4]([F:14])=[C:5]([CH:9]=[C:10]([F:13])[C:11]=1[F:12])[C:6](F)=[O:7])#[N:2].[Cl-].[Al+3].[Cl-].[Cl-].[Si](Cl)(Cl)(Cl)[Cl:20]>>[C:1]([C:3]1[C:4]([F:14])=[C:5]([CH:9]=[C:10]([F:13])[C:11]=1[F:12])[C:6]([Cl:20])=[O:7])#[N:2]
Reactant: N#Cc1c(F)c(F)cc(C(=O)F)c1F
Reactant: Cl[Si](Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: N#Cc1c(F)c(F)cc(C(=O)Cl)c1F

Procedure:
76.6 g of 3-cyano-2,4,5-trifluoro-benzoyl fluoride are introduced at 60-65° C. together with 1 g of anhydrous aluminium chloride and then 25 g of silicon tetrachloride are added dropwise in the course of the evolution of gas. After the evolution of gas at 65° C. has ended, the mixture is distilled in vacuo. 73.2 g of 3-cyano-2,4,5-trifluoro-benzoyl chloride pass over in the boiling range from 120-122° C./14 mbar.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C@@H:6]([NH:14][C:15](=[O:30])[CH2:16][N:17]1[C:25]2[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=2[C:19]([C:26]([F:29])([F:28])[F:27])=[N:18]1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.I[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.COC1C2C(=C3C(=CC=2)C(OC)=CC=N3)N=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN1C(=O)CCC1>[C:8]1([CH2:7][C@H:6]([NH:14][C:15](=[O:30])[CH2:16][N:17]2[C:25]3[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=3[C:19]([C:26]([F:27])([F:28])[F:29])=[N:18]2)[C:2]2[N:1]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:5]=[CH:4][N:3]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Ic1ccccc1
Reactant: O=C(Cn1nc(C(F)(F)F)c2c1CCCC2)N[C@@H](Cc1ccccc1)c1ncc[nH]1
Agent: COc1ccnc2c1ccc1c(OC)ccnc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: O=C(Cn1nc(C(F)(F)F)c2c1CCCC2)N[C@@H](Cc1ccccc1)c1nccn1-c1ccccc1
Temperature: 115 °C

Procedure:
To (S)-N-(1-(1H-imidazol-2-yl)-2-phenylethyl)-2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide (111 mg, 0.27 mmol) in NMP (0.6 mL) was added iodobenzene (27 μL, 0.24 mmol), Cu2O (1 mg), PEG 3500 (50 mg), 4,7-dimethoxy-1,10-phenanthroline (6 mg) and Cs2CO3 (110 mg, 0.34 mmol). The reaction was heated to 115° C. for 4 hr. After cooling to ambient temperature, the reaction mixture was filtered over a heavy metal scavenging column and eluted with DCM. The solvents were removed in vacuo and the residue purified by RP HPLC to provide the title compound: 1H NMR (400 MHz, DMSO-d6) δ 9.16 (s), 7.55 (s, 1H), 7.42 (t, 1H), 7.14 (q, 2H), 7.01 (d, 1H), 6.84 (dd, 1H), 4.77-4.71 (m, 1H), 3.08 (d, 1H), 2.36 (s, 1H), 1.62 (d, 2H). MS (m/z) 494.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[NH:15][C:16]4[CH:21]=[CH:20][N:19]=[CH:18][C:17]=4[N:22]=3)[CH2:9]2)[N:5]=[C:4]([NH2:23])[N:3]=1.[F:24][C:25]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[NH2:23][C:4]1[N:3]=[C:2]([C:31]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([F:24])[CH:32]=2)[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[NH:15][C:16]4[CH:21]=[CH:20][N:19]=[CH:18][C:17]=4[N:22]=3)[CH2:9]2)[N:5]=1
Reactant: Nc1nc(Cl)cc(N2CCOC(c3nc4cnccc4[nH]3)C2)n1
Reactant: CC1(C)OB(c2ccc(C#N)c(F)c2)OC1(C)C
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+]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1ccc(-c2cc(N3CCOC(c4nc5cnccc5[nH]4)C3)nc(N)n2)cc1F
Temperature: 140 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
A mixture of 4-chloro-6-[2-(1H-imidazo[4,5-c]pyridin-2-yl)-4-morpholinyl]-2-pyrimidinamine (403 mg, 1.21 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (390 mg, 1.58 mmol), Na2CO3 (322 mg, 3.04 mmol) and Pd(PPh3)4 (140 mg, 0.121 mmol) in 1,4-dioxane (6 mL) and water (2 mL) was heated at 140° C. under microwave conditions with stirring for 1 hour. The mixture was filtered, washed by EtOAc (150 mL), and evaporated to give a yellow solid which was chromatographed to afford the title compound (430 mg) as a yellow solid. LC-MS (ES) m/z=417 [M+H]+.