Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:23]=[N:24][CH:25]=[C:26]([CH:31]=4)[C:27]([O:29]C)=O)=[N:14][CH:13]=[N:12][C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1.[NH3:32]>C(O)CCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:23]=[N:24][CH:25]=[C:26]([CH:31]=4)[C:27]([NH2:32])=[O:29])=[N:14][CH:13]=[N:12][C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cncc(OCCCCc2ncnc3scc(-c4ccc(F)cc4)c23)c1
Reactant: N
Solvent: CCCCO
Product: NC(=O)c1cncc(OCCCCc2ncnc3scc(-c4ccc(F)cc4)c23)c1
Temperature: 180 °C
Yield: 34.8 %

Procedure:
Methyl 5-{4-[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]butoxy}nicotinate (0.015 g, 0.034 mmol) and ammonia (3.00 mL, 20%, 0.02 mol) were mixed in 1-butanol (1.00 mL) and the resulting mixture was heated at 180° C. for 20 h. The solvent was removed by evaporation, and the product was purified by preparative HPLC to give 5 mg (36%) 5-{4-[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]butoxy}nicotinamide hydroformate as a white solid. MS [M+H]=423.1, LC/MS (EI) tR 3.45 min (Method D), 1H NMR (7% MeOD/CDCl3) δ (ppm) 8.92 (s, 1H), 8.50 (s, 1H), 8.25 (s, 1H), 7.62 (s, 1H), 7.40-7.30 (m, 3H), 7.10 (t, J=8.4 Hz, 2H), 3.84 (t, J=6.0 Hz, 2H), 2.66 (t, J=7.5 Hz, 2H), 1.75-1.58 (m, 2H), 1.59-1.45 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[NH:15][CH:14]=[C:13]([N+:21]([O-:23])=[O:22])[C:12]2=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:27])=O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][C:13]([N+:21]([O-:23])=[O:22])=[C:12]2[Cl:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2[nH]cc([N+](=O)[O-])c(=O)c2cc1OCc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc2ncc([N+](=O)[O-])c(Cl)c2cc1OCc1ccccc1
Temperature: 100 °C
Yield: 99.5 %

Procedure:
6-Benzyloxy-7-methoxy-3-nitro-1H-quinolin-4-one (9.10 g, 27.89 mmol, see Acta Pharmacologica Sinica 2008, 29(12), 1529-1538) was suspended in dry N,N-dimethylformamide (70 ml). Phosphoryl chloride (2.82 ml, 30.68 mmol) was subsequently added, and the mixture was heated at 100° C. for 30 min. After cooling, the reaction mixture was added to ice-water (500 ml) with stirring and stirred for a further 30 min. The precipitate formed was filtered off with suction, washed with water and dried in vacuo, giving 6-benzyloxy-4-chloro-7-methoxy-3-nitroquinoline (9.57 g, 27.76 mmol) as solid. MS: 345.1 (M+H+), TLC (HPTLC): Rf=0.44 (cyclohexane/ethyl acetate 2:1, parts by volume).
Reaction SMILES: CS([O:5][CH:6]1[CH:11]([CH3:12])[CH2:10][C:9]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])=[CH:8][CH:7]1[NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(=O)=O.C(N(CC)CC)C.C[C:38]([O:41]C(OC(OC(C)(C)C)=O)=O)(C)C>N1C=CC=CC=1>[CH3:12][CH:11]1[CH:6]2[CH:7]([N:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:38](=[O:41])[O:5]2)[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[CH2:10]1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CC1CC(c2ccncc2[N+](=O)[O-])=CC(NC(=O)OC(C)(C)C)C1OS(C)(=O)=O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC1CC(c2ccncc2[N+](=O)[O-])=CC2C1OC(=O)N2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 66 %

Procedure:
A solution of (+/−)-2-(tert-butoxycarbonylamino)-6-methyl-4-(3-nitropyridin-4-yl)cyclohex-3-enyl methanesulfonate (1.0 equiv.) in pyridine (0.2 M) in a microwave vessel was heated to 110° C. for 10 min. The orange solution was then concentrated to dryness and worked up by partitioning between ethyl acetate and water. The organic phase was dried with sodium sulfate, filtered and concentrated. The crude material was dissolved in DCM (0.2 M) and triethyl amine (1.8 equiv.) was added to the reaction, followed by Boc2O (1.2 eqiv.). After stirring at room temperature for 40 min, the reaction was concentrated in vacuo and purified via silica gel column chromatography eluting with ethyl acetate and hexanes (1:1) to give (+/−)-tert-butyl 7-methyl-5-(3-nitropyridin-4-yl)-2-oxo-3a,6,7,7a-tetrahydrobenzo[d]oxazole-3(2H)-carboxylate as a white foam in 66% yield. LC/MS=376.0 (M+H), Rt=0.87 min.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH:13]([C:14]([O:16][CH3:17])=[O:15])[CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].[Cl:18][C:19]1[CH:20]=[C:21]([S:25](Cl)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1.C(N(CC)CC)C.O>CN(C=O)C>[CH3:17][O:16][C:14]([CH:13]1[CH2:12][N:11]([S:25]([C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([Cl:18])[CH:20]=2)(=[O:27])=[O:26])[CH2:10][CH2:9][N:8]1[C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])=[O:15]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: COC(=O)C1CNCCN1C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)C1CN(S(=O)(=O)c2cccc(Cl)c2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-1-Boc-2-piperazinecarboxylic acid methyl ester (CAS Reg. No: [129799-15-1]) (1 g) in DMF (5 mL) was added 3-chlorobenzenesulfonyl chloride (0.95 g) and triethylamine (1.71 mL). The reaction mixture was stirred at RT overnight. Water was added and the mixture was extracted with ethyl acetate (×2). The combined organic layers were washed with water (×2) and brine, were dried (Na2SO4), filtered and evaporated. Purification by chromatography (SiO2, n-heptane/ethyl acetate 3:1) yielded 4-(3-chloro-benzenesulfonyl)-piperazine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester as white foam (1.66 g), MS: 436.3 ([M+NH4, 1Cl]+).
Reaction SMILES: [Cl:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[NH:5][CH2:4]1.Br[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>O1CCOCC1>[Cl:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[N:5]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=2)[CH2:4]1
Reactant: O=C1NC[C@@H](CCl)O1
Reactant: Clc1ccc(Br)nc1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: O=C1O[C@H](CCl)CN1c1ccc(Cl)cn1
Temperature: 85 °C
Reaction time: 12 h
Yield: 62.3 %

Procedure:
A mixture of (5S)-5-(chloromethyl)-1,3-oxazolidin-2-one (2.15 g, INTERMEDIATE 4), 2-bromo-5-chloropyridine (3.05 g), cesium carbonate (20.67 g), bispalladium tribenzylideneacetone (2.18 g) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (2.07 g) in 16 ml of dioxane was stirred at 85° C. for 12 h. The sample was then cooled to room temperature, and purified was purified via column chromatography (2×) on a Biotage Horizon 65i column eluting with 0% ethyl acetate in hexanes (1 column volumes), followed by a gradient to 60% ethyl acetate in hexanes (over 10 column volumes), and held at 60% ethyl acetate for 4 column volumes to provide the title compound (2.44 g, 61%). Mass spectrum (ESI) 249.0 (M+2).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:31])=[C:9]([CH2:11][O:12][C:13]2[CH:28]=[CH:27][C:16]([CH2:17][O:18][C:19]3[N:26]=[CH:25][CH:24]=[CH:23][C:20]=3[CH:21]=O)=[CH:15][C:14]=2[O:29][CH3:30])[N:10]=1.[CH2:32](P(=O)(OCC)OCC)[P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36].CN(C)C=O.[H-].[Na+]>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:31])=[C:9]([CH2:11][O:12][C:13]2[CH:28]=[CH:27][C:16]([CH2:17][O:18][C:19]3[C:20](/[CH:21]=[CH:32]/[P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])=[CH:23][CH:24]=[CH:25][N:26]=3)=[CH:15][C:14]=2[O:29][CH3:30])[N:10]=1
Reactant: COc1cc(COc2ncccc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(/C=C/c1cccnc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1)OCC
Reaction time: 15 h
Yield: 63.2 %

Procedure:
To a mixture of 2-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]nicotinaldehyde (0.30 g), tetraethyl methylenediphosphonate (0.21 g) and N,N-dimethylformamide (15 mL) was added sodium hydride (60% in oil, 0.040 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (3:1, v/v) to give diethyl (E)-2-{2-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]pyridin-3-yl}ethenylphosphonate as a colorless oil (0.25 g, yield 64%).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([CH2:10][C:11]([OH:13])=O)=[CH:8][CH:7]=[CH:6][C:5]=12.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C.Cl.[O:43]=[S:44]1(=[O:66])[CH2:49][CH2:48][CH2:47][N:46]2[C:50](=[O:65])[N:51]([CH2:61][CH2:62][CH2:63][NH2:64])[C:52](=[O:60])[C:53]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[C:45]12>O.ClCCl>[O:66]=[S:44]1(=[O:43])[CH2:49][CH2:48][CH2:47][N:46]2[C:50](=[O:65])[N:51]([CH2:61][CH2:62][CH2:63][NH:64][C:11](=[O:13])[CH2:10][C:9]3[N:4]4[CH:3]=[CH:2][N:1]=[C:5]4[CH:6]=[CH:7][CH:8]=3)[C:52](=[O:60])[C:53]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[C:45]12
Reactant: NCCCn1c(=O)c(-c2ccccc2)c2n(c1=O)CCCS2(=O)=O
Reactant: O=C(O)Cc1cccc2nccn12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1cccc2nccn12)NCCCn1c(=O)c(-c2ccccc2)c2n(c1=O)CCCS2(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a dichloromethane solution of 601 mg (2.5 mmol) of imidazo[1,2-a]pyridin-5-acetic acid and 383 mg (2.5 mmol) of HOBt, 479 mg (2.5 mmol) of WSC and 0.5 ml (3.6 mmol) of triethylamine were added. After the reaction mixture was stirred at 0° C. for 30 minutes, 1.158 g (3 mmol) of 3-(1,1,6,8-tetraoxo-9-phenyl-2,3,4,8-tetrahydropyrimido[6,1-b][1,3]thiazin-7-yl)propylamine hydrochloride and 0.84 ml (6 mmol) of triethylamine were added, followed by stirring at room temperature for 3 hours and then at 40° C. for 14 hours. After water was added, the mixture was extracted with dichloromethane and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, chloroform→chloroform/methanol=25/1) to yield 74.7 mg (5.9%, yellow oily substance) of the desired product.
Reaction SMILES: C([O:3][C:4](=[O:21])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:7][C:6]=1[NH:17][CH:18]1[CH2:20][CH2:19]1)C.[OH-].[Na+]>CO.O1CCCC1.C(OCC)(=O)C>[CH:18]1([NH:17][C:6]2[CH:7]=[C:8]([N:12]3[CH2:13][CH2:14][CH2:15][CH2:16]3)[C:9]([F:11])=[CH:10][C:5]=2[C:4]([OH:21])=[O:3])[CH2:19][CH2:20]1
Reactant: CCOC(=O)c1cc(F)c(N2CCCC2)cc1NC1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc(F)c(N2CCCC2)cc1NC1CC1
Temperature: 80 °C
Reaction time: 20 h
Yield: 89.9 %

Procedure:
To a solution of 4-(pyrrolidin-1-yl)-2-cyclopropylamino-5-fluorobenzoic acid ethyl ester (Example 3e, 3.10 g, 10.4 mmol) in methanol (50 mL) and tetrahydrofuran (20 mL) is added 1N solution of sodium hydroxide (35 mL). The reaction mixture is stirred at 80° C. for 20 hours, cooled to room temperature, and diluted with ethyl acetate. The organic layer is washed with 1N hydrochloric acid, water, and brine. The organic layer is dried over MgSO4, filtered, and the filtrate concentrated to afford the title compound as a solid (2.47 g). MS CI: m/z 263 (M+).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][CH:10]=1)[C:4]([O:6][CH3:7])=[O:5].[C:16]([O-])(=[O:18])[CH3:17].[Na+].C(OC(=O)C)(=O)C>Cl>[C:16]([NH:2][C@@H:3]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([I:15])=[CH:13][CH:14]=1)[C:4]([O:6][CH3:7])=[O:5])(=[O:18])[CH3:17]
Reactant: COC(=O)[C@@H](N)Cc1ccc(I)cc1
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: COC(=O)[C@H](Cc1ccc(I)cc1)NC(C)=O
Temperature: 0 °C
Yield: 56 %

Procedure:
To a solution of 93 (2.25 g, 6.80 mmol) in 10% HCl (10 mL) at 0° C. was added 4M sodium acetate (115 mL) and the resulting reaction was allowed to stir whilst equilibrating to 0° C. Acetic anhydride (50 mL) was added and the reaction allowed to proceed with vigorous stirring. After 1 h the product was collected by vacuum filtration, dissolved in ethyl acetate (30 mL) and washed with 2M sodium bicarbonate (2×30 mL). The organic layer was dried and evaporated to yield the title compound (1.31 g, 3.79 mmol, 56%) as a white solid. Mp 118-120° C. [α]D)27+93.8 (c. 0.1, CHCl3). 1H NMR (CDCl3, 300 MHz): δ 7.61 (d, J=8.4 Hz, 2H, ArH2′ and ArH6′); 6.84 (d, J=8.1 Hz, 2H, ArH3′ and ArH5′); 5.92 (d, J=7.2 Hz, 1H, NH); 4.87 (m, 1H, H2); 3.73 (s, 3H, OCH3); 3.11 (dd, J=6.0, 13.8, Hz, 1H, H3a); 3.03 (dd, J=5.4, 13.8 Hz, 1H, H3b); 1.99 (s, 3H, NCOCH3). Mass Spectrum (CI, +ve) m/z 348 (100%) [MH+]. HRMS calcd for C12H15NO3I 348.0097, found 348.0104.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH:10]([F:12])[F:11])[NH2:5].C(N(CC)CC)C.[CH3:20][C:21]1([C:24](Cl)=[O:25])[CH2:23][CH2:22]1.O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:24]([C:21]2([CH3:20])[CH2:23][CH2:22]2)=[O:25])[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([F:11])[F:12]
Reactant: CC1(C(=O)Cl)CC1
Reactant: Nc1ccc(OC(F)F)c(Cl)c1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(C(=O)Nc2ccc(OC(F)F)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
To a solution of 3-chloro-4-difluoromethoxyaniline (1.95 g) in methylene chloride (50 ml), triethylamine (1.1 g) was added, and a solution of 1-methylcyclopropanecarbonyl chloride (1.2 g) in methylene chloride was dropwise added while cooling with ice-water. The reaction mixture was stirred at room temperature for 1 hour, admixed with water and extracted with ether. The extract was washed with 1 N hydrochloric acid, sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated to give crude crystals (2.6 g). Recrystallization from ethanol gave N-(3-chloro-4-difluoromethoxyphenyl)-1-methylcyclopropanecarboxamide (2.2 g). M.P., 59°-60° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[Cl:11].C(O)(=O)C.C(N)=N.[H][H]>[Ni].CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[Cl:11]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Agent: [Ni]
Agent: N=CN
Solvent: CC(=O)O
Solvent: CO
Product: Nc1ccc(Cl)c(Cl)c1
Reaction time: 1 h

Procedure:
48.0 g of 1,2-dichloro-4-nitrobenzene, 2 g of Raney nickel (60%, aqueous), 1.5 g of formamidine acetate and 120 ml of methanol are introduced in an autoclave equipped with gas introduction stirrer. The air in the autoclave is then displaced by nitrogen and then by hydrogen. The hydrogenation is carried out at a pressure of 12 bar and a temperature of 80° C. The hydrogenation time is 1 hour. 1,2-Dichloro-4-aminobenzene, 99.7% pure (analysed by gas chromatography), is obtained in quantitative yield.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].CCN(CC)CC.[C:13]([O:17][C:18](=[O:24])[NH:19][CH2:20][CH2:21][CH2:22][OH:23])([CH3:16])([CH3:15])[CH3:14]>C(Cl)Cl>[C:13]([O:17][C:18]([NH:19][CH2:20][CH2:21][CH2:22][O:23][S:2]([CH3:1])(=[O:4])=[O:3])=[O:24])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
MsCl (6.5 mL, 84 mmol) was added slowly to a solution of Et3N (16.0 mL, 114 mmol) and (3-hydroxy-propyl)-carbamic acid tert-butyl ester (13.4 g, 76.5 mmol) in CH2Cl2 (200 mL) at 0° C. (bath temp). The reaction mixture was stirred at rt for 2 h and then quenched with H2O (100 mL). The aqueous layer was extracted with CH2Cl2 and the organic fractions were then dried (MgSO4) and concentrated in vacuo. The title compound was isolated as a colorless oil: yield 18.9 g (98%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([NH2:7])=[O:6].[NH:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[N:13]1.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24](S(O)(=O)=O)=[CH:23][CH:22]=1>>[N:12]1([CH:3]([NH:7][C:5](=[O:6])[C:4]2[CH:3]=[C:2]([Cl:1])[CH:10]=[C:9]([Cl:11])[CH:8]=2)[C:4]([CH3:8])([CH3:5])[CH2:31][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[N:13]1
Reactant: NC(=O)c1cc(Cl)cc(Cl)c1
Reactant: c1ccc2[nH]nnc2c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)(Cc1ccccc1)C(NC(=O)c1cc(Cl)cc(Cl)c1)n1nnc2ccccc21

Procedure:
3,5-Dichlorobenzamide, the product from Example 18A, benzotriazole, and p-toluenesulfonic acid were processed as described in Example 18B to provide the title compound.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10](Cl)=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[CH2:13]([OH:16])[C:14]#[CH:15].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:7]([O:6][P:4]([CH2:9][C:10]([O:16][CH2:13][C:14]#[CH:15])=[O:11])([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: C#CCO
Reactant: CCOP(=O)(CC(=O)Cl)OCC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C#CCOC(=O)CP(=O)(OCC)OCC
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 93 %

Procedure:
The above 2-(diethoxyphosphoryl)acetic acid chloride and 31.4 g (0.56 mol) of propargyl alcohol were dissolved in 100 mL of toluene and cooled to 5° C. 67.1 g (0.66 mol) of triethylamine was dropwise added to the solution at 15° C. or lower, then stirred at room temperature for 90 minutes, and disappearance of the starting materials was confirmed through gas chromatography. The formed salt was filtered and washed with 30 ml of a saturated saline solution. The organic layer was concentrated under reduced pressure, and the resulting residue was purified through silica gel column chromatography (ethyl acetate/hexane=1/1 for elution) to give 111.9 g (yield 93%) of the intended 2-propynyl 2-(diethoxyphosphoryl)acetate. The obtained 2-propynyl 2-(diethoxyphosphoryl)acetate was analyzed through 1H-NMR to confirm the structure thereof. The results are shown below.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][C:3]#[CH:4].C([Li])CCC.Cl[Si:12]([CH3:15])([CH3:14])[CH3:13]>O1CCCC1>[CH3:13][Si:12]([CH3:15])([CH3:14])[O:5][CH2:1][CH2:2][C:3]#[C:4][Si:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: C#CCCO
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#CCCO[Si](C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 16.4 %

Procedure:
Into a 1-L three neck round-bottom flask, was placed a solution of but-3-yn-1-ol (20.0 g, 285 mmol, 1.00 equiv) in tetrahydrofuran (300 mL) and the mixture was purged with nitrogen. The mixture was cooled to −78° C., then n-butyllithium (2.5 M in THF) (270 mL, 2.40 equiv) was added drop-wise followed by the addition of chlorotrimethylsilane (67.9 g, 625 mmol, 2.20 equiv). The resulting mixture was then stirred for 1 h at 25° C., then carefully quenched with aqueous sodium bicarbonate (250 mL). The aqueous was extracted with ether (3×100 mL) and the combined organics was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography with ether/petroleum ether (1:10-1:1) as the eluent to obtain the title compound as a colorless oil (10.0 g, 16%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH2:25][CH2:24][N:23](C(OCC4C=CC=CC=4)=O)[CH2:22][CH:21]=3)=[CH:16][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]>[Pd].C(O)(C)C.CO.C(Cl)Cl>[NH3:4].[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[CH:18][CH:19]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(CCCOc2ccc(C3=CCN(C(=O)OCc4ccccc4)CC3)cc2)CC1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Solvent: CC(C)O
Product: CC(=O)N1CCN(CCCOc2ccc(C3CCNCC3)cc2)CC1
Product: N
Yield: 152.9 %
Yield: 10 %

Procedure:
Benzyl 4-[4-[3-(4-acetylpiperazin-1-yl)propoxy]phenyl]-5,6-dihydropyridine-1(2H)-carboxylate (17 g, 35.59 mmol) and 5% palladium on carbon (3.37 g, 31.68 mmol) in iso-propanol (170 mL) were stirred under an atmosphere of hydrogen at 5 bar and 40° C. for 2 hours. The reaction mixture was filtered through diatomaceous earth, washing through with iso-propanol. The combined organics were evaporated to dryness to give crude product, which was purified by silica gel chromatography eluting with 0-10% MeOH in DCM, then 10% 7M ammonia in methanol in DCM, to give 4-[4-[3-(4-acetylpiperazin-1-yl)propoxy]phenyl]piperidine (9.4 g, 27.2 mmol, 76%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)=[CH:20][C:19]=3[O:31][CH3:32])[N:12]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2].[H-].[Na+].[CH3:35]I>O1CCCC1.CS(C)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)=[CH:20][C:19]=3[O:31][CH3:32])[N:12]=2)[N:8]([CH3:35])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)c1c[nH]c(-c2ccnc(Nc3ccc(N4CCN(C)CC4)cc3OC)n2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCOC(=O)c1cc(-c2ccnc(Nc3ccc(N4CCN(C)CC4)cc3OC)n2)n(C)c1
Reaction time: 12 h
Yield: 74.4 %

Procedure:
To a solution of 5-{2-[2-Methoxy-4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1H-pyrrole-3-carboxylic acid ethyl ester (0.5 g, 1.14 mmol) in tetrahydrofuran (25 mL) and dimethylsulfoxide (5 mL) cooled in a ice-water bath, NaH (50 mg, 1.26 mmol) and methyl iodide (0.08 mL, 1.26 mmol) were added. The reaction was continued at room temperature for 12 h, tetrahydrofuran was removed under vacuo, then dichloromethane (25 mL) was added and the organic phase washed with water (25 mL). The aqueous fraction was extracted with dichloromethane (2×20 mL). The organic fractions were combined, dried over sodium sulfate, filtered, and concentered in vacuo. Purification by flash chromatography on silica gel (eluant: dichloromethane/methanol 95/5) provided 382 mg (74%) of the title compound as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20]Br)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[OH:22][CH2:23][CH2:24][NH2:25]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][NH:25][CH2:24][CH2:23][OH:22])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: BrCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Reactant: NCCO
Product: OCCNCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
In analogy to example 3.1, 3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole and Hydroxyethylamine were converted to yield 2-{3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propylamino}-ethanol as white semisolid, MS: 407 (MH+, 1Br).
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]([C:25]2[S:26][CH:27]=[CH:28][N:29]=2)=[CH:4][CH2:3]1.O[Li].O>C1COCC1.O>[CH3:1][C:2]1([CH3:30])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]([C:25]2[S:26][CH:27]=[CH:28][N:29]=2)=[CH:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2nccs2)=CCC3(C)C)cc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CC=C(c2nccs2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21

Procedure:
A solution of 33.9 mg (0.08 mmol) of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(2-thiazolyl) naphth-3-yl)ethynyl]benzoate (Compound 67) and 8.5 mg (0.20 mmol) of LiOH-H2O in 3 ml of THF/water (3:1, v/v), was stirred overnight at room temperature. The reaction was quenched by the addition of sat. aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated in vacuo to give the title compound as a colorless solid.