Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=1)(=[O:7])=[O:6].[C:16]([O:20][C:21]([N:23]1[CH2:30][CH:29]2[O:31][CH:25]([CH2:26][NH:27][CH2:28]2)[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:16]([O:20][C:21]([N:23]1[CH2:24][CH:25]2[O:31][CH:29]([CH2:28][N:27]([CH2:2][CH2:3][NH:4][S:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=3)(=[O:7])=[O:6])[CH2:26]2)[CH2:30]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C1)O2
Reactant: N#Cc1ccc(S(=O)(=O)NCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC2CN(CCNS(=O)(=O)c3ccc(C#N)cc3)CC(C1)O2
Temperature: 60 °C
Reaction time: 8 h
Yield: 67.4 %

Procedure:
A suspension of N-(2-bromoethyl)-4-cyanobenzenesulfonamide (5 g, 0.017 mol; see step (i) above), 9-oxa-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (3.96 g, 0.0173 mol; see WO 01/28992) and potassium carbonate (3.6 g, 0.025 mol) in acetonitrile (50 mL) was stirred at 60° C. overnight. The reaction mixture was filtered and the solvent concentrated under reduced pressure to yield the crude product, which was purified by column chromatography (using methanol in chloroform as the eluent) to yield (5 g) of the sub-title compound as pale yellow solid.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:16])=[C:12]([Cl:15])[CH:13]=2)[NH:8][C:7]=1[Si](CC)(CC)CC)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CO.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>[Cl:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][C:11]=1[Cl:16])[NH:8][CH:7]=[C:6]2[CH2:5][CH2:4][NH2:1]
Reactant: CC[Si](CC)(CC)c1[nH]c2cc(Cl)c(Cl)cc2c1CCN=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: NCCc1c[nH]c2cc(Cl)c(Cl)cc12

Procedure:
2-(5,6-dichloro-1H-indol-3-yl)ethanamine was prepared according to method D Step V with 3-(2-azidoethyl)-5,6-dichloro-2-(triethylsilyl)-1H-indole (0.497 g; 1.35 mmol) and triphenylphosphine (0.529 g; 1.35 mmol) in methanol (10 mL) and tetrabutylamonium fluoride (4.04 mL 1M) in THF (stirred for 36 hours).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:12][NH2:13].C(O[CH:17]=[C:18]([C:21]#[N:22])[C:19]#[N:20])C>CO>[NH2:22][C:21]1[N:12]([C:3]2[CH:4]=[CH:5][C:6]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:7][C:2]=2[F:1])[N:13]=[CH:17][C:18]=1[C:19]#[N:20]
Reactant: CCOC=C(C#N)C#N
Reactant: CS(=O)(=O)c1ccc(NN)c(F)c1
Solvent: CO
Product: CS(=O)(=O)c1ccc(-n2ncc(C#N)c2N)c(F)c1
Temperature: -6 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 2-fluoro-4-methylsulfonylphenyl hydrazine (1) (4.0336 Kg; 1 eq) (commercially available from, e.g., Peakdale Molecular, Ltd.) in methanol (12.7723 Kg) was added a suspension of ethoxymethylene malononitrile (2.6564 Kg, 1.101 equivalents) in methanol (11.212 Kg) at a rate sufficiently slow to maintain the reaction mixture at −10° to 0° C. with reactor jacket cooling. After the addition had been completed, the reaction mixture was stirred for 1 hour at −6° C. and then heated to reflux for 5 hours, at which time the reaction mixture gave a pyrazole (3): hydrazine (1) HPLC peak area ratio of 105:1. Solvent (20.5153 Kg) was then distilled off the reaction mixture at atmospheric pressure, leaving a residue having less than 20% of the original volume. The resulting mixture was used directly in the next step.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[CH3:45][N:46]1[CH:50]=[CH:49][C:48]([NH:51][C:52]2[C:61]3[C:56](=[CH:57][CH:58]=[C:59]([O:62][C:63]4[N:68]=[CH:67][C:66](O)=[CH:65][CH:64]=4)[CH:60]=3)[N:55]=[CH:54][N:53]=2)=[N:47]1>C(Cl)(Cl)Cl.O1CCCC1>[CH3:45][N:46]1[CH:50]=[CH:49][C:48]([NH:51][C:52]2[C:61]3[C:56](=[CH:57][CH:58]=[C:59]([O:62][C:63]4[N:68]=[CH:67][C:66]([O:1][CH2:2][CH:3]5[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]5)=[CH:65][CH:64]=4)[CH:60]=3)[N:55]=[CH:54][N:53]=2)=[N:47]1
Reactant: Cn1ccc(Nc2ncnc3ccc(Oc4ccc(O)cn4)cc23)n1
Reactant: CC(C)(C)OC(=O)N1CC(CO)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: Cn1ccc(Nc2ncnc3ccc(Oc4ccc(OCC5CN(C(=O)OC(C)(C)C)C5)cn4)cc23)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
Tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (110 mg, 0.60 mmol), triphenyl phosphine (160 mg, 0.60 mmol) and diethyl azodicarboxylate (0.095 mmol, 0.60 mmol) were added to a tetrahydrofuran solution (3 ml) of 6-({4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-yl}oxy)pyridin-3-ol (100 mg, 0.30 mmol) obtained in Example 6-3), and the reaction solution was stirred at room temperature for 30 minutes. The reaction solution was diluted with chloroform, the organic layer was washed with water and saturated saline water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=96:4) and amine-type silica gel column chromatography (hexane:ethyl acetate=50:50) to obtain tert-butyl 3-({[6-({4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-yl}oxy)pyridin-3-yl]oxy}methyl)azetidine-1-carboxylate (136 mg, yield: 90%) as a pale yellow amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[CH:12]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C(#N)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:18][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: NC1CCCCC1
Solvent: CC#N
Product: Clc1nc(NC2CCCCC2)c2nc[nH]c2n1
Temperature: 50 °C

Procedure:
2,6-Dichloropurine (2.5 g, 13.23 mmol) and cyclohexylamine (1.51 mL, 13.2 mmol) were dissolved in acetonitrile (25 mL) and heated to 50° C. for 5 days. The white precipitate was collected by filtration and used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]2[CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][C:14]=2[NH:15][N:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl.FC(F)(F)C(O)=O>>[NH:15]1[C:14]2[CH2:17][NH:18][CH2:19][C:13]=2[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:16]1
Reactant: CC(C)(C)OC(=O)N1Cc2[nH]nc(NC(=O)OCc3ccccc3)c2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1n[nH]c2c1CNC2)OCc1ccccc1
Reaction time: 1 h

Procedure:
To the product from Step B was added 4 mL of 1:1 dichloromethane/trifluoroacetic acid, and the solution was stirred for 60 min then concentrated in vacuo. The crude oil was purified by preparative thin layer chromatography using an Analtech® 1500 micron plate (10% methanol/ethyl acetate, 1% concentrated ammonium hydroxide) to give the title compound as a white solid. LC/MS 259.2 (M+1).
Reaction SMILES: [NH2:1][CH:2]([CH3:15])[C:3]([N:5]([CH:12]([CH3:14])[CH3:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH:16](O)=O>C1(C)C=CC=CC=1>[N+:1]([CH:2]([CH3:15])[C:3]([N:5]([CH:12]([CH3:14])[CH3:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4])#[C-:16]
Reactant: O=CO
Reactant: CC(N)C(=O)N(c1ccccc1)C(C)C
Solvent: Cc1ccccc1
Product: [C-]#[N+]C(C)C(=O)N(c1ccccc1)C(C)C
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
α-amino-N-isopropylpropionanilide (88.5 g.) was mixed with 80 g. of concentrated formic acid, then heated at 125° C. for 2 hours. The temperature was lowered to 100° C. and toluene added. The mixture was then refluxed. Water and formic acid were removed azeotropically. Upon crystallization, the toluene solvent was removed and the residue, identified as N-isopropyl-2-formamido propionanilide, triturated with ether and filtered. The formamide, (23.4 g.), was dissolved in methylene chloride and 50.5 g. triethylamine added thereto. The clear solution was cooled to -10° C. and 22.8 g. POCl3 added. After stirring at below zero temperature for 15 minutes, excess 10% sodium carbonate solution was added, taking care that temperature did not exceed 20° C. The mixture was allowed to stir at ambient temperature briefly, then the layers were separated. The organic layer was washed with 100 ml 2% salt solution, dried over MgSO4, filtered and stripped. The oily residue was taken up in methylcyclohexane and stirred. The cyclohexane solution was decanted from the insoluble oil and cooled and scratched to produce a solid which was filtered and air-dried. Recrystallization from heptane provided 2-isocyano-N-isopropylpropionanilide melting at 47°-50° C.
Reaction SMILES: CS[C:3]1[NH:8][C:7](=[O:9])[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][N:4]=1.[NH2:16][CH2:17][CH2:18][S:19][CH2:20][C:21]1[O:25][C:24]([CH2:26][N:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=1>>[CH3:29][N:27]([CH2:26][C:24]1[O:25][C:21]([CH2:20][S:19][CH2:18][CH2:17][NH:16][C:3]2[NH:8][C:7](=[O:9])[C:6]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:5][N:4]=2)=[CH:22][CH:23]=1)[CH3:28]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: CSc1ncc(-c2ccccc2)c(=O)[nH]1
Product: CN(C)Cc1ccc(CSCCNc2ncc(-c3ccccc3)c(=O)[nH]2)o1
Yield: 79.2 %

Procedure:
A mixture of 2-(methylthio)-5-phenyl-4(3H)-pyrimidinone (1.09 g) and 5-[[(2-aminoethyl)thio]methyl]-N,N-dimethyl-2-furanmethanamine (2.14 g) was heated at 140° for 4 h. The cooled residue was chromatographed (silica/ethyl acetate-methanol, 1:1) to give a product which was crystallised from methyl acetate-light petroleum (b.p. 60°-80°) yielding the title compound (1.52 g) m.p. 116°-118°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[CH2:15]1[O:23][C@@H:16]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1OC1C1C=CC=CC=1>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C@@H:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[OH:23])[CH2:11][CH2:10]1
Reactant: c1ccc([C@@H]2CO2)cc1
Reactant: COc1ccccc1N1CCNCC1
Agent: c1ccc(C2CO2)cc1
Solvent: CC#N
Product: COc1ccccc1N1CCN(C[C@H](O)c2ccccc2)CC1
Yield: 11 %

Procedure:
2-Methoxyphenylpiperazine (19.84 g, 0.103 m) in dry acetonitrile (150 ml) was refluxed with (R)-styrene oxide (12.4 g, 0.104 m). The residue on evaporation was chromatographed on silica using ethyl acetate as eluant to give two main fractions. The first fraction (4.3 g) contained some styrene oxide, which was removed by acid-base extraction to give 3.55 g of pure title compound. The second fraction (9.5 g) was 95% title compound and approximately 5% of the regioisomer.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[H][H]>CO.[C].[Pd]>[NH2:11][C:8]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: [H][H]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(F)c(C(=O)O)c1
Yield: 83.5 %

Procedure:
2-Fluoro-5-nitrobenzoic acid (60 g) was suspended in 300 ml of methanol, 6.0 g of 5% palladium-carbon was added thereto and the mixture was reduced at 40 ° C. with hydrogen pressure of 6.5 atm. The catalyst was removed, the solvent was evaporated and the crystals separated out therefrom were filtered to give 42 g of 5-amino-2-fluorobenzoic acid, m.p. 189°-192° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(C1C=CC(S([O-])(=O)=O)=CC=1)(=O)C.[Na+].[CH3:28][NH:29][CH3:30]>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:29]([CH3:30])[CH3:28])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CNC
Agent: CC(=O)c1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Product: CC(=O)c1ccc(S(=O)(=O)N(C)C)cc1

Procedure:
From the damp 4-acetylbenzenesulfonyl chloride from 200 g. of sodium 4-acetylbenzenesulfonate, and 1 1. of 20% aqueous dimethylamine, following the procedure of c) above, there is obtained 4-acetyl-N,N-dimethylbenzenesulfonamide; m.p. 97°-99° C. after crystallization from aqueous ethanol.
Reaction SMILES: [C:1]([O:8][CH2:9]Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:11]1[CH:12]=[CH:13][C:14]2[S:19][N:18]=[C:17]([N:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][C:28]4[CH:29]=[C:30]5[CH2:38][C:36](=[O:37])[NH:35][C:31]5=[CH:32][C:33]=4[Cl:34])[CH2:22][CH2:21]3)[C:15]=2[CH:16]=1.C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1.C.[Cl-].[Cl-]>[C:1]([O:8][CH2:9][N:35]1[C:31]2[C:30](=[CH:29][C:28]([CH2:27][CH2:26][N:23]3[CH2:24][CH2:25][N:20]([C:17]4[C:15]5[CH:16]=[CH:11][CH:12]=[CH:13][C:14]=5[S:19][N:18]=4)[CH2:21][CH2:22]3)=[C:33]([Cl:34])[CH:32]=2)[CH2:38][C:36]1=[O:37])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC(=O)OCCl
Reactant: O=C1Cc2cc(CCN3CCN(c4nsc5ccccc45)CC3)c(Cl)cc2N1
Agent: C
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCC(=O)OCN1C(=O)Cc2cc(CCN3CCN(c4nsc5ccccc45)CC3)c(Cl)cc21
Reaction time: 24 h
Yield: 27 %

Procedure:
Chloromethyl hexanoate (3.18 g, 19.0 mmol) in dichloromethane (6 mL) was added to a suspension of Ziprasidone free base (4.0 g, 9.6 mmol), triethyl amine (4.0 mL, 27 mmol) and 4-dimethylamino pyridine (DMAP, 0.708 g, 5 mmol) in dichloride methane (240 mL) at 25-30° C. The reaction solution was stirred for 24 h at same temperature. The crude mixture was washed with water (100 mL) followed by brine solution (100 mL), upon solvent evaporation under vacuum below 40° C. provided crude title product, Compound 322, which was further purified by silica gel column chromatography. (1.4 g, 27% yield).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:27]=[CH:28][N:29]=3)[N:17]=[C:18]([C:20]3[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=3)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+].CS(O[CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45][CH2:44]1)(=O)=O.O>CN(C=O)C>[C:52]([O:51][C:49]([N:46]1[CH2:47][CH2:48][N:43]([CH2:42][CH2:41][O:26][C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([C:18]3[CH:19]=[C:14]([NH:13][C:11]4[CH:10]=[CH:9][CH:8]=[C:7]([N:3]5[CH2:4][CH2:5][CH2:6][CH:2]5[CH3:1])[N:12]=4)[C:15]4[N:16]([CH:27]=[CH:28][N:29]=4)[N:17]=3)[CH:21]=2)[CH2:44][CH2:45]1)=[O:50])([CH3:55])([CH3:54])[CH3:53]
Reactant: CC1CCCN1c1cccc(Nc2cc(-c3cccc(O)c3)nn3ccnc23)n1
Reactant: CC(C)(C)OC(=O)N1CCN(CCOS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1CCCN1c1cccc(Nc2cc(-c3cccc(OCCN4CCN(C(=O)OC(C)(C)C)CC4)c3)nn3ccnc23)n1
Temperature: 50 °C
Yield: 32.4 %

Procedure:
To a mixture of 3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)phenol (50 mg, 0.129 mmol) and K2CO3 (36 mg, 0.258 mmol) in DMF (5 mL) was added tert-butyl 4-(2-(methylsulfonyloxy)ethyl)piperazine-1-carboxylate (48 mg, 0.155 mmol). The mixture was heated at 50° C. for 16 h. After cooling, the mixture was poured into water and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine and dried over MgSO4. After filtration and concentration, the residue was washed by petroleum ether to give tert-butyl-4-(2-(3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)phenoxy)ethyl)piperazine-1-carboxylate (25 mg, 33%) as crude oil. LC-MS: 599.4 [M+H]+, tR=1.53 min.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8]1([CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]1)[O:7][CH2:6]2)=O.CO.Cl.[OH:25][NH2:26].C([O-])(=O)C.[Na+]>O>[OH:25][N:26]=[CH:1][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8]1([CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]1)[O:7][CH2:6]2
Reactant: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C=O)ccc12
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C=NO)ccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of tert-butyl 5′-formyl-3′H-spiro[azetidine-3,1-isobenzofuran]-1-carboxylate (Preparation 42, 1.5 g, 5.184 mmol, 1 eq) in mixture of methanol (20 mL) and water (10 mL) was added hydroxyl amine hydrochloride (0.537 g, 7.777 mmol, 1.5 eq) followed by addition of sodium acetate (0.765 g, 9.332 mmol, 1.8 eq) at room temperature. Resulting reaction mixture was stirred at room temperature for 24 hours. After complete consumption of starting material, reaction mixture was concentrated in vacuo to afforded yellow colored residue, which was diluted by water (70 mL) and extracted with ethyl acetate (3×30 mL). Combined organic phase was washed with brine solution (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to get yellow semi solid (1.9 g, crude). Crude was purified by Combiflash using 40 g Redisep column. Desired compound was eluted in 24% ethyl acetate in hexane to afford title compound as yellow semi solid (1.1 g, 69.62%). 1H NMR (400 MHz, CDCl3) δ: 1.47 (s, 9H), 4.13 (d, J=9.6 Hz, 2H), 4.31 (d, J=9.84 Hz, 2H), 5.10 (s, 2H), 7.43 (s, 1H), 7.47 (d, J=7.88 Hz, 1H), 7.56 (d, J=7.92 Hz, 1H), 8.14 (s, 1H). (m/z): 303.3 (M−H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]([CH3:20])[CH2:8][CH2:9][CH2:10][C:11]1[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[NH:13][CH:12]=1.O.[OH-].[Na+].CN(C)[CH:26]=[O:27]>>[CH3:20][N:7]([CH3:6])[CH2:8][CH2:9][CH2:10][C:11]1[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[NH:13][C:12]=1[CH:26]=[O:27]
Reactant: CN(C)CCCc1c[nH]c2c1CCCC2
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)CCCc1c(C=O)[nH]c2c1CCCC2
Yield: 50 %

Procedure:
Phosphorus oxychloride (9.2 g, 0.06 mol) was slowly added to 12 ml of dimethylformamid at 0° C. with stirring and the mixture stirred for 30 minutes. Dimethyl-[3-(4,5,6,7-tetrahydro-1H-indol-3-yl)-propyl]-amine ( 6.2 g, 0.03 mol) was dissolved in 10 ml of dimethylformamide and added to the mixture. The reaction was stirred for 2 hours at room temperature. The stirred mixture was cooled in an ice bath and water was slowly added followed by 10 N sodium hydroxide solution until pH was 10. The mixture was stirred at room temperature for 45 minutes and extracted with ethyl acetate. The ethyl acetate extract was washed with brine, dried over anhydrous sodium sulfate and concentrated to give 3-(3-dimethylamino-propyl)-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde (3.5 g, 50% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[CH:10]=[CH2:11].CCN(C(C)C)C(C)C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:8][C:5]1[N:6]=[CH:7][C:2](/[CH:11]=[CH:10]/[C:9]([O:13][CH2:14][CH3:15])=[O:12])=[CH:3][CH:4]=1
Reactant: C=CC(=O)OCC
Reactant: Nc1ccc(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc(N)nc1
Temperature: 100 °C
Yield: 36 %

Procedure:
To a glass bomb were charged with 5-bromopyridin-2-amine (10.0 g, 57.8 mmol), ethyl acrylate (8.14 mL, 75 mmol) and DIEA (25.2 mL, 144 mmol) in DMF (40 mL). The mixture was purged with argon, followed by addition of Pd(OAc)2 (0.649 g, 2.89 mmol) and (o-Tol)3P (3.87 g, 12.72 mmol), and finally purged thoroughly with argon. The mixture was sealed, and heated with 100° C. oil bath overnight. The reaction mixture was cooled down to room temperature, and the precipitates were removed by filtering through a thin layer of Celite. The filtrate was concentrated as much as possible via rotavap, and the residue was partitioned between EtOAc/water (150 mL/100 mL). EtOAc layer was washed with water (2×100 mL), dried over Na2SO4, and concentrated. A brown slid was obtained as crude product. The crude product was triturated with EtOAc (40 mL) and the yellow solid was collected via filtration. The filter cake was rinsed with small amount of EtOAc and dried under vacuum as the first crop of product (5.0 g). The mother liquor from trituration was stripped by dilute aqueous 1 N HCl (30 mL) and water (70 mL). Aqueous layer was transferred to a clean separate funnel, basicified with 20 mL sat. Na2CO3, and extracted with EtOAc (60 mL). EtOAc layer was dried over Na2SO4, concentrated and provided the second portion of product (4.0 g). The two crops of product were combined to afford 81% yield. LCMS (m/z) 193.2 (MH+), 0.39 min.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)(=O)=O)[N:3]=1.[C:19]1([CH2:25][CH2:26][CH2:27][OH:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:28][CH2:27][CH2:26][CH2:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:3]=1
Reactant: OCCCc1ccccc1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(OCCCc2ccccc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, 3-phenyl-1-propanol and DBU in DME. ES-MS m/e (%): 359 (M+K+, 20), 343 (M+Na+, 21), 321 (M+H+, 100).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH:9]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:8][CH2:7][CH2:6][NH:5]1.Br[CH2:19][C:20]1[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:21]=1[F:28]>CN(C)C=O>[F:28][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]([O:26][CH3:27])[C:20]=1[CH2:19][N:5]1[CH2:6][CH2:7][CH2:8][CH:9]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])[C:4]1=[O:3]
Reactant: COc1cccc(F)c1CBr
Reactant: CC(C)(C)OC(=O)NC1CCCNC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(F)c1CN1CCCC(NC(=O)OC(C)(C)C)C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (82 mg, 2.054 mmol) was added to a solution of tert-butyl 2-oxopiperidin-3-ylcarbamate (200 mg, 0.933 mmol) in dimethylformamide (2 ml) at 23° C. and the resulting mixture was allowed to stir for 30 minutes. The mixture was then cooled to 0° C., and a solution of 2-(bromomethyl)-1-fluoro-3-methoxybenzene (214 mg, 0.977 mmol) in dimethylformamide (1.2 ml) added to the reaction mixture drop-wise. The resulting solution was allowed to stir for 90 minutes and was quenched with methanol. The mixture was then diluted with EtOAc, washed with water and brine, dried with magnesium sulfate, filtered and concentrated to afford tert-butyl 1-(2-fluoro-6-methoxybenzyl)-2-oxopiperidin-3-ylcarbamate. The crude product was progressed to the next step without purification.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([C:11]1[N:12]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[N:13]=[C:14]2[C:19]=1[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[NH2:38][C:39]1[CH:46]=[CH:45][C:42]([C:43]#[N:44])=[CH:41][C:40]=1[F:47]>C1COCC1>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([N:12]2[C:11]([CH:4]([CH:5]3[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]3)[C:3]([NH:38][C:39]3[CH:46]=[CH:45][C:42]([C:43]#[N:44])=[CH:41][C:40]=3[F:47])=[O:2])=[C:19]3[C:14]([CH2:15][CH2:16][CH2:17][CH2:18]3)=[N:13]2)=[CH:21][CH:22]=1
Reactant: COC(=O)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1
Reactant: N#Cc1ccc(N)c(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc(NC(=O)C(c2c3c(nn2-c2ccc(Cl)cc2)CCCC3)C2CCCCC2)c(F)c1
Reaction time: 0.5 h

Procedure:
To a stirred solution of [rac]-[2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-cyclohexyl-acetic acid methyl ester (250 mg, 0.64 mmol) in dry THF was added LiHMDS (1.0 M solution in THF; 4.5 ml, 4.5 mmol) at −30° C. and stirring continued for another 30 min at that temperature. 4-Amino-3-fluoro-benzonitrile (90.64 mg, 0.768 mmol; CAS Reg. No. 115661-37-5) in THF (1 ml) was then added at that temperature and slowly brought to room temperature. Reaction mixture was then stirred at room temperature for 13 h. TLC shows formation of a new spot. LC-MS of the crude material shows formation of desired product. Reaction mixture was quenched with saturated NH4Cl and the aqueous layer was extracted with EtOAc (3×5 ml). Combined organic layers were washed with brine and concentrated under reduced pressure to give crude material (260 mg); which was then purified by column chromatography [SiO2 (230-400 mesh), EtOAc:hexane 30:70] to give the title compound (130 mg, 42%) as light yellow solid.