Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[C:13]1[C:21]2[C:20]([NH:22][C@H:23]([C:25]3[N:30]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:29](=[O:37])[C:28]4=[C:38]([CH3:41])[CH:39]=[CH:40][N:27]4[N:26]=3)[CH3:24])=[N:19][CH:18]=[N:17][C:16]=2[N:15](COCC[Si](C)(C)C)[CH:14]=1.FC(F)(F)C(O)=O.N>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:12])(=[O:10])=[O:11])=[CH:4][C:3]=1[C:13]1[C:21]2[C:20]([NH:22][C@H:23]([C:25]3[N:30]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:29](=[O:37])[C:28]4=[C:38]([CH3:41])[CH:39]=[CH:40][N:27]4[N:26]=3)[CH3:24])=[N:19][CH:18]=[N:17][C:16]=2[NH:15][CH:14]=1
Reactant: Cc1ccc(NS(C)(=O)=O)cc1-c1cn(COCC[Si](C)(C)C)c2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c12
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(NS(C)(=O)=O)cc1-c1c[nH]c2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c12
Yield: 75.4 %

Procedure:
(S)—N-(4-Methyl-3-(4-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)methanesulfonamide (50 mg, 0.07 mmol) was treated with trifluoroacetic acid (2 ml, 25 mmol) and a solution of ammonia (7N in methanol, 2 ml, 117 mmol) according to the method described in Example 27 to give 30 mg (73% yield) of the title compound as a yellow solid. Purity 99%.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]3[CH2:16][CH2:15][C:14]([C:18]4[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH3:26])=[CH:20][CH:19]=4)(O)[CH2:13][CH2:12]3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)CO>C1(C)C=CC=CC=1>[CH2:24]([C:21]1[CH:20]=[CH:19][C:18]([C:14]2[CH2:15][CH2:16][CH:11]([CH:8]3[CH2:7][CH2:6][C:5]4([O:1][CH2:2][CH2:3][O:4]4)[CH2:10][CH2:9]3)[CH2:12][CH:13]=2)=[CH:23][CH:22]=1)[CH2:25][CH3:26]
Reactant: CCCc1ccc(C2(O)CCC(C3CCC4(CC3)OCCO4)CC2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: OCCO
Product: CCCc1ccc(C2=CCC(C3CCC4(CC3)OCCO4)CC2)cc1

Procedure:
250 g (about 0.7 mol) of crude 4-(1,4-dioxaspiro[4.5]dec-8-yl)-1-(4-propylphenyl)cyclohexanol are heated on a water separator together with 13.2 g (69 mmol) of p-toluenesulfonic acid monohydrate and 40.7 ml (0.73 mol) of ethylene glycol in 800 ml of toluene. The solution is washed a number of times with water and dried using sodium sulfate. The crude product remaining after removal of the solvent is purified by chromatography (SiO2, n-heptane:MTBE=5:1). 8-[4-(4-Propylphenyl)cyclohex-3-enyl]-1,4-dioxaspiro[4.5]decane is obtained as a colourless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[C:6]([CH:10]=1)[C:7]([NH:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23])=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1COc1cccc(F)c1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2COc2cccc(F)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 6 of Example 1 from 5-chloro-2-[(3-fluorophenoxy)methyl]benzoic acid (step 2) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 5 of Example 1):
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[C:5]([CH3:12])[CH:4]=1)#[N:2].[CH3:13][C:14]1([CH3:21])[C:19](=[O:20])[CH:18]=[CH:17][CH2:16][CH2:15]1.C([O-])(=O)C.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)(=O)C>[CH3:13][C:14]1([CH3:21])[CH2:15][CH2:16][CH:17]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[CH3:12])[CH2:18][C:19]1=[O:20]
Reactant: Cc1cc(C#N)ccc1B(O)O
Reactant: CC1(C)CCC=CC1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(C#N)ccc1C1CCC(C)(C)C(=O)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 49.7 %

Procedure:
4-Cyano-2-methylphenylboronic acid (0.81 g, 5 mmol), 6,6-dimethylcyclohex-2-enone (Canadian Journal of Chemistry, 1981, 59, 2096-2115) (0.55 g, 5 mmol), SbCl3 (0.11 g, 0.5 mmol), sodium acetate (0.82 g, 10 mmol), and palladium acetate (0.11 g, 0.5 mmol) are added to acetic acid (30 mL) under an atmosphere of argon. The reaction mixture is stirred at room temperature for three days. The mixture is filtered and the filtrate is poured into water (150 mL). The organic phase is separated and the aqueous phase is extracted with ethyl acetate (3×100 mL). The combined organic layers are washed with saturated sodium bicarbonate solution (3×100 mL), brine (3×50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue is purified by silica gel column chromatography eluting with pet ether: EtOAc=10:1 to give the title compound as a light yellow solid (0.6 g, 50%). GC/MS 241 (M+1).
Reaction SMILES: [CH:1]1[N:5]=[CH:4][NH:3][C:2]=1/[CH:6]=[CH:7]/[C:8]([OH:10])=[O:9]>O.[Pd]>[NH:5]1[CH:1]=[C:2]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])[N:3]=[CH:4]1
Reactant: O=C(O)/C=C/c1cnc[nH]1
Agent: [Pd]
Solvent: O
Product: O=C(O)CCc1c[nH]cn1
Yield: 96 %

Procedure:
A suspension of urocanic acid (2.00 g, 14.5 mmol) in H2O (40 mL) was shaken at room temperature with a suspension of 10% Pd/C (200 mg, 0.19 mmol) under hydrogen atmosphere (30 psi) for 2 h. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo to give a colourless solid (1.95 g, 96%). 1H NMR (D2O) δ 2.52 (t, 2H, J=7.2 Hz), 2.92 (t, 2H, J=7.2 Hz), 7.16 (s, 1H), 8.49 (s, 1H).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([N:9]2[C:13]3[CH:14]=[CH:15][C:16](N)=[CH:17][C:12]=3[N:11]=[CH:10]2)[CH:6]=[CH:5][N:4]=1.C(ON=O)CC(C)C.[I:27]CI>>[CH3:1][S:2][C:3]1[N:8]=[C:7]([N:9]2[C:13]3[CH:14]=[CH:15][C:16]([I:27])=[CH:17][C:12]=3[N:11]=[CH:10]2)[CH:6]=[CH:5][N:4]=1
Reactant: CSc1nccc(-n2cnc3cc(N)ccc32)n1
Reactant: ICI
Agent: CC(C)CCON=O
Product: CSc1nccc(-n2cnc3cc(I)ccc32)n1
Temperature: 100 °C

Procedure:
2-Methylthio-4-[5-aminobenzimidazol-1-yl]pyrimidine (EXAMPLE 3, 513 mg) was dissolved in diiodomethane (5 mL), isoamylnitrite (0.32 mL) was added and the resulting solution was heated to 100° C. for 30 minutes. Upon cooling to rt, the reaction mixture was directly purified by column chromatography (SiO2, 5% MeOH in CH2Cl2) to yield 342 mg of the title compound. Mass spectrum 371.1 (ESI) (M+).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].N1C=CC=CC=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:23]3[C:24](=[O:43])[N:25]([CH:28]4[CH2:33][CH2:32][N:31]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=5[CH2:40][NH:41][CH3:42])[CH2:30][CH2:29]4)[CH2:26][CH2:27][C:22]=3[C:21]([C:44]([NH2:46])=[O:45])=[N:20]2)=[CH:15][CH:14]=1>C(Cl)Cl>[C:1]([N:41]([CH2:40][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[N:31]1[CH2:32][CH2:33][CH:28]([N:25]2[CH2:26][CH2:27][C:22]3[C:21]([C:44]([NH2:46])=[O:45])=[N:20][N:19]([C:16]4[CH:15]=[CH:14][C:13]([O:12][CH3:11])=[CH:18][CH:17]=4)[C:23]=3[C:24]2=[O:43])[CH2:29][CH2:30]1)[CH3:42])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CNCc1ccccc1N1CCC(N2CCc3c(C(N)=O)nn(-c4ccc(OC)cc4)c3C2=O)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(-n2nc(C(N)=O)c3c2C(=O)N(C2CCN(c4ccccc4CN(C)C(C)=O)CC2)CC3)cc1
Yield: 10 %

Procedure:
A solution of the product from Part H (17 mg, 0.02 mmol), acetyl chloride (0.05 mL), and pyridine (0.05 mL) in anhydrous CH2Cl2 (1 mL) was stirred at room temperature for 2 h under N2. Two products (1:5) were detected by LC/MS (ESI+): 531.6 (M+H) and 513.6 (M+H) for the amide (I-1) and the nitrile (I-2), respectively. The mixture was then concentrated in vacuo, and the residue was purified by prep LC-MS (5-98% CH3CN/H2O in a 10-min run) to obtain the product I-1, 6-[1-(2-{[acetyl(methyl)amino]methyl}phenyl)-4-piperidinyl]-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (1.6 mg, 10%). LC/MS (ESI+), 531.6 (M+H). And product I-2, N-(2-{4-[3-cyano-1-(4-methoxyphenyl)-7-oxo-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl]-1-piperidinyl}benzyl)-N-methylacetamide (8 mg, 50%). LC/MS (ESI+), 513.6 (M+H).
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13]([C:15]3[N:20]4[CH:21]=[C:22]([CH2:24][C:25](O)=[O:26])[N:23]=[C:19]4[CH:18]=[CH:17][CH:16]=3)=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:28][C@@H:29]1[CH2:34][NH:33][CH2:32][CH2:31][NH:30]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O.O>[C:1]12([CH2:11][NH:12][C:13]([C:15]3[N:20]4[CH:21]=[C:22]([CH2:24][C:25]([N:33]5[CH2:32][CH2:31][NH:30][C@H:29]([CH3:28])[CH2:34]5)=[O:26])[N:23]=[C:19]4[CH:18]=[CH:17][CH:16]=3)=[O:14])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: O=C(O)Cc1cn2c(C(=O)NCC34CC5CC(CC(C5)C3)C4)cccc2n1
Reactant: C[C@@H]1CNCCN1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(C(=O)Cc2cn3c(C(=O)NCC45CC6CC(CC(C6)C4)C5)cccc3n2)CCN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of {5-[(adamantan-1-ylmethyl)-carbamoyl]-imidazo[1,2-a]pyridin-2-yl}-acetic acid (40 mg, 0.1 mmol) in DMF (1 mL) is sequentially added (R)-2-methyl-piperazine (43 mg, 0.44 mmol) and 96 mg of BOP (0.2 mmol). After stirring for 2 h at RT, the reaction mixture is diluted with EtOAc and water. The organic layer is separated, and the aqueous layer is back extracted with EtOAc. The combined organic layers are washed with water and brine, dried over sodium sulfate, and concentrated. Purification of the residue by PTLC (10% MeOH, 1% NH4OH in DCM) affords the title compound.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[N:9]=[C:8]([C:10]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]3[N:11]=2)[CH:7]=[CH:6][CH:5]=1.[CH2:26]([OH:28])[CH3:27]>>[CH2:26]([O:28][C:4]1[N:9]=[C:8]([C:10]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]3[N:11]=2)[CH:7]=[CH:6][CH:5]=1)[CH3:27]
Reactant: CCO
Reactant: Fc1ccc(-c2c(-c3cccc(Cl)n3)nn3ccccc23)cc1
Agent: [H-]
Agent: [Na+]
Product: CCOc1cccc(-c2nn3ccccc3c2-c2ccc(F)cc2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
Add sodium hydride (20.7 mg, 0.52 mmol) to a solution of 2-(6-chloro-pyridin-2-yl)-3-(4-fluoro-phenyl)-pyrazolo[1,5-a]pyridine (33.5 mg, 0.10 mmol) in ethanol (2.5 mL) at 0° C. Stir the reaction mixture at 0° C. for 30 minutes and at 80° C. for 48 hours. Cool the reaction mixture to room temperature and concentrate in vacuo Using the same procedure as above afforded the title compound 31 mg (93%) as an off-white solid.
Reaction SMILES: FC1C=CC(C(C2C=CC(F)=CC=2)=O)=CC=1.CN1C(=O)CCC1.C(=O)([O-])[O-].[K+].[K+].[N+]([C:33]1[CH:34]=[C:35]([C:41]#[N:42])[C:36](=[CH:39][CH:40]=1)[C:37]#[N:38])([O-])=O>O.C1(C)C=CC=CC=1>[C:41](#[N:42])[C:35]1[C:36](=[CH:39][CH:40]=[CH:33][CH:34]=1)[C:37]#[N:38]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Agent: O=C([O-])[O-]
Agent: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1ccccc1C#N
Temperature: 25 °C
Reaction time: 4 h
Yield: 386 %

Procedure:
To a 100 ml, 3-necked flask equipped with a thermometer and a Dean-Stark trap was added 2.0 gm (9.2 mmol) of 4,4'-difluorobenzophenone, 6.16 gm (18.3 mmol) of bisphenol A6F, and 50 ml of N-methyl pyrrolidinone (NMP). After flushing the mixture for 30 minutes with dry nitrogen, 5.0 gm (36.2 mmol) of pulverized anhydrous potassium carbonate was added with stirring. The reaction mixture was stirred at 70° C. for 1 hour. Toluene was added to the Dean-Stark trap and to the reaction vessel (4 ml). The reaction mixture was refluxed at 175°-180° C. for 12 hours. Water which formed as a by-product was removed by azeotropic distillation. The reaction temperature was reduced to 160° C. and the toluene was sweep out of the reaction vessel by removing the glass stopper from the 3-necked flash. When the temperature reached 180° C., it was assumed that the toluene had been removed. Upon cooling to room temperature, 3.17 gm (18.4 mmol) of 4-nitrophthalonitrile was added. The temperature of the mixture was increased to 100° C. and held at this temperature for 4 hours. FTIR spectroscopy showed the absence of hydroxy and nitro bands. The room temperature mixture was then poured into 300 ml of water with stirring. The solid precipitate was collected by suction filtration, washed exhaustively with water, and dried to afford 9.1 gm of oligomeric phthalonitrile monomer.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][NH:7][CH2:8][CH2:9][C:10]1[NH:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.C(N(CC)CC)C.N>C(Cl)(Cl)Cl>[Cl:1][CH2:2][C:3]([N:7]([CH3:6])[CH2:8][CH2:9][C:10]1[NH:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: CNCCc1[nH]c2ccccc2c1-c1ccccc1
Agent: N
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(CCc1[nH]c2ccccc2c1-c1ccccc1)C(=O)CCl
Reaction time: 0.5 h

Procedure:
A solution of 17.5 ml chloroacetyl chloride in 100 ml chloroform is added dropwise within 15 minutes to a solution of 50.1 g N-methyl-3-phenyl-1H-indol-2-ethanamine and 30.7 ml triethylamine in 500 ml chloroform. After 30 minutes the mixture is made alkaline with aqueous ammonia. The organic phase is separated, washed with water and dried. Evaporation of the solvent gives the heading compound, m.p. 135°-138° (from methylene chloride/ether).
Reaction SMILES: [ClH:1].[C:2]1([C@H:8]2CCC[C@H:9]2[NH2:13])[CH:7]=[CH:6][CH:5]=CC=1.Cl.[OH:15][C:16]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20][CH2:19][CH2:18][CH:17]1[NH2:21]>>[ClH:1].[NH:13]1[CH2:9][CH2:8][CH2:2][CH2:7][CH2:6][C:5]1=[N:21][CH:17]1[CH2:18][CH2:19][CH2:20][C:16]1([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[OH:15]
Reactant: NC1CCCC1(O)c1ccccc1
Reactant: N[C@@H]1CCC[C@@H]1c1ccccc1
Agent: Cl
Product: OC1(c2ccccc2)CCCC1N=C1CCCCCN1

Procedure:
Following the procedure described in Example 1, only substituting for cis-2-phenylcyclopentylamine hydrochloride an appropriate amount of 2-hydroxy-2-phenylcyclopentylamine hydrochloride and employing a reaction time of 47 days the desired product was obtained, M.P. 261°-262° C.
Reaction SMILES: C[C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([O:9]C)=O.[BH4-].[Na+].[CH3:17]O.Cl>C1COCC1>[CH3:17][C:4]1[C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=[CH:2][CH:3]=1)[CH2:7][OH:9]
Reactant: CO
Reactant: COC(=O)c1cc(C)ccc1[N+](=O)[O-]
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccc(CO)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 100 %

Procedure:
To a refluxed solution of methyl 5-methyl-2-nitrobenzoate (50 g, 0.256 mol) and sodium borohydride (29 g, 0.768 mol) in THF (400 mL) was added dropwise methanol (60 mL) over 2.5 h. After the addition was completed, the mixture was refluxed for 1 h and allowed to cool at room temperature. The excess reagent was decomposed by addition of diluted hydrochloric acid (300 mL) and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated to give 43.0 g of the title compound (100%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.N1C=CC=CC=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O.O1CCOCC1.CO>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][S:23]([C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)(=[O:25])=[O:24])[C:3]([Cl:9])=[N:4][CH:5]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: Nc1cc(Br)cnc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: CO
Solvent: C1COCCO1
Product: O=S(=O)(Nc1cc(Br)cnc1Cl)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.4 %

Procedure:
To a 50-mL, round-bottomed flask was added 3-amino-5-bromo-2-chloropyridine (0.50 g, 2.4 mmol, Asymchem, Morrisville, N.C.), pyridine (10 mL, 120 mmol) and 4-fluorobenzenesulfonyl chloride (2.0 g, 10 mmol, Fluka, Buchs, Switzerland). The mixture was stirred at 25° C. After 18 hours, the mixture was concentrated in vacuo. To the residue was added methanol (10 mL), 1,4-dioxane (10 mL) and potassium carbonate (3.4 g, 25 mmol). The mixture was stirred at 60° C. After 16 hours, the mixture was poured into water (100 mL) and the pH was adjusted to ˜7 with 1 N HCl. The solution was extracted with EtOAc (3×75 mL) and the combined extracts were washed with water (100 mL), brine (100 mL) and then dried (Na2SO4) and concentrated onto silica. Purification by silica gel chromatography (2.0 to 30% EtOAc/hexane) afforded the title compound as a white solid (0.53 g, 58% yield). MS (ESI pos. ion) m/z: 367 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.63 (br. s, 1H), 8.42 (d, J=2.3 Hz, 1H), 7.94 (d, J=2.3 Hz, 1H), 7.77-7.84 (m, 2H), 7.40-7.47 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[Li+].CC([N-]C(C)C)C.CON(C)[C:20](=[O:22])[CH3:21].O>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:20](=[O:22])[CH3:21])[CH:5]=[CH:4][N:3]=1
Reactant: CON(C)C(C)=O
Reactant: Cc1ccnc(Br)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Cc1ccnc(Br)c1
Temperature: -78 °C
Reaction time: 0.58 h
Yield: 66.6 %

Procedure:
To a stirred solution of 2-bromo-4-methylpyridine (Compound 15) (20.20 g, 117.4 mmol) in THF (250 mL) at −78° C. was added LDA (2.0 M THF/Hex, 70.5 mL, 141 mmol) dropwise over 10 min. The solution was stirred at −78° C. for 35 min. Then a solution of N-methoxy-N-methyl acetamide (14.5 g, 141 mmol) in THF (30 mL) was added dropwise over 10 min. After 15 min. at −78° C., the solution was warmed to 0° C. and stirred for 1 h. The solution was poured into H2O (250 mL), extracted with Et2O (3×250 mL), dried (MgSO4), filtered and concentrated. Flash chromatography (SiO2, 20% EtOAc-hexanes) provided the title compound (16.75 g, 78.2 mmol, 67%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[CH:12]=[CH:13][C:14]([CH:16]=O)=[CH:15][C:4]=2[N:3]=1.[Br-].[CH2:19]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:16]([C:14]1[CH:13]=[CH:12][C:5]2=[C:6]3[C:11](=[C:2]([NH2:1])[N:3]=[C:4]2[CH:15]=1)[N:10]=[CH:9][CH:8]=[CH:7]3)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1nc2cc(C=O)ccc2c2cccnc12
Reactant: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Product: Nc1nc2cc(CCc3ccccc3)ccc2c2cccnc12

Procedure:
8-Phenethylbenzo[f][1,7]naphthyridin-5-amine was prepared from 5-aminobenzo[f][1,7]naphthyridine-8-carbaldehyde (from Example 87) with benzyltriphenylphosphonium bromide following the procedures described for Example 91 (wittig reaction) and Example 92 (reduction). 1H NMR (acetone-d6): δ 8.99 (dd, 1H), 8.88 (dd, 1H), 8.35 (d, 1H), 7.83 (dd, 1H), 7.49 (d, 1H), 7.29-7.15 (dd, 6H), 6.70 (br s, 2H), 3.10-3.00 (m, 4H). LRMS [M+H]=300.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]2[O:26][C:13]3([CH2:18][CH2:17][CH2:16][N:15]([C:19](OC(C)(C)C)=O)[CH2:14]3)[NH:12][C:11](=[O:27])[C:10]=2[CH:28]=1.[C:30]1([CH2:36]C=O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[BH3-]C#N.[Na+]>>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]2[O:26][C:13]3([CH2:18][CH2:17][CH2:16][N:15]([CH2:19][CH2:36][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:14]3)[NH:12][C:11](=[O:27])[C:10]=2[CH:28]=1
Reactant: O=CCc1ccccc1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)NC1(CCCN(C(=O)OC(C)(C)C)C1)O2
Agent: [BH3-]C#N
Agent: [Na+]
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)NC1(CCCN(CCc3ccccc3)C1)O2

Procedure:
(±)-(E)-3-{1′-(2-Phenyl-ethyl)-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-acrylic acid methyl ester was synthesized starting from Intermediate 5 (339 mg, 1.00 mmol), according to the procedure described in Example 40, Step A, using phenylacetaldehyde (0.13 ml, 1.2 mmol) and NaBH3CN (63 mg, 1.2 mmol). The product was obtained as a yellow solid (320 mg).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[N:55]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1[CH3:64])=[C:56]=[O:57]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:56]([NH:55][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=2[CH3:64])=[O:57])[CH2:49][CH2:48]1
Reactant: Cc1ccccc1N=C=O
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccccc1NC(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 31 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 1-isocyanato-2-methylbenzene as starting materials in 31% yield. LCMS for C32H34ClN8O2 (M+H)+: m/z=597.2.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:5]([NH2:6])=[C:4]([CH3:12])[CH:3]=1>C(O)C.[Ni]>[Br:1][C:2]1[CH:8]=[C:7]([NH2:9])[C:5]([NH2:6])=[C:4]([CH3:12])[CH:3]=1
Reactant: Cc1cc(Br)cc([N+](=O)[O-])c1N
Agent: [Ni]
Solvent: CCO
Product: Cc1cc(Br)cc(N)c1N

Procedure:
A solution of 15 g (64.9 mmol) of 4-bromo-2-methyl-6-nitroaniline in 300 ml of ethanol is hydrogenated at about 27° for 4 hours in the presence of 1.5 g of Raney nickel. The reaction mixture is then filtered and evaporated. The title compound is obtained as a brown oil.