Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]([CH3:10])=[C:5]([CH3:9])[C:6]=1[C:7]#[N:8].[CH3:11]OC(OC)N(C)C.[NH2:19][C:20]1[CH:21]=[C:22]([C:26]([O:28][CH3:29])=[O:27])[Se:23][C:24]=1[CH3:25]>>[CH3:9][C:5]1[C:6]2[C:7]([NH:19][C:20]3[CH:21]=[C:22]([C:26]([O:28][CH3:29])=[O:27])[Se:23][C:24]=3[CH3:25])=[N:8][CH:11]=[N:1][C:2]=2[NH:3][C:4]=1[CH3:10]
Reactant: Cc1[nH]c(N)c(C#N)c1C
Reactant: COC(OC)N(C)C
Reactant: COC(=O)c1cc(N)c(C)[se]1
Product: COC(=O)c1cc(Nc2ncnc3[nH]c(C)c(C)c23)c(C)[se]1

Procedure:
The reaction of 2-amino-4,5-dimethyl-1H-pyrrole-3-carbonitrile with dimethylformamide-dimethylacetal and methyl 4-amino-5-methylselenophene-2-carboxylate as described in the example 10, gave title compound as a pale brown color solid, mp 238-240° C. 1H NMR (400 MHz, CDCl3): δ 8.74 (1H, br s, exchangeable with D2O), 7.95 (1H, s), 7.37 (1H, s), 3.86 (3H, s), 2.43 (3H, s), 2.32 (3H, s), 2.25 (3H, s); LC-MS (positive ion mode): m/z 363, 365 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7]C(=O)OC(C)(C)C)[CH2:2]1.[F:15][CH2:16][C:17](=O)[CH2:18][F:19].[Na].[Cl:22]CCl>>[ClH:22].[F:15][CH2:16][CH:17]([N:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH2:7])[CH2:2]1)[CH2:18][F:19]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: ClCCl
Reactant: O=C(CF)CF
Agent: [Na]
Product: Cl
Product: N[C@@H]1CCCN(C(CF)CF)C1
Reaction time: 2 h

Procedure:
A solution of (R)-tert-butyl piperidin-3-ylcarbamate (0.500 g), 1,3-difluoropropan-2-one (0.258 g) and sodium triacetoxyhydroborate (0.794 g) were stirred together in dichloromethane (5 mL) overnight. The reaction was quenched with saturated aqueous NaHCO3 (10 mL) and extracted with dichloromethane (30 mL). The organic layer was washed with brine (20 mL), dried over magnesium sulfate, filtered, and concentrated. The crude material was treated with HCl (4.0M dioxane, 2 mL) in methanol (2 mL). After stirring for 2 hours, the reaction was concentrated to provide the title compound.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:20]1([C:26]2[S:27][C:28]([C:31]#[N:32])=[CH:29][N:30]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH:1]1([O:6][C:7]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:8]=2[C:9]([N:23]2[CH2:24][CH2:25][N:20]([C:26]3[S:27][C:28]([C:31]#[N:32])=[CH:29][N:30]=3)[CH2:21][CH2:22]2)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)O)c1
Reactant: N#Cc1cnc(N2CCNCC2)s1
Product: CS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)N2CCN(c3ncc(C#N)s3)CC2)c1
Yield: 64 %

Procedure:
Prepared in analogy to example 1 (b) from 2-cyclopentyloxy-5-methanesulfonyl-benzoic acid (Example A4) and 2-piperazin-1-yl-thiazole-5-carbonitrile (Example 6(a)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as an off-white crystalline solid (yield 64%). MS (m/e): 461.3 (M+H+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:19])[CH2:13][CH2:12][NH:11][CH2:10][C:9]2([CH2:15][O:16][CH2:17][CH3:18])[CH3:14])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:27][CH2:28][CH:29]=[C:30]1[C:36]2[CH:37]=[CH:38][CH:39]=[N:40][C:35]=2[CH2:34][O:33][C:32]2[CH:41]=[CH:42][C:43]([C:45]([OH:48])([CH3:47])[CH3:46])=[CH:44][C:31]1=2>C(#N)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:19])[CH2:13][CH2:12][N:11]([CH2:27][CH2:28][CH:29]=[C:30]3[C:36]4[CH:37]=[CH:38][CH:39]=[N:40][C:35]=4[CH2:34][O:33][C:32]4[CH:41]=[CH:42][C:43]([C:45]([OH:48])([CH3:47])[CH3:46])=[CH:44][C:31]3=4)[CH2:10][C:9]2([CH2:15][O:16][CH2:17][CH3:18])[CH3:14])=[CH:4][CH:3]=1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: CCOCC1(C)CNCCC1(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOCC1(C)CN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CCC1(O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 65 %

Procedure:
To a solution of 4-(4-chloro-phenyl)-3-ethoxymethyl-3-methyl-piperidin-4-ol (0.038 g, 0.13 mmol) in acetonitrile/water (8:2) (1.3 mL) was added K2CO3 (0.075 g, 0.53 mmol) and 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.050 g, 0.13 mmol). The solution was allowed to stir at room temperature for 48 h. The reaction was concentrated and partitioned between EtOAc/H2O, extracted with EtOAc (3×). The organics were collected, dried over MgSO4, filtered and evaporated in vacuo, then purified by Biotage flash chromatography (75% ethyl acetate/25% hexane) to yield the title compound in 65% yield. 1H-NMR (CDCl3): δ 0.81 (s, 3H), 0.98 (t, 3H), 1.58 (s, 6H), 1.84 (s, 1H), 2.31-2.49 (m, 5H), 2.58 (d, 1H), 2.67 (s, 1H), 2.77 (d, 2H), 3.26 (q, 2H), 3.65 (d, 2H), 5.33 (bs, 2H), 6.16 (t, 1H), 6.82 (d, 1H), 7.22-7.36 (m, 7H), 7.45 (d, 1H), 7.60 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:27])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[C:14]([F:26])[CH:13]=3)[O:11][C:6]=2[C:5]([F:28])=[CH:4][C:3]=1[F:29].[H-].[Na+].[CH3:32][O:33][CH2:34]Cl.O>CN(C)C=O>[NH2:1][C:2]1[C:7]2[C:8](=[O:27])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])[CH2:32][O:33][CH3:34])=[C:14]([F:26])[CH:13]=3)[O:11][C:6]=2[C:5]([F:28])=[CH:4][C:3]=1[F:29]
Reactant: COCCl
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCN(C(=O)OC(C)(C)C)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 92.3 %

Procedure:
2.41 g (5.94 mmol) of Compound 51 obtained in Example 51 was dissolved in 60 mL of dimethylformamide under argon atmosphere, 237 mg (5.94 mmol) of sodium hydride (60% oil dispersion) and 0.47 mL (6.24mmol) of chloromethyl methyl ether were added under ice-cooling and the mixture was stirred at room temperature for 40 minutes. The reaction solution was cooled on ice, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:acetonitrile=30:l) to give 2.47 g of 5-amino-2-[4-[N-(tert-butoxycarbonyl)-N-methoxymethylamino]-3-fluorophenyl)-6,8-difluoro-4H-1-benzopyran-4-one (yield: 92%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([NH:5][C@H:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:15])[CH:13]=2)[C@@H:8]([OH:16])[CH2:7]1)=[O:4].[CH2:19](O[C@H]1C2C(=CC(OCCC)=CC=2)[C@@H](N)C1)C=C.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+]>>[F:1][C:2]([F:17])([F:18])[C:3]([NH:5][C@H:6]1[C:14]2[C:9](=[C:10]([CH3:19])[CH:11]=[C:12]([CH3:15])[CH:13]=2)[C@H:8]([OH:16])[CH2:7]1)=[O:4]
Reactant: C=CCO[C@@H]1C[C@H](N)c2cc(OCCC)ccc21
Reactant: Cc1ccc2c(c1)[C@H](NC(=O)C(F)(F)F)C[C@@H]2O
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Product: Cc1cc(C)c2c(c1)[C@H](NC(=O)C(F)(F)F)C[C@H]2O
Yield: 85 %

Procedure:
Step BM (2): The crude product from Step BM (1) was reduced with L-selectride by following a procedure analogous to Step BJ (1) to afford 6.5 g (85% yield) of trans-2,2,2-trifluoro-N-(3-hydroxy-4,6-dimethyl-2,3-dihydro-1H-inden-1-yl)acetamide (6.5 g, 85% yield). LC-MS (M+H)+=274.10 1H NMR (500 MHz, CDCl3) δ ppm 7.32 (d, 1H) 6.98-7.03 (m, 1H) 6.93-6.97 (m, 1H) 5.22 (t, 1H) 5.12 (d, 1H) 2.81-2.98 (m, 1H) 2.64-2.74 (m, 1H) 2.32-2.37 (m, 3H) 2.27-2.32 (m, 3H) 1.94 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:31]([O:35][CH2:36][CH3:37])(=[O:34])[CH:32]=[CH2:33].C(N(CC)C(C)C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5](/[CH:33]=[CH:32]/[C:31]([O:35][CH2:36][CH3:37])=[O:34])=[CH:4][N:3]=1
Reactant: Clc1ncc(I)cn1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)/C=C/c1cnc(Cl)nc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a mixture of 2-chloro-5-iodopyrimidine (7.62 g), palladium(II) acetate (356 mg), tri(o-tolyl)phosphine (965 mg), and DMF (32 mL) was added ethyl acrylate (17.2 mL) and N,N-diisopropylethylamine (13.8 mL). After stirring for 3 hours at 100° C., the reaction mixture was partitioned between ethyl acetate and H2O. The organic layer was dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give ethyl (2E)-3-(2-chloro-5-pyrimidinyl)acrylate (2.32 g).
Reaction SMILES: [C:1]([N:4]1[CH:9]([CH3:10])[CH2:8][N:7]([C:11]2[CH:16]=[C:15]([N:17]3[CH:21]=[N:20][C:19]([NH:22][C:23]4[CH:31]=[CH:30][C:26](C(O)=O)=[CH:25][CH:24]=4)=[N:18]3)[CH:14]=[CH:13][N:12]=2)[CH2:6][CH:5]1[CH3:32])(=[O:3])[CH3:2].CC[N:35](C(C)C)C(C)C.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.C(O)(C(F)(F)F)=O.Cl>CN1C(=O)CCC1.CO>[NH2:35][C:26]1[CH:30]=[CH:31][C:23]([NH:22][C:19]2[N:20]=[CH:21][N:17]([C:15]3[CH:14]=[CH:13][N:12]=[C:11]([N:7]4[CH2:6][CH:5]([CH3:32])[N:4]([C:1](=[O:3])[CH3:2])[CH:9]([CH3:10])[CH2:8]4)[CH:16]=3)[N:18]=2)=[CH:24][CH:25]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(=O)N1C(C)CN(c2cc(-n3cnc(Nc4ccc(C(=O)O)cc4)n3)ccn2)CC1C
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCCC1=O
Product: CC(=O)N1C(C)CN(c2cc(-n3cnc(Nc4ccc(N)cc4)n3)ccn2)CC1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.6 %

Procedure:
To a solution of 8 g of 4-{1-[2-(4-Acetyl-3,5-dimethyl-piperazin-1-yl)-pyridin-4-yl]-1H-[1,2,4]triazol-3-ylamino}-benzoic acid (18.3 mMol, 1.00 equiv) in 150 mL of NMP was added 9 mL of Hunig's base followed by 6 g of DPPA (21.8 mMol, 1.19 equiv). The reaction was stirred for 30 min at 25° C. To the reaction mixture was then added 200 mL of TFA and the resulting solution was warmed to 90° C. for 12 hr. After cooling to 25° C., the reaction was quenched with 200 mL of concentrated ammonium hydroxide and concentrated. The resulting oil was triturated with CH2Cl2 and the solid was isolated by filtration. The solid was then dissolved in MeOH (100 mL) and concentrated to 50 mL. The resulting precipitate was isolated and treated with 50 mL of 1 N HCl and concentrated via rotary evaporation. The oil was triturated with ethanol and the resulting solid was removed by filtration. The ethanol solution was concentrated to give 2.5 g of 1-(4-{4-[3-(4-Amino-phenylamino)-[1,2,4]triazol-1-yl]-pyridin-2-yl}-2,6-dimethyl-piperazin-1-yl)-ethanone (6.15 mMol, 33.6% yield) as the HCl salt. 1H NMR (500 MHz, CDCl3) ∂ 8.39 (1H, s), 8.10 (1H, d), 7.22 (2H, d), 7.15 (2H, d), 6.95 (1H, s), 6.92 (2H, m), 6.75 (1H, m), 6.65 (2H, d), 4.15 (2H, m), 3.08 (2H, m), 2.99 (2H, m), 2.10 (3H, s), 1.30 (6H, m) ppm. LC/MS: 0.54 min/407.3 (M+1)
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([CH:9]([OH:13])[C:10]([OH:12])=O)[CH:6]=[N:7][CH:8]=1.[C:14]1([CH:20]([NH2:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C1COCC1.C(OCC)(=O)C>[CH:20]([NH:27][C:10](=[O:12])[CH:9]([C:5]1[CH:6]=[N:7][CH:8]=[C:3]([Br:2])[CH:4]=1)[OH:13])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: O=C(O)C(O)c1cncc(Br)c1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC(c1ccccc1)c1ccccc1)C(O)c1cncc(Br)c1
Temperature: 60 °C
Yield: 84.5 %

Procedure:
(5-Bromo-pyridin-3-yl)-hydroxy-acetic acid HCl salt (1.19 g, 4.47 mmol), C,C-Diphenyl-methylamine (1.3 g, 5.36 mmol), HOAT (2.0 g, 5.36 mmol) and DIEA (1.94 mL, 11.17 mmol) were all combined in THF (43.0 mL) and heated in a closed vial for 20 min. at 60° C. The solution was diluted with ethyl acetate and washed with saturated sodium bicarbonate (1×) and brine (1×). The material was purified by silica gel chromatography using a gradient of hexanes and ethyl acetate (0-100%) to afford N-benzhydryl-2-(5-bromo-pyridin-3-yl)-2-hydroxy-acetamide (1.5 g, 73.5%) as a waxy white solid. MS: m/z 397 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11](Cl)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[NH:16][NH2:17].FC1C=CC(C2N=NC(NNC([O-])=O)=CC=2)=CC=1>C(O)CCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([NH:17][NH:16][C:15]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)NN
Reactant: Fc1ccc(-c2ccc(Cl)nn2)cc1
Agent: O=C([O-])NNc1ccc(-c2ccc(F)cc2)nn1
Solvent: CCCCO
Product: CCOC(=O)NNc1ccc(-c2ccc(F)cc2)nn1

Procedure:
A mixture of 5.0 g. of 6-(p-fluorophenyl)-3-chloropyridazine, 5.0 g. of ethyl carbazate and 50 ml. of n-butanol is refluxed for 2 hours. The solvent is removed and the residue washed with water and recrystallized from ethanol to give 1.75 g. of 3-[6-(p-fluorophenyl)-3-pyridazinyl]carbazate as crystals, m.p. 173°-174° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:28]=[CH:29][C:30]=1[CH3:31])[O:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]([NH:22]C(=O)OCC)=S)=[N:17][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].O[NH3+].C([N:38](CC)C(C)C)(C)C.C(O)C>CO>[NH2:38][C:20]1[N:19]=[C:16]2[CH:15]=[CH:14][C:13]([O:12][C:11]3[CH:28]=[CH:29][C:30]([CH3:31])=[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH:10]=3)=[CH:18][N:17]2[N:22]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)NC(=S)Nc1ccc(Oc2ccc(C)c(NC(=O)OC(C)(C)C)c2)cn1
Agent: [Cl-]
Agent: [NH3+]O
Solvent: CCO
Solvent: CO
Product: Cc1ccc(Oc2ccc3nc(N)nn3c2)cc1NC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 12 h
Yield: 167.7 %

Procedure:
A mixture of ethyl {[(5-{3-[(tert-butoxycarbonyl)amino]-4-methylphenoxy}pyridin-2-yl)amino]carbonothioyl}carbamate (11.5 g, 15.4 mmol), hydroxylammonium chloride (15.4 g, 0.223 mol), N,N-diisopropylethylamine (23.0 mL, 0.132 mol), ethanol (200 mL) and methanol (200 mL) was stirred at 80° C. for 12 hr. The reaction solution was concentrated under reduced pressure and ethyl acetate was added to the residue. The mixture was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate-hexane to give the title compound (9.18 g, 100%) as a white solid.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][S:11][CH2:10][CH2:9][NH:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:13]=[C:14]1[C:18]2[S:19][CH:20]=[CH:21][C:17]=2[CH:16]([C:22]([Cl:24])=[O:23])[CH2:15]1>C(N(CC)CC)C>[ClH:24].[O:13]=[C:14]1[C:18]2[S:19][CH:20]=[CH:21][C:17]=2[CH:16]([C:22]([SH:11]2[CH2:10][CH2:9][NH:8][CH:7]([CH2:6][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH2:12]2)=[O:23])[CH2:15]1
Reactant: O=C1CC(C(=O)Cl)c2ccsc21
Reactant: C1CCN(CC2CSCCN2)C1
Solvent: CCN(CC)CC
Product: Cl
Product: O=C1CC(C(=O)[SH]2CCNC(CN3CCCC3)C2)c2ccsc21
Yield: 25.8 %

Procedure:
The procedure described in Example 24 was repeated, but using 0.96 g of 3-(pyrrolidin-1-ylmethyl)thiomorpholine, 1.39 ml of triethylamine and 1.0 g of 4,5-dihydro-6 oxo-6H-cyclopenta[b]thiophene-4-carbonyl chloride, to afford 0.5 g of the title compound, melting at 204°-223° C.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[OH:11][NH:12][CH2:13][CH2:14][CH2:15][P:16](=[O:19])([OH:18])[OH:17].[CH2:20]([CH2:22][NH2:23])[OH:21]>C(O)C>[CH2:20]([CH2:22][NH2:23])[OH:21].[CH:1]([N:12]([CH2:13][CH2:14][CH2:15][P:16](=[O:17])([OH:19])[OH:18])[OH:11])=[O:3]
Reactant: O=CO
Reactant: O=P(O)(O)CCCNO
Solvent: CC(=O)OC(C)=O
Solvent: CCO
Solvent: NCCO
Product: O=CN(O)CCCP(=O)(O)O
Reaction time: 0.5 h

Procedure:
Formic acid (1.0 ml.) was added dropwise to acetic anhydride (1.2 ml.) at ambient temperature with stirring. The stirring was continued at the same temperature for 30 minutes and then 3-(N-hydroxyamino)propylphosphonic acid (1.51 g.) was added to the mixture. The reaction mixture was stirred at ambient temperature for 1.5 hours and concentrated under reduced pressure to give an oily residue, which was dissolved in ethanol (20 ml.). To the aqueous solution was added ethanolamine (0.61 g.) to precipitate an oil, which was separated by decantation and crystallized with ethanol (20 ml.) to give crystals. The crystals were separated by filtration, washed with ethanol and dried to give crystalline monoethanolamine salt of 3-(N-formyl-N-hydroxyamino)propylphosphonic acid (1.75 g.), a part (1.5 g.) of which was recrystallized from 90% aqueous ethanol to give the purified object compound (1.15 g). M.p. 139°-142° C.
Reaction SMILES: [CH:1]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][CH:23]=[C:22]([C:25]([OH:27])=O)[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3][CH2:2]1.[C:28]([O:32][C:33](=[O:42])[NH:34][C@H:35]1[CH2:40][CH2:39][C@H:38]([NH2:41])[CH2:37][CH2:36]1)([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33](=[O:42])[NH:34][C@H:35]1[CH2:36][CH2:37][C@H:38]([NH:41][C:25]([C:22]2[C:18]3[N:19]=[CH:20][N:21]=[C:16]([C:8]4[C:9]5[O:13][CH2:12][O:11][C:10]=5[CH:14]=[CH:15][C:7]=4[O:6][CH2:5][CH:1]4[CH2:4][CH2:3][CH2:2]4)[C:17]=3[NH:24][CH:23]=2)=[O:27])[CH2:39][CH2:40]1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: O=C(O)c1c[nH]c2c(-c3c(OCC4CCC4)ccc4c3OCO4)ncnc12
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CCC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from 4-(5-Cyclobutylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A68) and trans-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.[CH:13]1([CH2:19][CH2:20][C:21](OCC)=[O:22])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C(O)(=O)C.O1CCCC1.C(OCC)C>[CH:13]1([CH2:19][CH2:20][C:21](=[O:22])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COP(C)(=O)OC
Reactant: CCOC(=O)CCC1CCCCC1
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COP(=O)(CC(=O)CCC1CCCCC1)OC
Yield: 52.3 %

Procedure:
135 g. of dimethyl methylphosphonate were dissolved in 800 ml. of tetrahydrofuran, and to the solution cooled to -65°C., a solution of butyllithium [prepared from 163 g. of butyl bromide and 16 g. of lithium] in 610 ml. of diethyl ether was added drop-wise. To the reaction mixture was added drop-wise a solution of 62.5 g. of ethyl 3-cyclohexylpropionate in 300 ml. of tetrahydrofuran and the resulting mixture was stirred at the same temperature for two hours and afterwards at 0°C., overnight. The reaction mixture was then neutralised with acetic acid, concentrated under reduced pressure and after the addition of water extracted with diethyl ether. The ethereal extract was dried and the solvent distilled off. The residue was subjected to distillation under reduced pressure to obtain 51 g. (yield 52.3%) of the title product as a colourless oil, b.p. 143°-148°C./0.2 - 0.4 mm.Hg. NMR spectrum (tetrachloromethane): δ = 3.82 (6H, doublet), 3.16 (2H, doublet), 2.4 (2H, triplet), 1.97 - 1.08 (13H, multiplet).
Reaction SMILES: C[N:2]([C@@H:10]1[C:18]2[C:13](=CC=CC=2)C[C@@H]1OC1CCCCO1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[C:26]1([CH3:36])[CH:31]=[CH:30][C:29](S(O)(=O)=O)=[CH:28][CH:27]=1.C([O-])(O)=[O:38].[Na+].O>CO.C(OCC)(=O)C>[C:5]([O:4][C:3](=[O:9])[NH:2][CH2:10][C@H:18]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:36][C@@H:13]1[OH:38])([CH3:6])([CH3:7])[CH3:8]
Reactant: O=C([O-])O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1c2ccccc2C[C@@H]1OC1CCCCO1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NC[C@H]1c2ccccc2C[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
tert-Butyl methyl[(1R,2S)-2-(tetrahydro-2H-pyran-2-yloxy)-2,3-dihydro-1H-inden-1-yl]carbamate (Method 16; 4.0 g, 11.5 mmol) was dissolved in methanol (50 mL), 4-toluene sulphonic acid added and the reaction stirred at ambient temperature for 2 hours. Saturated NaHCO3 (50 mL), water (100 mL) was added and ethyl acetate (100 mL) was added and the mixture stirred for 30 mins. The organic phase was separated, washed with water (50 mL), brine (50 mL) and dried (MgSO4). The volatiles were removed by evaporation under reduced pressure to give the title compound (3.0 g, 99%) as an oil.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(C)(C)C.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:19]Br.C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:23]=1)[CH2:19][N:11]1[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]1
Reactant: Fc1cc(CBr)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(Cc2cc(F)cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
A mixture of piperidin-4-ylcarbamic acid tert-butyl ester (4 g, 20 mmol), 3-fluoro-5-(trifluoromethyl)benzyl bromide (4.6 g, 18.1 mmol) and diisoproylethylamine (4.7 ml, 27.1 mmol) in dichloromethane (25 ml) was stirred at room temperature for 2 h. After this period, trifluoroacetic acid (32 ml) was added and the reaction mixture was stirred for a further 2 h. The solvent was evaporated in vacuo and a saturated solution of sodium carbonate was added. The mixture was extracted with dichloromethane and the separated organic layer was dried (Na2SO4), filtered, and the solvent evaporated in vacuo to yield D7 (4 g, 80%) as a solid. C13H16F4N2 requires 276. Found 277 (MH+)
Reaction SMILES: [F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[C:24][CH2:25][O:26]C3CCCCO3)=[CH:19][C:18]=2[F:33])=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]>CCO.Cl.O>[F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[C:24][CH2:25][OH:26])=[CH:19][C:18]=2[F:33])=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: O=C(NOCCO)c1ccc(F)c(F)c1Nc1ccc(C#CCOC2CCCCO2)cc1F
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C(NOCCO)c1ccc(F)c(F)c1Nc1ccc(C#CCO)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
3,4-Difluoro-2-{2-fluoro-4-[3-(tetrahydro-2H-pyran-2-yloxy)-1-propynyl]anilino}-N-(2-hydroxyethoxy)benzamide (115 mg, 0.25 mmol) was dissolved in EtOH (4 mL) to which was added 1 M HCl (5 drops). This reaction mixture was stirred overnight at RT, then the mixture was diluted with water (50 mL) and extracted with EtOAc (4×30 mL). The combined EtOAc fractions were washed with water (2×20 mL), brine (50 mL) and dried (Na2SO4) then the solvent removed under reduced pressure to afford a white solid which was purified by filtration through a plug of silica gel (EtOAc as eluant) to afford 3,4-difluoro-2-[2-fluoro-4-(3-hydroxy-1-propynyl)anilino]-N-(2-hydroxyethoxy)benzamide as a cream solid (94 mg, 100%); m.p. (Et2O/hexane) 169-172° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.84 (br s, 1 H), 8.91 (br s, 1 H), 7.46-7.40 (m, 1 H), 7.29-7.19 (m, 2 H), 7.10 (dd, J=8.3, 1.6 Hz, 1 H), 6.78 (ddd, J=8.9, 8.9, 4.8 Hz, 1 H), 5.29 (t, J=5.9 Hz, 1 H), 4.76 (br s, 1 H), 4.27 (d, J=5.9 Hz, 2 H), 3.84 (t, J=4.8 Hz, 2 H), 3.56 (t, J=4.8 Hz, 2 H). Anal. calcd. for C18H15F3N2O4: C, 56.9; H, 4.0; N, 7.4. Found C, 56.8; H, 4.0; N, 7.4.