Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([C:9]2([OH:32])[CH2:15][CH:14]3[N:16]([CH:17]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[Cl:31])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:24])[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C1(P([N:47]=[N+:48]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>>[N:1]([CH2:2][C:3]1[C:4]([C:9]2([OH:32])[CH2:10][CH:11]3[N:16]([CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:24])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[Cl:31])[CH:14]([CH2:13][CH2:12]3)[CH2:15]2)=[N:5][CH:6]=[CH:7][CH:8]=1)=[N+:47]=[N-:48]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: NCc1cccnc1C1(O)CC2CCC(C1)N2C(c1ccccc1Cl)c1ccccc1Cl
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=NCc1cccnc1C1(O)CC2CCC(C1)N2C(c1ccccc1Cl)c1ccccc1Cl

Procedure:
Follow the procedure of Step 5 of Example 15, using the product from Step 4 (95.2 mg, 0.213 mmol), diphenylphosphoryl azide (67.4 mg, 0.245 mmol) and 1,8-diazabicyclo [5,4,0]undec-7-ene (52.96 mg, 0.32 mmol) to give the desired compound as the minor product.
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[CH:11]=2)=[C:6]([F:25])[CH:5]=[CH:4][C:3]=1[OH:26].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].O>CN(C=O)C>[F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[CH:11]=2)=[C:6]([F:25])[CH:5]=[CH:4][C:3]=1[O:26][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]
Reactant: CCOC(=O)CBr
Reactant: COc1cc(CNc2c(F)ccc(O)c2F)cc(-c2cccc(F)c2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(F)c(NCc2cc(OC)cc(-c3cccc(F)c3)c2)c1F
Reaction time: 1 h
Yield: 80.2 %

Procedure:
To a solution of 2,4-difluoro-3-[[3-(3-fluorophenyl)-5-methoxy-phenyl]methylamino]phenol (500 mg, 1.4 mmol, 1.0 eq) in DMF (10 mL) was added Cs2CO3 (634 mg, 1.9 mmol, 1.4 eq). The reaction mixture was stirred for 1 h, then ethyl 2-bromoacetate (279 mg, 1.7 mmol, 1.2 eq) was added. The reaction mixture was stirred for a further 1 h, then poured into water and extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The crude residue obtained was purified by column chromatography (EtOAc:petroleum ether, 0:1 to 1:10) to give the title compound as an oil (500 mg, 80%).
Reaction SMILES: O[Li].O.[Cl:4][C:5]1[CH:18]=[CH:17][C:8]([O:9][CH2:10][CH2:11][C:12]([O:14]CC)=[O:13])=[C:7]([CH3:19])[CH:6]=1>O.C1COCC1>[Cl:4][C:5]1[CH:18]=[CH:17][C:8]([O:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[C:7]([CH3:19])[CH:6]=1
Reactant: CCOC(=O)CCOc1ccc(Cl)cc1C
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Cl)ccc1OCCC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.4 %

Procedure:
A solution of LiOH.H2O (0.50 g; 12 mmol) in water (10 mL) was added to a solution of ethyl 3-(4-chloro-2-methylphenoxy)propionate (1.98 g; 8.15 mmol; from step (i) above) in THF (20 mL). The reaction mixture was stirred at room temperature overnight, THF was evaporated and the water phase was washed with ether. The resultant solution was acidified with HCl (2M), whereafter a solid material precipitated. The product was filtered and air-dried yielding 0.62 g (35%) of the sub-title compound.
Reaction SMILES: C([O:8][N:9]1[C:14](=[O:15])[C:13]2[CH:16]=[C:17]([F:25])[C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[N:19][C:12]=2[N:11]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[C:10]1=[O:36])C1C=CC=CC=1>C1COCC1.[Pd]>[F:25][C:17]1[C:18]([N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[N:19][C:12]2[N:11]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=3)[C:10](=[O:36])[N:9]([OH:8])[C:14](=[O:15])[C:13]=2[CH:16]=1
Reactant: O=c1c2cc(F)c(N3CCCC3)nc2n(-c2cccc(C(F)(F)F)c2)c(=O)n1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=c1c2cc(F)c(N3CCCC3)nc2n(-c2cccc(C(F)(F)F)c2)c(=O)n1O
Yield: 57.3 %

Procedure:
Using the method of Example 56, 20% Pd/C (25 mg), 3-benzyloxy-6-fluoro-7-pyrrolidin-1-yl-1-(3-trifluoromethylphenyl)-1H-pyrido[2,3-d]pyrimidine-2,4-dione (Example S-4, 0.17 g, 0.34 mmol) were combined in 25 mL of THF, to give 0.08 g of the title compound as a solid, mp 136-138° C.
Reaction SMILES: N1C=CC=CC=1.[CH:7]1([N:13]([CH3:36])[C:14](=[O:35])[CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=[C:24]2[NH:29][C:30](=[O:34])[CH:31]([CH2:32]O)[N:23]2[CH2:22]3)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.S(Cl)(C)(=O)=O.CCN(C(C)C)C(C)C>O>[CH:7]1([N:13]([CH3:36])[C:14](=[O:35])[CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=[C:24]2[NH:29][C:30](=[O:34])[C:31](=[CH2:32])[N:23]2[CH2:22]3)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CN(C(=O)CCCOc1ccc2c(c1)CN1C(=N2)NC(=O)C1CO)C1CCCCC1
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: C=c1c(=O)[nH]c2n1Cc1cc(OCCCC(=O)N(C)C3CCCCC3)ccc1N=2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 500 ml of pyridine was added 5.14 g of N-cyclohexyl-N-methyl-4-(2-oxo-3-hydroxymethyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutanamide to which was added 0.9 ml of mesyl chloride. This solution was cooled to about 0°-5° C., at which time 7.12 ml of DIPEA was added. This solution was stirred at room temperature for 3 hours. The pyridine was stripped under high vacuum at about 40° C. to give a suspension which was trituratured with water, centrifuged and crystals of the captioned compound collected by filtration: m.p. 176°-178° C.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10](OCC)=[O:11])[N:7]([NH2:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.[CH:20](N)=[NH:21].C(OCCO)C.C(Cl)(Cl)Cl>CO>[C:1]([C:5]1[CH:9]=[C:8]2[N:7]([CH:6]=1)[N:15]=[CH:20][N:21]=[C:10]2[OH:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: N=CN
Reactant: CCOC(=O)c1cc(C(C)(C)C)cn1N
Solvent: CO
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1cc2c(O)ncnn2c1
Yield: 25.6 %

Procedure:
Ethyl 3-tert-butyl-1-aminopyrrole-5-carboxylate (1.00 g, 4.76 mmol, 1 eq), formamidine acetate (1.46 g, 14.3 mmol, 3 eq.) and 2-ethoxyethanol (10 mL) were mixed and refluxed for 3 hours. The solvent was stripped and then restripped from chloroform (3×) to yield a solid. This solid was stirred in 5 mL MeOH, filtered, and the collected solids rinsed with Et2O and dried to yield 233 mg of 6-tert-butyl-pyrrolo[2,1-f][1,2,4]triazin-4-ol as a white solid. LCMS found: (M+H)+=191.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:23]2[C:6](=[CH:7][C:8]3[O:12][C:11]([C:13]4[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=4)=[N:10][C:9]=3[CH:22]=2)[C:5]([CH3:25])([CH3:24])[CH2:4][CH2:3]1.[Cl:27]CCl>>[CH3:1][C:2]1([CH3:26])[C:23]2[C:6](=[CH:7][C:8]3[O:12][C:11]([C:13]4[CH:21]=[CH:20][C:16]([C:17]([Cl:27])=[O:18])=[CH:15][CH:14]=4)=[N:10][C:9]=3[CH:22]=2)[C:5]([CH3:25])([CH3:24])[CH2:4][CH2:3]1
Reactant: CC1(C)CCC(C)(C)c2cc3oc(-c4ccc(C(=O)O)cc4)nc3cc21
Reactant: ClCCl
Product: CC1(C)CCC(C)(C)c2cc3oc(-c4ccc(C(=O)Cl)cc4)nc3cc21

Procedure:
p-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth[2,3-d]oxazolyl) benzoic acid (4.57 g - 13.1 mmoles) is suspended in dichloromethane (200 ml). There is then slowly added dicyclohexylamine (2.37 g - 13.1 mmoles) and the dichloromethane is then evaporated.
Reaction SMILES: C[O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[NH:13])[NH:11][OH:12])[CH:5]=1.C(N(C(C)C)CC)(C)C.[F:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](Cl)=O>C1COCC1>[F:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]1[O:12][N:11]=[C:10]([C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:2])=[O:14])[N:13]=1
Reactant: COC(=O)c1cccc(C(=N)NO)c1
Reactant: O=C(Cl)c1ccccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(O)c1cccc(-c2noc(-c3ccccc3F)n2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
To a solution of 3-(N-Hydroxycarbamimidoyl)-benzoic acid methyl ester (60 g, 310 mmol) in anhydrous THF (200 mL) was added diisopropylethylamine (75 mL, 434 mmol) at 5° C., and then to the mixture was added 2-fluorobenzoyl chloride (48.1 mL, 403 mmol) over 20 min. The reaction mixture was stirred for 1 h at room temperature. The precipitate was filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethylacetate (400 mL) and then washed with water (200 mL×2). The solvent was removed under reduced pressure and the desired product was crystallized in 60% ethylacetate in hexane to yield the desired product (81 g, 83% yield) as a white solid. 1H-NMR (CDCl3) δ 8.18 (1H), 8.03 (2H), 7.48 (2H), 7.18 (2H), 5.61 (2H), 3.82 (3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]2[CH2:7][CH2:8][C:9]3[CH:10]=[CH:11][N:12]([CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])[C:13]=3[C:5]=2[CH:4]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]2=[CH:7][CH:8]=[C:9]3[C:13]([N:12]([CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])[CH:11]=[CH:10]3)=[C:5]2[CH:4]=1
Reactant: COc1ccc2c(c1)-c1c(ccn1CCNC(C)=O)CC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: COc1ccc2ccc3ccn(CCNC(C)=O)c3c2c1
Yield: 83.7 %

Procedure:
254 mg of N-[2-(4,5-dihydro-8-methoxy-1H-benz[g]indol-1-yl)ethyl]-acetamide were dissolved in 10 ml of dioxane under argon, 238 mg of DDQ were added and the mixture was heated to reflux for 1 hour. Separated crystals were removed by filtration, the filtrate was evaporated and the residue was chromatographed on 50 g of silica gel with methylene chloride/acetone 9:1. 211 mg (83%) of N-[2-(8-methoxy-1H-benz[g]indol-1-yl)ethyl]-acetamide were obtained as a light yellowish solid. Tlc (silica gel): Rf=0.25 (methylene chloride/acetone 9:1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH3:26])([N:14]2[C:25]3[C:17](=[CH:18][N:19]=[C:20]4[C:24]=3[CH:23]=[CH:22][NH:21]4)[N:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:26][C:11]1([N:14]2[C:25]3[C:17](=[CH:18][N:19]=[C:20]4[C:24]=3[CH:23]=[CH:22][NH:21]4)[N:16]=[N:15]2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(n2nnc3cnc4[nH]ccc4c32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(n2nnc3cnc4[nH]ccc4c32)CCNCC1
Reaction time: 1.5 h
Yield: 101 %

Procedure:
A mixture of 4-methyl-4-(6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-piperidine-1-carboxylic acid tert butyl ester (200 mg, 0.56 mmol) in DCM/TFA was stirred for 1.5 hours. The solvent was evaporated under vacuum and the resulting residue purified by column chromatography using an Isolute® SCX-2 column (gradient: 0 to 50% [2M NH3 in methanol] in DCM) to afford 145 mg (100%) of 1-(4-methyl-piperidin-4-yl)-1,6-dihydro-1,2,3,5,6-pentaaza-as-indacene. LCMS (Method I, ESI): RT=0.32 & 1.58 min, m+H=257.3; 1H NMR (400 MHz, DMSO) δ: 12.41 (s, 1H), 9.04 (s, 1H), 7.62 (d, 1H), 7.04 (m, 1H), 2.90 (m, 2H), 2.79 (m, 2H), 2.70 (m, 2H), 2.05 (m, 2H), 1.84 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]([Cl:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.CO.[CH:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)=O.[BH3-]C#N.[Na+]>CCOC(C)=O.C(O)(=O)C>[Cl:14][C:12]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:5]([NH:4][CH2:3][CH2:2][NH:1][CH2:22][C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)[N:13]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CNCCNc2nc(Cl)nc3c2ncn3C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 60.8 %

Procedure:
The operation is carried out as in Stage 2 of Example 7 starting from 280 mg of the product obtained in Stage 1 of Example 7, 4 ml of methanol, 230 mg of methyl 4-formylbenzoate in place of the benzaldehyde and 0.2 ml of acetic acid then the reaction medium is agitated at ambient temperature for 5 hours. Then 100 mg of NaBH3CN is added and the reaction medium is agitated at ambient temperature for approximately 1 hour. 10 ml AcOEt is added, followed by washing with 2×5 ml H2O, then 5 ml of a saturated aqueous solution of NaCl, drying and evaporating the solvent. After purification by chromatography on silica eluting with methylene chloride/methanol/ammonium hydroxide in a proportion of 95/05/0.5, 260 mg of expected product is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CI.[C:11](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:11])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(Cl)cc1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc(Cl)cc1
Temperature: 60 °C
Yield: 75 %

Procedure:
p-Chlorophenol (2 g, 15 mmol), methyl iodide (1.36 ml, 21.8 mmol) and potassium carbonate (2.07 g, 15.6 mmol) in dry acetone (15 ml) were taken in a 50 ml flask. After refluxing for 3 hrs at 60° C., acetone was removed using a rotary evaporator. Water was added and the product was extracted with CH2Cl2 to afford 2.2 g of crude product, which was purified by column chromatography using hexane as eluent to yield p-chloroanisole in 75% yield (1.59 g).
Reaction SMILES: [N+](=[CH:3][C:4]([CH:6]1[O:12][CH:11]2[CH:8]([C:9](=[O:27])[N:10]2[C:13](=[C:24]([CH3:26])[CH3:25])[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[N:7]1[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])=[O:5])=[N-].CCOCC.C(Cl)[Cl:44]>>[Cl:44][CH2:3][C:4]([CH:6]1[O:12][CH:11]2[CH:8]([C:9](=[O:27])[N:10]2[C:13](=[C:24]([CH3:26])[CH3:25])[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[N:7]1[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])=[O:5]
Reactant: ClCCl
Reactant: CC(C)=C(C(=O)OCc1ccccc1)N1C(=O)C2C1OC(C(=O)C=[N+]=[N-])N2C(=O)OCc1ccccc1
Solvent: CCOCC
Product: CC(C)=C(C(=O)OCc1ccccc1)N1C(=O)C2C1OC(C(=O)CCl)N2C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 435 mg of benzyl α-(3ξ-diazoacetyl-2-carbobenzoxy-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate in 4 ml of methylene chloride is added 1 ml of ether containing 16% hydrogen chloride, and the mixture stirred at room temperature for 30 minutes and then concentrated under reduced pressure to yield 433 mg of benzyl α-(3ξ-chloroacetyl-2-carbobenzoxy-7-oxo-4-oxa-2,6-diazabicyclo-[3.2.0]heptan-6-yl)-α-isopropylideneacetate as crystals.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].B(F)(F)F.[CH3:32]COCC>CO>[F:1][C:2]1[CH:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:32])=[O:5]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)c(F)c1
Reactant: CCOCC
Agent: FB(F)F
Solvent: CO
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OC)c(F)c1
Temperature: 0 °C

Procedure:
A solution of 50.5 g of 2-fluoro-4-(hexadecylamino)-benzoic acid and 34.4 ml of boron trifluoride etherate in 200 ml of methanol is stirred under reflux for 44 hours, allowed to cool, and poured into 1.20 liters of ice cold 5% aqueous sodium carbonate solution. The white solid is collected by filtration and recrystallized from benzene-ethanol to yield methyl 2-fluoro-4-(hexadecylamino)benzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][N:21]([C:23](=[O:38])/[CH:24]=[CH:25]/[C@@H:26]5[CH2:30][CH2:29][CH2:28][N:27]5C(OC(C)(C)C)=O)[CH2:22][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].Cl>CC(O)C.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][N:21]([C:23](=[O:38])/[CH:24]=[CH:25]/[C@@H:26]5[CH2:30][CH2:29][CH2:28][NH:27]5)[CH2:22][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1/C=C/C(=O)N1CCc2c(sc3ncnc(Nc4ccc(F)c(Cl)c4)c23)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: O=C(/C=C/[C@@H]1CCCN1)N1CCc2c(sc3ncnc(Nc4ccc(F)c(Cl)c4)c23)C1
Temperature: 70 °C
Reaction time: 3 h
Yield: 42.6 %

Procedure:
tert-Butyl (2S)-2-[(1E)-3-{4-[(3-chloro-4-fluorophenyl)amino]-5,8-dihydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-7(6H)-yl}-3-oxoprop-1-en-1-yl]pyrrolidine-1-carboxylate from Example 14A (397 mg, 0.712 mmol) was dissolved in 2-propanol (4 mL), and a 4 M solution of gaseous hydrogen chloride in dioxane (0.36 mL) was added. The mixture was stirred for 3 h at 70° C. The solvent was then removed in vacuo. The residue was dissolved in ethyl acetate and washed with 1 N aqueous sodium hydroxide solution. The organic layer was dried over sodium sulfate, and the solvent was evaporated. The crude product was purified by preparative HPLC to yield 139 mg (42%) of the title compound.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:11]=[C:12]([C:13](OCC)=[O:14])[C:7]=2[CH:6]=[N:5]1)[CH3:3].[OH-].[Na+].[Al].[NH2:27][CH2:28][C:29]1[C:30](=[O:39])[NH:31][C:32]([CH3:38])=[CH:33][C:34]=1[CH2:35][CH2:36][CH3:37].Cl.CN(C)CCCN=C=NCC.O.N1C2C(=NC=CC=2)N(O)N=1.CN1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.CO.O.CS(C)=O>[CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:11]=[C:12]([C:13]([NH:27][CH2:28][C:29]3[C:30](=[O:39])[NH:31][C:32]([CH3:38])=[CH:33][C:34]=3[CH2:35][CH2:36][CH3:37])=[O:14])[C:7]=2[CH:6]=[N:5]1)([CH3:1])[CH3:3]
Reactant: CCCc1cc(C)[nH]c(=O)c1CN
Reactant: CCOC(=O)c1cc(-c2ccccc2)nc2c1cnn2C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CN1CCOCC1
Solvent: CS(C)=O
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccccc2)nc2c1cnn2C(C)C

Procedure:
Ethyl 1-(1-methylethyl)-6-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (270 mg, 0.873 mmol) was suspended in THF (1913 μl) and Methanol (6378 μl). To the mixture was added 3N NaOH (436 μl, 1.309 mmol) and the contents heated on an aluminum block at 55° C. overnight. The solvent was removed in vacuo. The remaining orange residue was dissolved with water (10 mL) and cooled with stirring in an ice bath. The contents were acidified by dropwise addition 1N HCl until precipitation ceased. The white solid was collected via vacuum filtration and the filter cake was dried open to the air, under vacuum overnight. The white solid was added to a 20 mL vial followed by 3-(aminomethyl)-6-methyl-4-propyl-2(1H)-pyridinone (208 mg, 0.960 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (251 mg, 1.309 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol hydrate (202 mg, 1.309 mmol) and DMSO (4 ml). To the same was added a magnetic stir bar and 4-methylmorpholine (618 mg, 6.11 mmol). The reaction was stirred at room temperature overnight. The reaction contents were slowly poured onto an aqueous solution of sat Na2CO3 (6 mL) and water (20 mL) and stirred in an ice bath. The resulting suspension was stirred 20 minutes. The solid was collected by vacuum filtration and dried under high vacuum overnight. The title compound was obtained as an off-white solid (388 mg, 99%). 1H NMR (400 MHz, DMSO-δ6) δ 9.00 (t, J=3.92 Hz, 1H), 8.38 (s, 1H), 8.23-8.29 (m, 2H), 8.16 (s, 1H), 7.46-7.62 (m, 3H), 5.93 (s, 1H), 5.34 (quin, J=6.63 Hz, 1H), 4.45 (d, J=4.55 Hz, 2H), 2.55 (s, 2H), 2.14 (s, 3H), 1.56 (d, J=6.57 Hz, 6H), 1.45-1.54 (m, 2H), 0.88 (t, J=7.20 Hz, 3H). LCMS(ES) [M+H]+ 444.3.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH2:12]([NH2:15])[CH2:13][CH3:14].C(N(C(C)C)CC)(C)C>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([CH2:14][CH2:13][CH2:12][NH2:15])[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CCCN
Reactant: Clc1nc(Cl)c2sccc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: NCCCc1nc(Cl)nc2ccsc12
Yield: 91.9 %

Procedure:
3.95 g (19.26 mmol) of 2,4-dichlorothieno[3,2-d]pyrimidine (III), 1.90 mL (23.11 mmol) of propylamine, and 6.71 mL (38.52 mmol) of diisopropylethylamine are stirred for 16 hours in 40 mL of tetrahydrofuran at ambient temperature. Then the reaction mixture is concentrated by evaporation, the residue is combined with water. The precipitate formed is suction filtered and dried. 4.03 g of product IV (92%) is obtained as a powder.
Reaction SMILES: C1(N(CCO)C(C2C(OCC3C=CC=CC=3)=C(O)N=C(CC3(C4C=CC=CC=4)CCCC3)N=2)=O)CC1.[Si]([O:44][CH2:45][CH2:46][N:47]([CH:77]1[CH2:80][CH2:79][CH2:78]1)[C:48]([C:50]1[C:55]([O:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[C:54]([OH:64])[N:53]=[C:52]([CH2:65][C:66]2([C:71]3[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=3)[CH2:70][CH2:69][CH2:68][CH2:67]2)[N:51]=1)=[O:49])(C(C)(C)C)(C)C>>[CH:77]1([N:47]([CH2:46][CH2:45][OH:44])[C:48]([C:50]2[C:55]([O:56][CH2:57][C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[C:54]([OH:64])[N:53]=[C:52]([CH2:65][C:66]3([C:71]4[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=4)[CH2:70][CH2:69][CH2:68][CH2:67]3)[N:51]=2)=[O:49])[CH2:78][CH2:79][CH2:80]1
Reactant: CC(C)(C)[Si](C)(C)OCCN(C(=O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1)C1CCC1
Agent: O=C(c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)C1CC1
Product: O=C(c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)C1CCC1
Yield: 99.7 %

Procedure:
This compound was prepared following the same method as described for 5-Benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid cyclopropyl-(2-hydroxyethyl)-amide (285) from 5-Benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid cyclobutyl-(2-hydroxyethyl)-amide (292) (420 mg, 0.68 mmol). The product was obtained as a white sticky solid (340 mg, 99.39%).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28](=[O:40])[NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=3)[CH:23]=[CH:22]4)=[N:13][CH:12]=[N:11][C:10]=2[CH:9]1[CH3:41])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:39][C:36]([F:37])([F:38])[C:32]1[CH:31]=[C:30]([NH:29][C:28]([N:24]2[C:25]3[C:21](=[CH:20][C:19]([O:18][C:14]4[C:15]5[CH2:16][CH2:17][NH:8][CH:9]([CH3:41])[C:10]=5[N:11]=[CH:12][N:13]=4)=[CH:27][CH:26]=3)[CH:22]=[CH:23]2)=[O:40])[CH:35]=[CH:34][CH:33]=1
Reactant: CC1c2ncnc(Oc3ccc4c(ccn4C(=O)Nc4cccc(C(F)(F)F)c4)c3)c2CCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1NCCc2c(Oc3ccc4c(ccn4C(=O)Nc4cccc(C(F)(F)F)c4)c3)ncnc21

Procedure:
A solution od 8-methyl-4-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylic acid tert-butyl ester (217 mg, 0.38 mmol), DCM (5 mL), and TFA (5 mL) is stirred at rt for 2 h. At that point the solution is concentrated in vacuo and the residue is separated via semi-prep HPLC (C18; 10-100% I/H2O with 0.1% NH4OH) to give the title compound. MS (ESI) m/z 468.1 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 10.39 (s, 1H), 8.51 (s, 1H), 8.28 (d, J=9.1 Hz, 1H), 8.06-8.15 (m, 2H), 7.97 (d, J=8.6 Hz, 1H), 7.65 (t, J=8.0 Hz, 1H), 7.43-7.53 (m, 2H), 7.13 (dd, J=9.0, 2.4 Hz, 1H), 6.80 (d, J=3.5 Hz, 1H), 4.19 (q, J=6.6 Hz, 1H), 3.34-3.42 (m, 1H), 3.08-3.20 (m, 1H), 2.88 (t, J=5.7 Hz, 2H), 1.49 (d, J=7.1 Hz, 3H).