Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CN=C1.CN(C)C(Cl)=O.[CH3:12][N:13]([CH3:21])[C:14]([N:16]1[CH:20]=[CH:19][N:18]=[CH:17]1)=[O:15].[Br:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>CC(C)=O.C(N(CC)CC)C>[Br-:22].[CH2:23]([N+:18]1[CH:19]=[CH:20][N:16]([C:14](=[O:15])[N:13]([CH3:21])[CH3:12])[CH:17]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCCCBr
Reactant: CN(C)C(=O)n1ccnc1
Agent: CN(C)C(=O)Cl
Agent: c1c[nH]cn1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCCCCCCCCC[n+]1ccn(C(=O)N(C)C)c1
Product: [Br-]
Temperature: 25 °C

Procedure:
To 13.6 gm (0.2 mole) of imidazole (Aldrich Chemical Co., Milwaukee, Wis., 99%) and 20.2 gm of triethylamine (Aldrich, 99%) in 100 ml dry acetone (Fisher Scientific Co., Pittsburgh, Pa.) in a magnetically stirred 250 ml round bottom flask under dry nitrogen was added 21.5 gm (0.2 mole) dimethylcarbamyl chloride (Aldrich, 99%) dropwise over a 20 min. period from a side-arm pressure equalizing addition funnel. A white precipitate formed during the addition under conditions of mild exothermicity. The addition funnel was replaced with a reflux condenser and the reaction refluxed for a further one hour. After cooling to room temperature, the precipitate was isolated by Buchner filtration onto Wattman #1 paper, rinsed on the filter with acetone, and discarded. The combined filtrate and rinse acetone solution was divided into two equal parts, each containing 0.1 mole of 1-dimethylcarbamoylimidazole. To one of these parts was added 22.1 gm (0.1 mole) of 1-bromodecane (Aldrich 98%) and the solution refluxed for seven hours under dry nitrogen. The acetone was evaporated at water aspirator vacuum in a rotoevaporator to the point where two layers formed. The upper layer contained largely unreacted bromodecane and the lower yielded 12 gm (0.043 mole for a 21.4% theorical yield) of the imidazolium salt as a waxy solid upon cooling to 5° C. The purity and identity of this product was confirmed by proton and carbon NMR in deuterium oxide solution.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][C:19]2[C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[O:24][C:18]=2[CH2:17]1)#[N:2].[OH-].[Na+].C([O:33]CCOCCO)C>O>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][C:19]2[C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[O:24][C:18]=2[CH2:17]1)(=[O:33])[NH2:2]
Reactant: N#Cc1ccc2[nH]cc(CCCCN3CCc4c(oc5ccccc45)C3)c2c1
Reactant: CCOCCOCCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=O)c1ccc2[nH]cc(CCCCN3CCc4c(oc5ccccc45)C3)c2c1
Reaction time: 3 h

Procedure:
A mixture of 36.9 g of 2-[4-(5-cyano-3-indolyl)butyl]-1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridine (obtainable from the corresponding 5-formyl compound via the oxime), 27.1 g of NaOH, 520 ml of water and 420 ml of diethylene glycol monoethyl ether is stirred at a bath temperature of 140° for 3 hours. The mixture is cooled, the usual working up is carried out, and 2-[4-(5-carbamoyl-3-indolyl)butyl]-1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridine is obtained.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]([C:14]3[CH:19]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([O:27]C)[CH:21]=4)[CH2:18][C:17](=[O:29])[NH:16][C:15]=3[CH3:30])=[O:13])[CH:9]=2)[NH:4][N:3]=1.B(Cl)(Cl)Cl>C(Cl)Cl.CCOC(C)=O.O.[OH-].[Na+]>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]([C:14]3[CH:19]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([OH:27])[CH:21]=4)[CH2:18][C:17](=[O:29])[NH:16][C:15]=3[CH3:30])=[O:13])[CH:9]=2)[NH:4][N:3]=1
Reactant: COc1cc(C2CC(=O)NC(C)=C2C(=O)Nc2ccc3[nH]nc(Br)c3c2)ccc1Cl
Agent: ClB(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(Br)c3c2)C(c2ccc(Cl)c(O)c2)CC(=O)N1
Temperature: 35 °C
Reaction time: 90 h
Yield: 27.7 %

Procedure:
The product from Example 94 (95 mg, 0.19 mmol, 1.0 equiv) was cooled to −78° C. in 2.0 mL CH2Cl2 and BCl3 (1.0 M in CH2Cl2, 2.90 mL, 2.91 mmol, 15.0 equiv) was added dropwise. The reaction was warmed to 35° C. and stirred for 90 hours. An additional portion of BCl3 (2.90 mL, 2.91 mmol, 15.0 equiv) was added dropwise and the reaction was stirred for another 96 hours. The reaction mixture was diluted with EtOAc and water and basified to pH 14 with 6N NaOH. The phases were separated, and the aqueous phase was acidified to pH 4 with 6N HCl. The precipitate was filtered and washed with Et2O. The residue was purified by reverse-phase HPLC (10-95% CH3CN/H2O, 0.1% TFA over 18 minutes, retention time 10.63 min) to provide 25 mg (27%) of the title compound as a white solid. MS (ES+) m/e 476 [M+H]+
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([O:23]CC)=[O:22])=[CH:15]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[OH-].[Na+]>C(O)C.O1CCCC1>[CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([OH:23])=[O:22])=[CH:15]3)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)nc3)ccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(Oc2ccc3[nH]c(C(=O)O)cc3c2)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 100.7 %

Procedure:
To a solution of ethyl 5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylate (5.6 g) in ethanol (100 mL) and tetrahydrofuran (100 mL) was added 1N aqueous sodium hydroxide solution (31.1 mL), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated, 1N hydrochloric acid (32 mL) was added, and the precipitated crystals were filtered and concentrated under reduced pressure to give the title compound (5.2 g, yield 100%) as white crystals.
Reaction SMILES: C[Si](C)(C)[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12](I)=[CH:11][C:10]=2F)=[C:5](F)[C:4]=1F.C([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)CC.OCC(C)(CO)C.O>CC(O)C.CC([O-])=O.CC([O-])=O.[Pd+2].CC(C)=O>[C:6]1([C:9]2[C:10]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:7]=[CH:8][CH:3]=[CH:4][CH:5]=1
Reactant: CCCc1ccc(B(O)O)cc1
Reactant: C[Si](C)(C)c1ccc(-c2ccc(I)cc2F)c(F)c1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(CO)CO
Solvent: CC(C)=O
Solvent: CC(C)O
Solvent: O
Product: c1ccc(-c2ccccc2-c2ccccc2)cc1
Yield: 89 %

Procedure:
A solution of (2 mmol) of 8, (2.2 mmol) of 4-propylphenylboronic acid, 250 mg (2.40 mmol) of neopentyl glycol, 1.53 g (4.84 mmol) of Ba(OH)2. 8 H2O, 1.35 ml (0.103 mmol, 5 mol %) of a 76 mM acetone solution of Pd(OAc)2 in 20 ml of 95% i-PrOH is stirred at 80° C. for 12 hours. The solvent is subsequently removed under reduced pressure. 5 ml of 2 M HCl are added to the residue, and the mixture is extracted with dichloromethane (3×5 ml). The combined organic phases are dried over MgSO4 and filtered through SiO2. The solvent is removed under reduced pressure, and the residue is converted into 10 (yield: 89%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][OH:8].C1C(=O)N([Br:16])C(=O)C1>C1(C)C=CC=CC=1>[Br:16][C:5]1[S:1][C:2]([CH2:6][CH2:7][OH:8])=[CH:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCCc1cccs1
Solvent: Cc1ccccc1
Product: OCCc1ccc(Br)s1
Temperature: -20 °C
Reaction time: 8 h

Procedure:
2-(2-thienyl)ethanol (Aldrich, 5.0 g, 39 mmol) was diluted in toluene (50 mL) and cooled to −20° C. using an ice/NaCl bath. NBS (6.95 g, 39 mmol, 1 eq) was added portionwise over 15 minutes and the mixture was stirred at rt overnight. After quenching with 10% aq potassium hydroxide (20 mL), the layers were separated and the aqueous layer was extracted twice with dichloromethane (50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. Purification by Isco Combiflash, eluting with 0-80% ethyl acetate in hexanes (120 g column), afforded the desired as a slightly yellow oil (6.72 g, 83%).
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:9]=[N+:10]=[N-:11].[Na+].Cl.C(NCC)C>C1(C)C=CC=CC=1>[C:2]1([C:1]2[NH:11][N:10]=[N:9][N:8]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCNCC
Product: c1ccc(-c2nnn[nH]2)cc1
Yield: 96 %

Procedure:
Into the same device as used in Example 1 were placed 5.16 g (0.050 mole) of benzonitrile, 4.23 g (0.065 mole) of sodium azide, 7.13 g (0.065 mole) of diethylamine hydrochloride and 52 ml of toluene. The mixture was reacted for 8 hours in the same manner as in Example 1, giving 7.02 g (0.048 mole) of 5-phenyl-1H-tetrazole (yield 96.0% based on benzonitrile).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:16]([N:18]1[CH2:28][CH2:27][CH2:26][C@H:19]1[C:20]([NH:22][CH2:23][CH2:24][OH:25])=[O:21])=[O:17])[CH2:10][C:11]1[N:15]=[CH:14][NH:13][CH:12]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][C@H:9]([C:16]([N:18]1[CH2:28][CH2:27][CH2:26][C@H:19]1[C:20]([NH:22][CH2:23][CH2:24][OH:25])=[O:21])=[O:17])[CH2:10][C:11]1[N:15]=[CH:14][NH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(=O)NCCO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(=O)NCCO
Reaction time: 2.5 h

Procedure:
In 25 ml of methylene chloride was dissolved 790 mg of compound (51) and then 20 ml of trifluoroacetic acid was added dropwise to the solution at 0° C. to 5° C. After stirring the mixture for 2.5 hours in an icebath, the reaction mixture was concentrated to dryness under reduced pressure. Furthermore, the product was azeotropically dried several times using toluene and the residue was triturated with dry ether to provide powder of L-histidyl-N-(2-hydroxyethyl)-L-prolinamide.2-trifluoroacetate with a quantitative yield.
Reaction SMILES: C1(C#C)C=CC=CC=1.[C:9]1([CH2:15][CH2:16][C:17]#[CH:18])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[N:19]([C:22]1[S:23][C:24]([C:28]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])=[C:25]([CH3:27])[N:26]=1)=[N+:20]=[N-:21]>>[CH2:31]([NH:30][C:28]([C:24]1[S:23][C:22]([N:19]2[CH:18]=[C:17]([CH2:16][CH2:15][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:21]=[N:20]2)=[N:26][C:25]=1[CH3:27])=[O:29])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: C#CCCc1ccccc1
Reactant: Cc1nc(N=[N+]=[N-])sc1C(=O)NCc1ccccc1
Solvent: C#Cc1ccccc1
Product: Cc1nc(-n2cc(CCc3ccccc3)nn2)sc1C(=O)NCc1ccccc1
Yield: 20 %

Procedure:
Following the procedure as described in Example 10, making variations as necessary to replace phenylacetylene with 4-phenyl-1-butyne to react with 2-azido-N-benzyl-4-methylthiazole-5-carboxamide, the title compound was obtained as a white solid in 20% yield: mp 167-170° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.02 (s, 1H), 7.37-7.19 (m, 10H), 6.15 (t, J=6.0 Hz, 1H), 4.62 (d, J=6.0 Hz, 2H), 3.14-3.02 (m, 4H), 2.67 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 160.9, 155.6, 153.3, 148.5, 140.5, 137.5, 128.9, 128.5, 128.3, 127.8, 126.3, 124.0, 118.6, 44.3, 35.0, 27.2, 17.4; MS (ES+) m/z 404.3 (M+1).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O>>[Cl:11][C:9]1[N:10]=[C:3]2[CH:2]=[CH:7][CH:6]=[C:5]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][O:13][CH3:12])[N:4]2[N:8]=1
Reactant: COCc1ccccc1B(O)O
Reactant: Clc1nc2c(Br)cccn2n1
Product: COCc1ccccc1-c1cccc2nc(Cl)nn12

Procedure:
2-Chloro-5-(2-methoxymethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (546.0 mg, 2.35 mmol) and 2-(methoxymethyl)phenylboronic acid (545.0 mg, 3.29 mmol) in a manner analogous to Example 2c. Product was isolated as a white solid (0.384 g, 60%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.72-7.41 (m, 6H), 7.09-7.05 (m, 1H), 4.30 (br s, 2H), 3.16 (s, 3H). MS=274 (MH)+.
Reaction SMILES: [NH2:1][CH:2]1[C:24](=[O:25])[N:4]2[C:5]([C:21]([OH:23])=[O:22])=[C:6]([CH2:9][S:10][C:11]3[CH:12]=[C:13]([NH2:20])[C:14]4[N:15]([N:17]=[N:18][N:19]=4)[N:16]=3)[CH2:7][S:8][C@H:3]12.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.[Cl:38][CH2:39][C:40](=[O:45])[CH2:41][C:42](Cl)=[O:43].C(O)(C)C>CN(C)C=O.C(Cl)Cl>[NH2:20][C:13]1[C:14]2[N:15]([N:17]=[N:18][N:19]=2)[N:16]=[C:11]([S:10][CH2:9][C:6]2[CH2:7][S:8][C@@H:3]3[CH:2]([NH:1][C:42](=[O:43])[CH2:41][C:40](=[O:45])[CH2:39][Cl:38])[C:24](=[O:25])[N:4]3[C:5]=2[C:21]([OH:23])=[O:22])[CH:12]=1
Reactant: Nc1cc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)nn2nnnc12
Reactant: O=C(Cl)CC(=O)CCl
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Solvent: CC(C)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Nc1cc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)CC(=O)CCl)[C@H]3SC2)nn2nnnc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
7-Amino-3-[(8-amino-6-tetrazolo[1,5-b]pyridazinyl)thiomethyl]-3-cephem-4-carboxylic acid (3.8 g; 0.01 mole) was suspended in anhydrous N,N-dimethylformamide (50 ml) and N,O-bis(trimethylsilyl)acetamide (8.13 g; 0.04 mole) was added. After 2 hours of stirring at room temperature almost all the starting material was dissolved. A solution of 4-chloroacetoacetyl chloride (2.35 g; approximately 0.015 mole) in anhydrous methylene chloride (20 cc) was dropped into the cooled mixture (at -30° C.). The mixture was stirred at -30° C. for 2 hours and allowed to come to room temperature within an additional hour, after which time isopropanol (40 ml) was added, in order to decompose the silylated compounds. The solvents were evaporated under reduced pressure and the oily residue was partitioned between water and ethyl acetate. The organic layer was separated, washed with aqueous sodium chloride solution, concentrated to a small volume under reduced pressure, and diethyl ether was added to complete the precipitation. The solid was collected by filtration, washed with fresh ether and dried under vacuum, thus giving 4.6 g of the title compound, which was used in the following step without further purification.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)([OH:22])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:38][CH2:39][C:40](Cl)=[O:41]>C1COCC1.O>[CH2:1]([N:8]([CH2:9][CH2:10][C:11]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)([OH:22])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:40](=[O:41])[CH2:39][Cl:38])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(OCC(O)(CCNCc2ccccc2)c2ccc(Cl)c(Cl)c2)cc1
Reactant: O=C(Cl)CCl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(OCC(O)(CCN(Cc2ccccc2)C(=O)CCl)c2ccc(Cl)c(Cl)c2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of (2RS)-4-amino-2-(3,4-dichlorophenyl)-1-(4-methoxyphenoxy)butan-2-ol (6.7 g) in methanol (20 mL) were added magnesium sulfate (3.35 g), triethylamine (1.3 mL) and benzaldehyde (2.1 ml), and the mixture was stirred at room temperature for 1.5 hr. To the reaction mixture was added sodium borohydride (3.55 g), and the mixture was stirred at 0° C. for 10 min, and then stirred while warming to room temperature for 1.5 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated. The concentrated residue was diluted with water, and the mixture was extracted with ethyl acetate. The obtained extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 4-(benzylamino)-2-(3,4-dichlorophenyl)-1-(4-methoxyphenoxy)butan-2-ol (8.47 g). To a solution of 4-(benzylamino)-2-(3,4-dichlorophenyl)-1-(4-methoxyphenoxy)butan-2-ol (8.47 g) in THF (45 mL) were added triethylamine (2.85 mL) and chloroacetyl chloride (1.64 ml), and the mixture was stirred at 0° C. for 10 min, and then stirred while warming to room temperature for 2 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The obtained extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (7.41 g).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[N:32]=[C:33]=[O:34].CCOCC>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:33]([NH:32][C:26]1[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:25]=1[F:24])=[O:34]
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: O=C=Nc1ccc(F)cc1F
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(Cl)c3)c2cc1OC
Yield: 46 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (214 mg) was dissolved in chloroform (5 ml), and 2,4-difluorophenyl isocyanate (180 μl) was then added to the solution. The mixture was allowed to react at 70° C. for 4 hr, and a large amount of ether was added to the reaction solution. The resultant precipitate was collected by suction filtration to give 146 mg (yield 46%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[CH2:11][CH2:12][C:13]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:3]1=2.C(N(CC)CC)C.Cl[CH2:27][C:28]1[CH:29]=[C:30]([O:34][CH3:35])[CH:31]=[CH:32][CH:33]=1.[Cl-].[Na+]>ClCCl>[CH3:35][O:34][C:30]1[CH:29]=[C:28]([CH2:27][N:16]2[CH2:17][CH2:18][C:13]3([C:3]4[N:2]([CH3:1])[C:10]5[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=5[C:4]=4[CH2:11][CH2:12]3)[CH2:14][CH2:15]2)[CH:33]=[CH:32][CH:31]=1
Reactant: Cn1c2c(c3ccccc31)CCC21CCNCC1
Reactant: COc1cccc(CCl)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(CN2CCC3(CCc4c3n(C)c3ccccc43)CC2)c1
Yield: 34.7 %

Procedure:
A solution of 1,4-dihydro-4-methylspiro[cyclopent[b]indole-3(2H), 4'-piperidine] (2.5 g) and triethylamine (2.9 ml) in dichloromethane (100 ml) and 3-(chloromethyl)anisole (1.95 g) was stirred overnight at ambient temperature, under nitrogen. Saturated sodium chloride solution was added and the mixture was extracted with dichloromethane. The extracts were dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was flashed chromatographed (silica gel), eluting with 10% anhydrous acetone/dichloromethane. The appropriate fractions were collected and concentrated to give 1.3 g (35%) of product, mp 100-101° C.
Reaction SMILES: [CH:1]([N:4]([C:12]1[S:13][C:14]([C:17]2[CH:18]=[C:19]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:20]3[N:21]([CH:23]=[C:24]([C:26](=[O:29])[NH:27][CH3:28])[N:25]=3)[CH:22]=2)=[CH:15][N:16]=1)C(=O)OC(C)(C)C)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]([NH:4][C:12]1[S:13][C:14]([C:17]2[CH:18]=[C:19]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:20]3[N:21]([CH:23]=[C:24]([C:26]([NH:27][CH3:28])=[O:29])[N:25]=3)[CH:22]=2)=[CH:15][N:16]=1)([CH3:3])[CH3:2]
Reactant: CNC(=O)c1cn2cc(-c3cnc(N(C(=O)OC(C)(C)C)C(C)C)s3)cc(-c3ccccc3)c2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1cn2cc(-c3cnc(NC(C)C)s3)cc(-c3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.8 %

Procedure:
A solution of tert-butyl isopropyl(5-(2-(methylcarbamoyl)-8-phenylimidazo[1,2-a]pyridin-6-yl)thiazol-2-yl)carbamate (30 mg) in methylenechloride (2 ml) was treated with TFA (4 ml) and stirred at room temperature for 2 hours. The solvent was removed under vacuum and the residue chromatographed on silica gel using ethyl acetate as eluent to give 15 mg of 6-(2-(isopropylamino)thiazol-5-yl)-N-methyl-8-phenylimidazo[1,2-a]pyridine-2-carboxamide as a tan solid. LCMS (Conditions C): 2.62 min (RT); (M+H)+=392.14 (100%). 1H NMR, 500 MHz, CDCl3/CD3OD: δ 8.20 (s, 1 H), 8.19 (d, J=1.65 Hz, 1 H), 7.89 (d, J=1.37 Hz, 1 H), 7.88 (s, 1 H), 7.42-7.53 (m, 3 H), 7.36 (d, J=1.92 Hz, 1 H), 7.34 (s, 1 H), 3.55-3.64 (m, 1 H), 1.34 (d, J=6.32 Hz, 6 H).
Reaction SMILES: C(O)(=O)/C=C/C(O)=[O:5].[CH2:9]([NH:12][C:13]([C:15]1[CH:28]=[CH:27][C:26]2[S:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH:29]([CH3:36])[CH2:30][N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[C:17]=2[CH:16]=1)=S)[CH2:10][CH3:11]>C(O)C.O>[CH2:9]([NH:12][C:13]([C:15]1[CH:28]=[CH:27][C:26]2[S:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH:29]([CH3:36])[CH2:30][N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[C:17]=2[CH:16]=1)=[O:5])[CH2:10][CH3:11]
Reactant: CCCNC(=S)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Reactant: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: O
Product: CCCNC(=O)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Fumaric acid (2.7 g) is added to a solution of N-propyl-10-[1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide, L series (9.5 g) in ethanol (100 cc). The solution obtained is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The merigue-like yellow residue is taken up with acetic acid (200 cc). Mercuric acetate (7.3 g) is added to the solution obtained, and the mixture is stirred for 16 hours at a temperature in the region of 20° C. The black suspension obtained is diluted with distilled water (200 cc) and filtered. The yellow filtrate is concentrated under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is taken up with ethyl acetate (250 cc) and distilled water (50 cc) and then treated with sodium hydroxide (d 1.33) to pH 13. The aqueous phase is separated after settling has taken place and extracted with ethyl acetate (250 cc). The organic phases are combined, washed successively with distilled water (2×100 cc) and with saturated aqueous sodium chloride solution (100 cc) and dried over magnesium sulphate. After filtration, the yellow filtrate is concentrated under reduced pressure (30 mm Hg; 4 kPa) at 40° C. and a crude yellow oil (9.2 g) is thereby obtained. This residue is purified by chromatography on a column (height: 22 cm; diameter: 4 cm) of silica gel (0.2-0.063 mm), eluting with a mixture (95:5 by volume) of methylene chloride and methanol. The first 1,500 cc are discarded and the next 1,500 cc are concentrated under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give N-propyl-10-[1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxamide, L series (7.3 g) in the form of a yellow gum.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5]O.[Cl:7][C:8]1[CH:16]=[C:12]([C:13]([OH:15])=[O:14])[C:11]([OH:17])=[CH:10][CH:9]=1>>[Cl:7][C:8]1[CH:16]=[C:12]([C:13]([O:15][CH3:5])=[O:14])[C:11]([OH:17])=[CH:10][CH:9]=1
Reactant: CO
Reactant: O=C(O)c1cc(Cl)ccc1O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Cl)ccc1O
Temperature: -5 °C

Procedure:
Thionyl chloride (900 g, 7.56 mol) is added dropwise to methanol (1977 g, 61.72 mol) at 20° C. over a period of 1.5 hours, maintaining the temperature between 15°-25° C. with an ice bath. The cooling bath is removed and 5-chlorosalicylic acid (1000 g, 5.8 mol) added in one portion, then slowly heated to reflux. On completion of the reaction the solution is cooled to -5° C. for 1 hour. The methyl 5-chlorosalicylate is filtered, washed with cold methanol (150 ml) and dionized water (2×1 L). The solid is dried under house vacuum at 30° C. for 24 hours to give methyl 5-chlorosalicylate; m.p. 44°-46° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][C:7]=2[F:15])[CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:19])=O>C1COCC1.CN(C=O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]([C:10]([Cl:19])=[O:11])=[CH:8][C:7]=2[F:15])[CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(OCC2CC2)c(F)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Cl)c1ccc(OCC2CC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(cyclopropylmethoxy)-3-fluorobenzoic acid (1.57 g) in THF (50 mL) were added oxalyl dichloride (0.982 mL) and DMF (2 drops), and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure to give 4-(cyclopropylmethoxy)-3-fluorobenzoyl chloride. This compound was used for the next reaction without further purification.