Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([N:12]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH3:13])=[O:11].Cl.C(N=C=NCCCN(C)C)C.[C:33]([C:37]1[CH:38]=[C:39]([CH:43]=[C:44]([C:47]([CH3:50])([CH3:49])[CH3:48])[C:45]=1[OH:46])[C:40](O)=[O:41])([CH3:36])([CH3:35])[CH3:34]>ClCCl>[F:8][C:6]1[CH:5]=[CH:4][C:3]([NH:9][C:10]([N:12]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH3:13])=[O:11])=[C:2]([NH:1][C:40](=[O:41])[C:39]2[CH:43]=[C:44]([C:47]([CH3:48])([CH3:49])[CH3:50])[C:45]([OH:46])=[C:37]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH:38]=2)[CH:7]=1
Reactant: CCCCCCCN(C)C(=O)Nc1ccc(F)cc1N
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCCCCCCN(C)C(=O)Nc1ccc(F)cc1NC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.1 %

Procedure:
A solution of 1-(2-amino-4-fluorophenyl)-3-heptyl-3-methylurea (0.82 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide monohydrochloride (0.67 g) and 3,5-di-t-butyl-4-hydroxybenzoic acid (0.88 g) dissolved in dichloromethane (10 ml) was stirred at room temperature overnight. The reaction solution was washed with water, saturated saline, dried over anhydrous MgSO4, and the solvent was distilled off. Purification of the residue by a silica gel column chromatography gave N-[5-fluoro-2-(3-heptyl-3-methylureido)phenyl]-3,5-di-t-butyl-4-hydroxybenzamide (0.84 g, 56%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[OH:5][C:6]1[CH:7]=[CH:8][C:9]2[O:14][CH2:13][C:12](=[O:15])[NH:11][C:10]=2[CH:16]=1>C(O)(=O)C>[OH:5][C:6]1[C:7]([N+:1]([O-:4])=[O:2])=[CH:8][C:9]2[O:14][CH2:13][C:12](=[O:15])[NH:11][C:10]=2[CH:16]=1
Reactant: O=C1COc2ccc(O)cc2N1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=C1COc2cc([N+](=O)[O-])c(O)cc2N1

Procedure:
Fumic nitric acid (δ1.52, 2.6 ml, 0.062 mole) in acetic acid (5 ml) was added dropwise under stirring to 6-hydroxy-2H-1,4-benzoxazin-3-(4-H)one (Coupler (1), 10.3 g, 0.062 mole) in acetic acid (100 ml) at room temperature. The 6-hydroxy-7-nitro-1,4-benzoxazin-3-one (6.7 g, 51%) separated as yellow prisms.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH:14]=[C:13](Br)[C:12]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[N:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:22](/B(O)O)=[CH:23]\[CH2:24][CH2:25][CH2:26][CH3:27].[O-]P([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>C(OCC)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1>[C:1]1([S:7]([N:10]2[CH:14]=[C:13]([CH:22]=[CH:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:12]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[N:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(Br)c(-c2cccnc2)n1
Reactant: CCCC/C=C/B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCCC=Cc1cn(S(=O)(=O)c2ccccc2)nc1-c1cccnc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 56.2 %

Procedure:
To toluene (20 ml) containing 36A (0.67 g, 1.84 mmol) (see Scheme 7), was added 1.5 eq of (E)-hexene-1-ylboronic acid (0.35 g). The resulting mixture was stirred for 2 hours under N2. Successively were added 2 eq of K3PO4 (0.78 g), 4 mol % of Pd(OAc)2 (16.5 mg) and 8 mol % of S-Phos (60.4 mg). After the addition, the resulting solution was warmed at 90° C. for 18 hours under N2. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed three times with a saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated. The resulting residue was purified by flash chromatography (diethyl ether/PE 1/1) to afford 3-(1-phenylsulfonyl-4-hex-1-enyl-1H-pyrazol-3-yl)-pyridine (46A) as an oil (0.38 g, 61%). 1H-NMR (400 MHz, CDCl3): δ 8.8 (d, J=2 Hz, 1H), 8.6 (dd, J=5 Hz, 2 Hz, 1H), 8.15 (s, 1H), 8.10-8.05 (m, 2H), 7.94 (dt, J=8 Hz, 2 Hz, 1H), 7.70-7.64 (m, 1H), 7.56 (bt, J=8 Hz, 2H), 7.37-7.33 (m, 1H), 6.19-6.02 (m, 1H), 2.2-2.13 (m, 2H), 1.45-1.29 (m, 4H), 0.90 (t, J=7 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH2:20][CH2:19][C:14]4([O:18][CH2:17][CH2:16][O:15]4)[CH2:13][CH:12]=3)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.BrC1NC2N=CN=C([C:30]3[C:31]([CH3:49])=[C:32]([NH:36][C:37](=[O:48])[C:38]4[CH:43]=[CH:42][C:41]([C:44]([CH3:47])([CH3:46])[CH3:45])=[CH:40][CH:39]=4)[CH:33]=[CH:34][CH:35]=3)C=2C=1>>[C:44]([C:41]1[CH:42]=[CH:43][C:38]([C:37]([NH:36][C:32]2[CH:33]=[CH:34][CH:35]=[C:30]([C:2]3[C:3]4[CH:10]=[C:9]([C:11]5[CH2:20][CH2:19][C:14]6([O:18][CH2:17][CH2:16][O:15]6)[CH2:13][CH:12]=5)[NH:8][C:4]=4[N:5]=[CH:6][N:7]=3)[C:31]=2[CH3:49])=[O:48])=[CH:39][CH:40]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1ncnc2[nH]c(Br)cc12
Reactant: Clc1ncnc2[nH]c(C3=CCC4(CC3)OCCO4)cc12
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1ncnc2[nH]c(C3=CCC4(CC3)OCCO4)cc12

Procedure:
Example 65 was prepared analogue to Intermediate 17 by replacing 4-chloro-6-iodo-7H-pyrrolo[2,3-d]pyrimidine with Intermediate 54.
Reaction SMILES: [N:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[OH:13])=O.[CH3:14][N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH3:29])([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:16]1=[CH2:30]>C(O)C>[CH3:14][N:15]1[C:16]2([O:13][C:4]3[CH:5]=[CH:6][C:7]4[C:12]([C:3]=3[N:1]=[CH:30]2)=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:17]([CH3:29])([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:18]2[C:23]1=[CH:22][CH:21]=[CH:20][CH:19]=2
Reactant: C=C1N(C)c2ccccc2C1(C)C(=O)OCC
Reactant: O=Nc1c(O)ccc2ccccc12
Solvent: CCO
Product: CCOC(=O)C1(C)c2ccccc2N(C)C12C=Nc1c(ccc3ccccc13)O2

Procedure:
A solution of 1-nitroso-2-naphthol (0.50 g, 2.89 mmol) and 1,3-dimethyl-3-carboethoxy-2-methylene-indoline (0.87 g, 2.77 mmol) in ethanol (70 ml) was heated under nitrogen and refluxed for 2 hrs. The solvent was then evaporated and the residue was chromatographed over silica (ethyl acetate/petroleum ether 1:10). After crystallization in ethanol, the yield of the pure product (colorless crystals) was 0.21 g (16%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[N:11]=[C:12](Cl)[C:13]2[CH:19]=[CH:18][CH:17]=[N:16][C:14]=2[N:15]=1.[NH2:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][N:26]=[CH:25]2.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[N:11]=[C:12]([NH:21][C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[NH:27][N:26]=[CH:25]3)[C:13]2[CH:19]=[CH:18][CH:17]=[N:16][C:14]=2[N:15]=1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: Clc1nc(-c2cc3ccccc3s2)nc2ncccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: c1ccc2sc(-c3nc(Nc4ccc5[nH]ncc5c4)c4cccnc4n3)cc2c1
Temperature: 100 °C
Reaction time: 24 h
Yield: 4.2 %

Procedure:
A mixture of 2-(1-benzothien-2-yl)-4-chloropyrido[2,3-d]pyrimidine (18.2 mg, 0.06 mmol), 5-aminoindazole (40 mg, 0.3 mmol) and potassium carbonate (83 mg, 0.6 mmol) in dioxane (20 mL) was heated to 100° C. and continued for 24 h. After removal of the solvent, the crude product was purified by silica gel column chromatography (gradient from 20% to 80% EtOAc/hexane) to give the product (1.0 mg, 4.0%); HPLC/MS: (M+H)+ 395.2 m/z; Retention time (LC-MS)=2.75 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=1)[C:8]#[N:9])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=1)[C:8]#[N:9]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Agent: [Pd]
Solvent: CO
Product: N#Cc1ccc(N)cc1C#N
Reaction time: 1 h
Yield: 86 %

Procedure:
A portion of 4-nitrophthalonitrile (5.15 g, 29.8 mmole) was dissolved in 125 mL methanol in a hydrogenation flask. The catalyst, 10% Pd/C (515 mg), was added to the mixture which was then flushed with H2 and stirred under 50 psi of H2 for 1 hour. The catalyst was removed by filtration and the solvent was distilled off under vacuum. The desired 4-aminophthalonitrile was obtained in 86% yield (3.66 g).
Reaction SMILES: [OH:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[I:15].[Sn](Cl)Cl>C(O)C>[NH2:12][C:11]1[CH:10]=[C:5]([CH:4]=[C:3]([I:15])[C:2]=1[OH:1])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(I)c(O)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: CCO
Product: COC(=O)c1cc(N)c(O)c(I)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
To a mixture of methyl 4-hydroxy-3-iodo-5-nitrobenzoate (2.99 g) in ethanol (40 mL) was added tin (II) chloride (10 g) portion wise. After stirring for 1 h at reflux, the mixture was cooled to 0° C. and quenched by saturated potassium carbonate (100 mL). The mixture was filtered through diatomaceous earth and the filtrate was extracted with ethyl acetate (4×100 mL). The combined organic extracts were dried (sodium sulfate), filtered, and concentrated under reduced pressure to give 2.5 g of the title compound: 1H NMR (300 MHz, DMSO-d6) δ 7.50, 7.24, 3.75.
Reaction SMILES: ClN1C(=O)CCC1=O.[CH:9](=[N:16][OH:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.[CH2:25]([O:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1)[C:26]#[CH:27]>C(Cl)Cl>[C:10]1([C:9]2[CH:27]=[C:26]([CH2:25][O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[O:17][N:16]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: ON=Cc1ccccc1
Reactant: C#CCOC1CCCCO1
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: c1ccc(-c2cc(COC3CCCCO3)on2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 69.5 %

Procedure:
1.47 g (11 mmol) of N-chlorosuccinimide were added at -30° C. to a solution of 1.21 g of benzaldoxime in 10 ml of methylene chloride. After 2 hours a solution of 1.0 g of triethylamine and 1.4 g of (RS)-tetrahydro-2-(2-propynyloxy)-2H-pyran in 5 ml of methylene chloride was added dropwise. The reaction mixture was stirred at room temperature for 5 hours, the solvent was thereafter distilled off and, for purification, the crude product was chromatographed on silica gel using methylene chloride as the eluent. There were obtained 1.8 g of (RS)-3-phenyl-5-(tetrahydro-pyran-2-yloxymethyl)-isoxazole as a colourless liquid; MS: 259 (M)+.
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[S:8][C:9]([CH3:28])=[C:10]([CH3:27])[C:11]=2[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[C:16]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:15]=2)=[O:13])=[CH:4][CH:3]=1.CC1SC=CC=1C>C(Cl)Cl>[Br:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[S:8][C:9]([CH3:28])=[C:10]([CH3:27])[C:11]=2[C:12]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:15]=2)=[O:13])=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)c2c(Cc3ccc(Br)cc3)sc(C)c2C)cc1C1CCCC1
Agent: Cc1ccsc1C
Solvent: ClCCl
Product: Cc1sc(Cc2ccc(Br)cc2)c(C(=O)c2ccc(O)c(C3CCCC3)c2)c1C
Yield: 73.6 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 3 using [2-(4-bromobenzyl)4,5-dimethyl-thiophen-3-yl]-(3-cyclopentyl-4-methoxy-phenyl)-methanone (4.05 g, 8.39 mmol) and 1M boron tribromide/CH2Cl 2(26.0 mL) in CH2Cl2. Purification on Biotage KP-Sil eluting with 15% acetone/hexane gave 2.90 g (74%) of the title compound. (DMSO-d6) δ1.41-1.48 (m, 2 H), 1.59-1.74 (m, 4 H), 1.82 (s, 3 H), 1.89-1.96 (m, 2 H), 2.27 (s, 3 H), 3.20 (quintet, 1 H), 3.84 (s, 2 H), 6.88 (d, 1 H), 7.03 (d, 2 H), 7.39-7.43 (m, 3 H), 7.54 (d, 1 H), 10.47 (s, 1 H).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[NH:20][N:19]=[N:18][N:17]=2)[CH:5]=[CH:4][C:3]=1[C:21](=[O:23])[CH3:22].Br.Br[CH2:26][CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1>>[OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[N:20]([CH2:26][CH2:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[N:19]=[N:18][N:17]=2)[CH:5]=[CH:4][C:3]=1[C:21](=[O:23])[CH3:22]
Reactant: BrCCc1cccnc1
Reactant: CCCc1c(OCCCCc2nnn[nH]2)ccc(C(C)=O)c1O
Agent: Br
Product: CCCc1c(OCCCCc2nnnn2CCc2cccnc2)ccc(C(C)=O)c1O

Procedure:
1-[2-Hydroxy-3-propyl-4-[4-(1H-tetrazol-5-yl)butoxy]phenyl]ethanone was allowed to react with (3-(2-bromoethyl)pyridine hydrobromide according to procedure A and the product was purified by high pressure liquid chromatography to give 1-[2-hydroxy-3-propyl-4-[4-[1-[2-(3-pyridinyl)ethyl]-1H-tetrazol-5-yl]butoxy]phenyl]ethanone, which is the N-1 isomer, and 1-[2-hydroxy-3-propyl-4-[4-[2-[2-(3-pyridinyl)ethyl]-2H-tetrazol-5-yl]butoxy]phenyl]ethanone, which is the N-2 isomer.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[NH2:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](O)=O>>[N:8]1[C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[O:1][C:12]=1[C:11]1[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=1[NH2:9]
Reactant: Nc1ccncc1O
Reactant: Nc1ccccc1C(=O)O
Product: Nc1ccccc1-c1nc2ccncc2o1
Yield: 31.5 %

Procedure:
3-Hydroxy-4-aminopyridine (2.220 g, 20.0 mmol) and 2-aminobenzoic acid (2.740 g, 20.0 mmol) in polyphosphoric acid (40 mL) were stirred at 140° C. for 6 hrs. The reaction mixture was poured into distilled water and sodium hydroxide was added until pH=8. The precipitate was collected by filtration and further purified by chromatography on silica gel eluted with petroleum ether:ethyl acetate:Et3N (160:40:1) to give 2-(oxazolo[5,4-c]pyridin-2-yl)benzenamine as yellow solid (1.332 g, Yield: 31%). 1H NMR (400 MHz, DMSO-d6) δ: 6.70 (1H, t, J=6.8 Hz), 6.94 (1H, d, J=8.4 Hz), 7.20 (2H, s), 7.33 (1H, t, J=6.8 Hz), 7.80 (1H, d, J=5.6 Hz), 7.95 (1H, d, J=8.4 Hz), 8.53 (1H, d, J=5.6 Hz), 9.05 (1H, s) ; MS(ESI) calcd. for C12H9N3O (m/z): 211, found: 212 [M+1]+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].Cl.[NH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(CC)CC)C>CO.C(=O)([O-])O.[Na+]>[N+:11]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[NH:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Reactant: CCOC(=O)CCCN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCNc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 120 h
Yield: 100 %

Procedure:
A mixture of 2-chloro-1,3-dinitrobenzene (30.0 g, 0.148 mol), ethyl 4-aminobutyrate hydrochloride (74.5 g, 0.444 mol), triethylamine (165 mL) in methanol (600 mL) was stirred at room temperature for 5 days. The mixture was diluted with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, washed with 1N hydrochloric acid, dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a brown oil (44.0 g, 0.148 mol, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH2:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.F[C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20].C(N(CC)C(C)C)(C)C>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:10][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[N+:19]([O-:21])=[O:20])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CC(N)c1cccc(Br)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1cc(F)ccc1[N+](=O)[O-])c1cccc(Br)c1
Reaction time: 18 h
Yield: 73.7 %

Procedure:
A mixture of 1-(3-bromophenyl)ethanamine (1.0 g, 5.0 mmol), 2,4-difluoro-1-nitrobenzene (0.8 g, 5.0 mmol), N,N-diisopropylethylamine (1.7 mL, 10.0 mmol) and acetonitrile (20 mL) was stirred for 18 h and concentrated in vacuo. The residue was dissolved in ethyl acetate; this solution was washed with water, dried over Na2SO4 and concentrated in vacuo to yield the title compounds as a yellow oil (1.25 g, 74%). 1H NMR (400 MHz, CDCl3): δ 8.51 (d, 1 H), 8.25 (m, 1 H), 7.48 (s, 1 H), 7.41 (m, 1 H), 7.25 (m, 2 H), 6.36 (m, 1 H), 6.24 (m, 1 H), 4.55 (m, 1 H), 1.63 (d, 3 H). MS (ESI) m/z: Calculated: 338; Observed: 339 (M+H+).
Reaction SMILES: [CH2:1]([C:3]([C:6]1[C:7]([Br:23])=[C:8]2[N:13]([C:14]=1[CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[N:12]=[CH:11][N:10]=[C:9]2[NH2:22])([OH:5])C)C.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C1COCC1>[NH2:22][C:9]1[C:8]2=[C:7]([Br:23])[C:6]([C:3](=[O:5])[CH3:1])=[C:14]([CH2:15][N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)[N:13]2[N:12]=[CH:11][N:10]=1
Reactant: CCC(C)(O)c1c(Br)c2c(N)ncnn2c1CN1CCOCC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Product: CC(=O)c1c(Br)c2c(N)ncnn2c1CN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
To a solution of THF (100 mL) was added ethyl 1-[4-amino-5-bromo-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]ethanol (419 mg, 1.18 mmol) followed by Dess-Martin periodinane (748 mg, 1.76 mmol). The solution was stirred at rt for 1 h and then quenched by addition of aqueous saturated sodium thiosulfate and NaHCO3 (100 mL) followed by EtOAc (100 mL) to the reaction. The solution was stirred for 30 min at rt and then transferred to a separatory funnel. The organic layer was isolated while the aqueous layers were back extracted with EtOAc (2×50 mL). The combined organic layers were collected, dried (MgSO4), filtered, and concentrated to dryness. The crude material was then triturated with THF-Et2O. The solid was collected, washed with Et2O (150 mL), and dried under vacuum. The mother liquor was concentrated and purified by MPLC (Isco) 100% CH2Cl2 to 9:1 v/v CH2Cl2-MeOH. The resulting purified fractions were combined with the solid and concentrated in vacuo yielding 344 mg of the above compound (0.97 mmol, yield 83%). 1H-NMR (DMSO-d6) δ 8.35 (br s, 1H), 7.94 (s, 1H), 7.13 (br s, 1H), 4.02 (s, 2H), 3.47 (m, 4H), 2.64 (s, 3H), 2.35 (m, 4H); MS [M+H]+=354.0; LCMS RT=1.11 min.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5](=[O:13])[C:6](=[O:12])[NH:7]2.[I:16]N1C(=O)CCC1=O>OS(O)(=O)=O>[I:16][C:9]1[CH:10]=[CH:11][C:3]([C:2]([F:1])([F:14])[F:15])=[C:4]2[C:8]=1[NH:7][C:6](=[O:12])[C:5]2=[O:13]
Reactant: O=C1Nc2cccc(C(F)(F)F)c2C1=O
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)O
Product: O=C1Nc2c(I)ccc(C(F)(F)F)c2C1=O
Temperature: 40 °C
Reaction time: 6 h
Yield: 41.5 %

Procedure:
A mixture of 4-trifluoromethylisatin (450 mg, 2.09 mmol) and N-iodosuccinimide (800 mg, 3.72 mmol) in conc. H2SO4 (5 mL) was stirred for 6 h at 40° C. and poured into crushed ice. The mixture was extracted with ethyl acetate and the extracts were washed with aqueous Na2SO3, dried over MgSO4, and concentrated. The residue was purified by silica gel column chromatography with 3:1 hexane/ethyl acetate to give the title compound (296 mg, 42%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:13]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)#[CH:14].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC>O.CC([O-])=O.CC([O-])=O.[Pd+2].[Cu]I.CN(C=O)C>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]#[C:14][C:2]2[CH:11]=[C:10]3[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]3)=[CH:4][CH:3]=2)=[CH:16][CH:17]=1
Reactant: O=c1[nH]cnc2cc(Br)ccc12
Reactant: C#Cc1ccc(F)cc1
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=c1[nH]cnc2cc(C#Cc3ccc(F)cc3)ccc12
Temperature: 70 °C
Reaction time: 3.5 h

Procedure:
A flask was charged with 7-bromoquinazolin-4(3H)-one (60 mg, 0.27 mmol, 1 equiv), 1-ethynyl-4-fluorobenzene (81 mg, 0.675 mmol, 2.5 equiv), Pd(OAc)2 (12.2 mg, 0.054 mmol, 0.2 equiv), PPh3 (63.7 mg, 0.24 mmol, 0.9 equiv), CuI (10.3 mg, 0.054 mmol, 0.2 equiv), Et3N (0.3 mL) and DMF (6 mL). A vacuum was applied and the reaction mixture was back filled with nitrogen three times. The mixture was stirred at 70° C. for 3.5 hours. After it was cooled to room temperature, the reaction mixture was diluted with H2O and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate, then concentrated under reduced pressure and purified by column chromatography to give the desired product. MS (ESI): 265 (MH+); 1H NMR (300 MHz, DMSO-d6) δ 12.38-12.33 (m, 1H), 8.13 (s, 2H), 7.81 (s, 1H), 7.69-7.54 (m, 3H), 7.39-7.29 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[CH:15]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:15]1([NH:20][C:2]2[C:7]([CH:8]=[O:10])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: NC1CCCC1
Product: CSc1ncc(C=O)c(NC2CCCC2)n1
Yield: 49.1 %

Procedure:
Ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (17 g, 73 mmol) and cyclopentylamine (12.4 g, 146 mmol) were combined by the 3-step procedure of Example C1 to provide 4-cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde (8.5 g, 49% yield over 3 steps). 1H NMR (400 MHz, DMSO-d6): δ 9.73 (s, 1 H), 8.55 (d, J=6.4 Hz, 1 H), 8.51 (s, 1 H), 4.43 (m, 1 H), 2.50 (s, 3 H, obscured by DMSO), 2.03-1.98 (m, 2 H), 1.69-1.48 (m, 6 H); MS (ESI) m/z: 238.3 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: ClCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 82.9 %

Procedure:
To an N,N-dimethylformamide (250 mL) solution of 4-hydroxybenzaldehyde (20 g, 164 mmol) and 2-picolyl chloride (27 g, 165 mmol) was added potassium carbonate (68 g, 492 mmol), which was stirred for 3 days at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (29 g, 83%). The title compound was not purified but used for the next reaction.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=2)[CH2:3][CH2:2]1.C(NC(C)C)(C)C.[CH:22]1([CH2:28]Br)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(OCC)(=O)C>C(O)C>[CH:22]1([CH2:28][N:1]2[CH2:6][CH2:5][CH:4]([NH:7][C:8]3[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=3)[CH2:3][CH2:2]2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: Cc1ccc(NC2CCNCC2)nc1
Reactant: BrCC1CCCCC1
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: Cc1ccc(NC2CCN(CC3CCCCC3)CC2)nc1
Yield: 75.3 %

Procedure:
A solution of 2-(piperidin-4-ylamino)-5-methylpyridine (191 mg), diisopropylamine (202 mg) and cyclohexylmethyl bromide (212 mg) in ethanol (2 mL) was refluxed for 16 hours. To the reaction solution was added ethyl acetate, and insolubles were filtered off, and then, concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (NH silica gel, hexane:ethyl acetate=4:1) to give the title compound (216 mg).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[CH:14]([CH2:15][C:16](O)=[O:17])[C:13]2[N:12]=[CH:11][CH:10]=[C:9]([Cl:19])[C:8]=2[CH2:7][CH2:6]1)=[O:4].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCOC(C)=O>[Cl:19][C:9]1[C:8]2[CH2:7][CH2:6][N:5]3[C:3](=[O:4])[CH2:2][NH:1][C:16](=[O:17])[CH2:15][CH:14]3[C:13]=2[N:12]=[CH:11][CH:10]=1
Reactant: NCC(=O)N1CCc2c(Cl)ccnc2C1CC(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C1CC2c3nccc(Cl)c3CCN2C(=O)CN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.6 %

Procedure:
94-9. To a stirred solution of 2-(7-(2-aminoacetyl)-4-chloro-5,6,7,8-tetrahydro-1,7-naphthyridin-8-yl)acetic acid (HCl-salt) (450 mg, 1.41 mmol) and triethylamine (1.17 mL, 8.43 mmol) in DCM (20 mL), T3P (1.25 mL, 2.11 mmol, 50% m/m in AcOEt) was added slowly and the suspension was stirred at RT for 1 h. Saturated aqueous NaHCO3 solution was added and the mixture was extracted with DCM (2×). The combined organic layers were dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude product was purified by flash-column chromatography over silicagel (Biotage Isolera One, eluent: gradient from 2% MeOH in AcOEt to 15% MeOH in AcOEt in 18 min) to yield the title compound as a beige solid (66 mg). UPLC-MS: MS 266.1 (M+H+); UPLC rt 0.57 min.