Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][Cl:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[K+].[CH:13]([NH2:16])([CH3:15])[CH3:14]>>[ClH:10].[C:1]1([S:7][CH2:8][CH2:9][NH:16][CH:13]([CH3:15])[CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCSc1ccccc1
Reactant: CC(C)N
Agent: [I-]
Agent: [K+]
Product: CC(C)NCCSc1ccccc1
Product: Cl
Yield: 76.9 %

Procedure:
A solution of 25 g (0.145 mole) of 2-chloroethyl phenyl sulfide and 1 g (0.006 mole) of potassium iodide in 500 ml of isopropylamine was heated in a bomb at 120° C. for 24 hr. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was extracted with dilute sulfuric acid. The acidic extract was made basic with 50% sodium hydroxide, and the basic solution was extracted with methylene chloride. The methylene chloride solution was dried over magnesium sulfate and the solvent was removed in vacuo to given an oil. This was converted to the hydrochloride salt, and the salt was recrystallized from methanol-ether to give 25.77 g (76.9%) of white crystalline solid, m.p. 124.5°-125.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=O)[C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[S:8](=[O:19])(=[O:18])[C:7]=2[CH:20]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[S:22])[C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[S:8](=[O:19])(=[O:18])[C:7]=2[CH:20]=1
Reactant: COc1ccc2c(c1)S(=O)(=O)c1ccccc1C(=O)N2
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: COc1ccc2c(c1)S(=O)(=O)c1ccccc1C(=S)N2

Procedure:
To 7-Methoxy-10,11-dihydrodibenzo[b,f][1,4]thiazepin-11-one-5,5-dioxide (0.6 g, 2.07 mmol) in pyridine (5 ml) was added phosphorus pentasulphide (0.62 g, 0.675 equivalents) and the mixture was heated under reflux for 6 hours. On cooling, the pyridine was removed under reduced pressure, the residue obtained was washed with water, 3% HCl-brine and recrystallised from methanol to give the title compound (0.5 g, m.p. 250°-252°, Rf 0.5 [silica, cyclohexane/ethyl acetate (1:1, v/v)].
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[C:15]1[CH:20]=[CH:19][N:18]=[C:17]2[CH:21]=[CH:22][S:23][C:16]=12>O1CCOCC1.[Cu]Br>[CH2:12]([O:11][C:3](=[O:10])[CH:4]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]2[CH:21]=[CH:22][S:23][C:16]=12)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:13]
Reactant: Brc1ccnc2ccsc12
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Cu]Br
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)C(C(=O)OCC)c1ccnc2ccsc12
Temperature: 0 °C
Yield: 57 %

Procedure:
Charge a flask containing sodium hydride (17.45 g, 0.44 moles) with anhydrous dioxane (500 ml) while cooling at 0° C. Add diethyl malonate (69.88 g, 0.44 moles) dropwise over one hour. Upon reaching ambient temperature, add copper (I) bromide (62.59 g, 0.44 moles). Add 7-bromothieno[3,2-b]pyridine (18.68 g, 87.26 mmol) as a solution in dioxane (50 mL). Heat the reaction to reflux for 18 hours. Concentrate the reaction solution to ˜175 mL. Pour the concentrate into concentrated ammonium hydroxide (2.5 L). Extract the aqueous phase with ethyl acetate (6×300 mL). Wash the organic layers exhaustively with 2 N sodium hydroxide until the blue color dissipates. Treat the organic layers with magnesium sulfate, filter and concentrate. Purification on silica utilizing a solution of 1:1:3 of ether, ethyl acetate and hexane as eluent yields the desired compound (14.6 gm, 57%).
Reaction SMILES: [Cl-].[F:2][C:3]([F:31])([F:30])[C:4]1[CH:29]=[CH:28][CH:27]=[CH:26][C:5]=1[CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:32]=O.[OH-].[Na+]>O>[F:31][C:3]([F:2])([F:30])[C:4]1[CH:29]=[CH:28][CH:27]=[CH:26][C:5]=1[CH:6]=[CH2:32]
Reactant: C=O
Reactant: FC(F)(F)c1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=Cc1ccccc1C(F)(F)F

Procedure:
457 g (1 mol) of o-trifluoromethylbenzyltriphenyl-phosphonium chloride and 150 g (5 mols) of paraformaldehyde are initially introduced into 1,200 ml of water. 150 ml of 50% strength by weight sodium hydroxide solution are added at about 20° C. The mixture is allowed to after-react at 40° to 50° C. for 1 hour and the o-trifluoromethylstyrene formed is then distilled out of the reaction mixture with steam. The organic phase of the distillate contains 170 g (about 98% of the theoretical yield) of o-trifluoromethylstyrene with a purity, according to analysis by gas chromatography, of 99%. nD20 :1.4663. Boiling point: 61° C. under 53 mbars.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][C:12]1[N:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:15]=[CH:14][C:13]=1[CH2:23][OH:24].C(N(CC)CC)C>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH3:11][C:12]1[N:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:15]=[CH:14][C:13]=1[CH:23]=[O:24]
Reactant: Cc1c(CO)cnn1-c1ccccn1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(C=O)cnn1-c1ccccn1
Temperature: -78 °C

Procedure:
Dissolve dimethyl sulfoxide (0.751 mL, 10.6 mmol) in DCM (20 mL) and cool to −78° C. Add oxalyl chloride (0.577 mL, 6.62 mmol) dropwise in DCM (8 mL) and stir for 15 min. Add (5-methyl-1-pyridin-2-yl-1H-pyrazol-4-yl)-methanol (0.501 g, 2.65 mmol) in DCM (20 mL) dropwise and stir for one hr. at −78° C. Add triethylamine (1.85 mL, 13.2 mmol) and warm the mixture to room temperature for one hr. Dilute the mixture with saturated sodium bicarbonate and extract 3 times with DCM. Dry (sodium sulfate) the solution, filter and concentrate to give the title preparation as a white solid (0.496 g, 100%). MS (ES): m/z=188 [M+H]+.
Reaction SMILES: [CH:1](P(=O)(O)O)=[CH2:2].P(Cl)(Cl)[Cl:8].C1OC1.[P:14]([O:23][CH2:24][CH2:25][Cl:26])([O:19][CH2:20][CH2:21][Cl:22])[O:15]CCCl>>[Cl:8][CH2:1][CH2:2][P:14](=[O:15])([O:19][CH2:20][CH2:21][Cl:22])[O:23][CH2:24][CH2:25][Cl:26]
Reactant: ClCCOP(OCCCl)OCCCl
Reactant: C=CP(=O)(O)O
Reactant: ClP(Cl)Cl
Solvent: C1CO1
Product: O=P(CCCl)(OCCCl)OCCCl

Procedure:
Vinylphosphonic acid, CH2 =CH--PO(OH)2, can be prepared in a known manner by the following method: Phosphorus trichloride is reacted with ethylene oxide, the resulting tris(2-chloroethyl) phosphite is rearranged to give bis(2-chloroethyl) 2-chloroethylphosphonate, followed by reaction of the bis(2-chloroethyl) 2-chloroethylphosphonate with phosgene in the presence of suitable catalysts to give 2-chloroethylphosphonic dichloride (German Patent No. 2,132,962). The 2-chloroethylphosphonic dichloride can then be converted into vinylphosphonic acid by eliminating HCl in the presence of suitable catalysts (BaCl2) and subsequent hydrolysis of the vinylphosphonic dichloride formed (Chem. Abstr. 54, page 265 (1960)).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([Cl:17])=[CH:10][C:11]([C:15]#[N:16])=[N:12]2)=[CH:7][CH:6]=1)=[N+:2]=[N-:3].[N+:18]([C:21]1[CH:38]=[CH:37][C:24]([C:25]([O:27][C:28]([CH2:35][CH3:36])([C:31]([F:34])([F:33])[F:32])[C:29]#[CH:30])=[O:26])=[CH:23][CH:22]=1)([O-:20])=[O:19].C(N(C(C)C)CC)(C)C>C1COCC1.C(OCC)(=O)C.[Cu](I)I>[N+:18]([C:21]1[CH:22]=[CH:23][C:24]([C:25]([O:27][C@@:28]([C:29]2[N:3]=[N:2][N:1]([CH2:4][C:5]3[CH:14]=[C:13]4[C:8]([C:9]([Cl:17])=[CH:10][C:11]([C:15]#[N:16])=[N:12]4)=[CH:7][CH:6]=3)[CH:30]=2)([C:31]([F:32])([F:33])[F:34])[CH2:35][CH3:36])=[O:26])=[CH:37][CH:38]=1)([O-:20])=[O:19]
Reactant: N#Cc1cc(Cl)c2ccc(CN=[N+]=[N-])cc2n1
Reactant: C#CC(CC)(OC(=O)c1ccc([N+](=O)[O-])cc1)C(F)(F)F
Agent: I[Cu]I
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@](OC(=O)c1ccc([N+](=O)[O-])cc1)(c1cn(Cc2ccc3c(Cl)cc(C#N)nc3c2)nn1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-(azidomethyl)-4-chloroquinoline-2-carbonitrile (560 mg, 2.3 mmol) and 1-ethyl-1-(trifluoromethyl)prop-2-yn-1-yl 4-nitrobenzoate (S-isomer, 728 mg, 2.42 mmol) in THF (18 mL) was added diisopropylethylamine (2.0 mL, 11.5 mmol) followed by copper iodide (655 mg, 3.45 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with a sat. sol. of NH4Cl, Brine and dried over anhydrous MgSO4. The solvent was removed under reduced pressure, and the resulting crude product was purified by flash chromatography (eluting solvent: 5% acetone in CH2Cl2) to afford the title compound. 1H NMR (400 MHz, acetone-d6): δ 8.55 (s, 1H), 8.45 (d, 2H), 8.37 (d, 1H), 8.30 (d, 2H), 8.22 (s, 1H), 8.07 (s, 1H), 7.90 (d, 1H), 6.05 (s, 2H), 3.05 (m, 1H), 2.85 (m, 1H), 1.15 (t, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[OH:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O.Cl.CO>O>[OH:13][C:14]1[CH:15]=[C:16]([CH:17]=[C:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([OH:1])[CH:3]=3)[C:8]2=[O:12])[CH:19]=[CH:20][CH:21]=1
Reactant: O=C1CCCc2cc(O)ccc21
Reactant: O=Cc1cccc(O)c1
Agent: Cl
Solvent: O
Solvent: CO
Product: O=C1C(=Cc2cccc(O)c2)CCc2cc(O)ccc21
Temperature: 25 °C
Yield: 56 %

Procedure:
After 6-hydroxy-1-tetralone 1.0 g and 3-hydroxybenzaldehyde 0.903 g were added to a mixture of concentrated hydrochloric acid 50 ml and methanol 75 ml, the mixture was refluxed for one hour and cooled to room temperature, and water 400 ml was added. The precipitated crystals were filtered. The crystals were dried over phosphorous pentoxide for six hours under reduced pressure to obtain the desired compound 0.92 g.
Reaction SMILES: [C:1]1([CH2:7][CH:8]([P:18](=[O:21])([OH:20])[OH:19])[NH:9][S:10]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)(=[O:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:22][C:23]1[C:28](O)=[CH:27][CH:26]=[CH:25][N:24]=1.ClC(Cl)(Cl)C#N>N1C=CC=CC=1>[NH4+:9].[Cl:22][C:23]1[C:28]([O:21][P:18]([CH:8]([NH:9][S:10]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:12])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:19])[O-:20])=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: O=P(O)(O)C(Cc1ccccc1)NS(=O)(=O)c1cccs1
Reactant: Oc1cccnc1Cl
Solvent: c1ccncc1
Solvent: N#CC(Cl)(Cl)Cl
Product: O=P([O-])(Oc1cccnc1Cl)C(Cc1ccccc1)NS(=O)(=O)c1cccs1
Product: [NH4+]
Temperature: 105 °C
Yield: 107.8 %

Procedure:
To a sealed tube containing phosphonic acid (xiii) (134 mg; 0.39 mmol) and 2-chloro-3-pyridinol (60 mg; 0.46 mmol) was added pyridine (1.9 mL) and trichloroacetonitrile (270 μL; 2.7 mmol). The reaction was heated to 105° C. for 6 hours then was cooled and concentrated. The residue was purified by flash chromatography (chloroform-methanol-concentrated ammonium hydroxide; 9:2:0.1) to yield the ammonium salt 46 (100 mg, 54%) as a colorless solid: 1H NMR: (400 MHz, CD3OD) δH 2.87 (td, J=9, 14 Hz, 1 H. CHPh), 3.28–3.36 (m, 1 H, CHPh), 4.01 (ddd, J=4.5, 9, 17 Hz, 1 H, NCHP), 6.81 (dd, J=3.5, 5 Hz, 1 H, Ar—H), 7.07–7.21 (m, 6 H. Ar—H), 7.28 (dd, J=4.5, 8 Hz, 1 H, Ar—H), 7.46 (dd, J=1.5, 5 Hz, 1 H, Ar—H), 7.91–7.93 (m, 1 H, Ar—H), 7.99–8.02 (m, 1 H, Ar—H); 31P NMR: (162 MHz, CD3OD) δP 17.0; 13C NMR: (100 MHz, DMSO-D6) δC 38.3, 55.6, (d, J=147.6 Hz), 124.3, 126.7, 128.1, 130.1, 130.4, 131.8, 132.1, 140.3 (d, J=10 Hz), 142.4, 142.7, 144.5, 147.9.
Reaction SMILES: [Na].CC(C)=O.Cl.[C:7]([NH2:15])(=[NH:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[Cl:16][C:17]1[CH:18]=[C:19]([N:24]=[C:25]=[S:26])[CH:20]=[CH:21][C:22]=1[Cl:23]>C1C=CC=CC=1.CCCCC>[Cl:16][C:17]1[CH:18]=[C:19]([NH:24][C:25]([NH:14][C:7](=[NH:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[S:26])[CH:20]=[CH:21][C:22]=1[Cl:23]
Reactant: S=C=Nc1ccc(Cl)c(Cl)c1
Reactant: CCCCCCC(=N)N
Agent: Cl
Agent: [Na]
Solvent: CCCCC
Solvent: CC(C)=O
Solvent: c1ccccc1
Product: CCCCCCC(=N)NC(=S)Nc1ccc(Cl)c(Cl)c1

Procedure:
Following a procedure similar to that described in Example 42 but using 2.3 g. sodium in 250 ml. dry acetone, 16.4 g. heptanamidine hydrochloride, and 20.4 g. 3,4-dichlorophenyl isothiocyanate (b.p. 149-152/15-16 mm.) in 150 ml. dry acetone there was obtained 1-(3,4-dichlorophenyl)-3-(heptanimidoyl)-2-thiourea, m.p. 89°-90°C. (from benzene-n-pentane); hydrochloride (27 g.), m.p. 158°-160°C. (from acetonitrile).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH:9]=O)=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.[NH2:12][C@@H:13]([CH3:16])[CH2:14][OH:15]>>[Cl:11][C:6]1[C:7]2[CH:8]=[CH:9][N:12]([C@@H:13]([CH3:16])[CH2:14][OH:15])[C:2]=2[N:3]=[CH:4][N:5]=1
Reactant: O=CCc1c(Cl)ncnc1Cl
Reactant: C[C@H](N)CO
Product: C[C@@H](CO)n1ccc2c(Cl)ncnc21

Procedure:
The title compound was prepared according to the method described for Preparation 1 using (4,6-dichloropyrimidin-5-yl)acetaldehyde and (S)-2-amino-1-propanol to afford the title compound as a cream solid in 98% yield, 10.9 g.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:20]=[C:13]3[N:14]=[C:15]([CH3:19])[CH:16]=[C:17](Cl)[N:12]3[N:11]=2)=[CH:6][CH:5]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>CN1CCCC1=O>[CH3:19][C:15]1[CH:16]=[C:17]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[N:12]2[N:11]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:21])=[CH:5][CH:6]=3)[CH:20]=[C:13]2[N:14]=1
Reactant: COC(=O)c1ccc(-c2cc3nc(C)cc(Cl)n3n2)cc1
Reactant: C1CCNC1
Solvent: CN1CCCC1=O
Product: Cc1cc(N2CCCC2)n2nc(-c3ccc(C(=O)O)cc3)cc2n1
Temperature: 80 °C
Yield: 80 %

Procedure:
To a solution of 4-(7-chloro-5-methyl-pyrazolo[1,5-a]pyrimidin-2-yl)-benzoic acid methyl ester (15.1 mmol) in 1-methyl-2-pyrrolidinone (50 ml) was added pyrrolidine (151 mmol) and the reaction heated at 80° C. for 72 hours. The resultant solid precipitate was filtered and dried under vacuum, then dissolved in 10% NaOH and the aqueous phase washed with ethyl acetate, acidified with conc. HCl, and the resultant precipitated white solid filtered and dried under vacuum to afford 4-(5-Methyl-7-pyrrolidin-1-yl-pyrazolo[1,5-a]pyrimidin-2-yl)-benzoic acid. (3.9 g, 80% yield) MS m/z @323 (m+1).
Reaction SMILES: [C:1]1([C:7](=[N:16][NH2:17])[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:20][C:21](=O)[CH2:22][N+:23]([O-:25])=[O:24])C.N1CCCCC1>C1C=CC=CC=1>[N+:23]([C:22]1[C:21](=[O:20])[NH:17][N:16]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([O-:25])=[O:24]
Reactant: NN=C(C(=O)c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C[N+](=O)[O-]
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: O=c1[nH]nc(-c2ccccc2)c(-c2ccccc2)c1[N+](=O)[O-]

Procedure:
8.96 g (0.040 mole) of benzilmonohydrazone, 5.3 g (0.040 mole) of ethylnitroacetate and 4.8 g (0.056 mole) of piperidine in 100 mL of benzene were heated in a round bottom flask with a Dean-Stark trap and condenser for 24 hrs.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[N:7]2[CH2:8][C:9]([CH3:13])([CH3:12])[CH2:10][N:11]=[C:6]2[S:5][C:4]=1[C:14]([OH:16])=O.C(OCC)C>S(Cl)(Cl)=O>[ClH:1].[CH3:2][C:3]1[N:7]2[CH2:8][C:9]([CH3:13])([CH3:12])[CH2:10][N:11]=[C:6]2[S:5][C:4]=1[C:14]([Cl:1])=[O:16]
Reactant: CC1=C(C(=O)O)SC2=NCC(C)(C)CN21
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: CC1=C(C(=O)Cl)SC2=NCC(C)(C)CN21
Yield: 198.1 %

Procedure:
In 6 ml of thionylchloride was suspended 1.0 g of 3,6,6-trimethyl-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidine-2-carboxylic acid hydrochloride obtained in Example 120, followed by reflux under heating for 30 minutes. After dissolving completely, the mixture was cooled. Under cooling with ice, to the mixture was added anhydrous diethylether. The precipitated crystals were collected by filtration and dried under reduced pressure to obtain 1.06 g of 3,6,6-trimethyl-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidine-2-carbonylchloride hydrochloride. The total amount of this compound and 610 mg of 3,5-dimethylaniline was dissolved in the mixture 60 ml of pyridine and 10 ml of dimethylformamide, followed by stirring at 60° C. for 17 hours. The reaction mixure was concentrated and to the concentrate was added 5% sodium hydrogencarbonate aqueous solution. The precipitated crystals were collected by filtration and washed diethylether. The obtained powder was suspended in diethylether. To the suspension was added 0.2 ml of saturated hydrogenchloride dioxane solution, followed by stirring at room temperature. The precipitated crystals were collected by filtration. The crystals were recrystallized from a mixed solvent of ethanol and diethylether to obtain 810 mg of the titled compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]([C@@H:15]([NH:19]C(OC(C)(C)C)=O)[CH:16]([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1>CO>[Cl:2][C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]([C@@H:15]([NH2:19])[CH:16]([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Agent: Cl
Solvent: CO
Product: CC(C)[C@H](N)C(=O)N1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Temperature: 70 °C
Reaction time: 2.5 h

Procedure:
1 N ethereal hydrogen chloride solution (80 ml, 80 mmol) was added to a solution of 1(S)-[4-(3,4-dichlorobenzyl)piperazin-1-ylcarbonyl]-N-(tert-butoxycarbonyl)-2-methylpropylamine (4.28 g, 9.64 mmol) in methanol (50 ml) and the reaction mixture was heated at 70° C. After 2.5 h, the reaction mixture was concentrated and the solid was suspended in ether and filtered to give 1-(S)-[4-(3,4-dichlorobenzyl)piperazin-1-yl carbonyl]-2-methylpropylamine as the bis hydrochloride salt. The product was dissolved in water, treated with triethylamine (4.0 ml, 28.9 mmol) and the free amine was extracted into ethyl acetate. The ethyl acetate layer was dried over magnesium sulfate, filtered and concentrated to give 1-(S)-[4-(3,4-dichlorobenzyl)piperazin-1-ylcarbonyl]-2-methylpropylamine (3.2 g) as the free amine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:13]=[C:12](Br)[C:11]([O:15]COC)=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1.[CH3:20][Zn]C.CCCCCC.Cl>O1CCOCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:13]=[C:12]([CH3:20])[C:11]([OH:15])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1
Reactant: COCOc1c(Br)cc(C(=O)OC)cc1C(=O)OC
Reactant: C[Zn]C
Agent: Cl
Solvent: CCCCCC
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C)c(O)c(C(=O)OC)c1
Temperature: 120 °C
Reaction time: 5.5 h

Procedure:
To a solution of 5-bromo-4-methoxymethoxyisophthalic acid dimethyl ester (6.00 g) in dioxane (60 mL) were added [1,1′ bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1:1) (600 mg) and 1M dimethylzinc/hexane solution (20 mL), and the mixture was stirred at 120° C. for 5.5 hours under heating. The reaction solution was allowed to stand for cooling down to room temperature, and 1M hydrochloric acid (40 mL) was added dropwise thereto. After the reaction solution was diluted with ethyl acetate (100 mL), the insoluble material was filtered through a Celite pad. The organic layer was separated, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=9:1, v/v) to give the title compound (2.97 g).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[N+:11]([CH2:14][CH3:15])([O-:13])=[O:12].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[CH3:9][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH:1]=[C:14]([N+:11]([O-:13])=[O:12])[CH3:15])[CH:3]=1
Reactant: CC[N+](=O)[O-]
Reactant: COc1cccc(C=O)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: COc1cccc(C=C(C)[N+](=O)[O-])c1

Procedure:
A mixture of 71.9 g (0.528 mole) of m-anisaldehyde, 118.9 g (1.584 mole) of nitroethane, 40.7 g (0.528 mole) of ammonium acetate, and 350 ml of glacial acetic acid was heated to reflux for one hour. The mixture was then allowed to cool and partitioned between ether and water. The ether layer was separated and washed sequentially with water, 3N sodium hydroxide, water and brine. The organic phase was dried over anhydrous magnesium sulfate and evaporated in vacuo to give the crude product. After a preliminary distillation at 125° C./0.0001 mm, the product was finally crystallized from absolute ethanol to yield the pure product, a yellow solid, mp 40°-42° C.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[C:27]1([CH:33]([NH2:35])[CH3:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[Cl:1][C:2]1[C:3]([NH:35][CH:33]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:34])=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Clc1cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc2c1Cl
Reactant: CC(N)c1ccccc1
Product: CC(Nc1c(Cl)cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc12)c1ccccc1
Temperature: 200 °C
Yield: 52.3 %

Procedure:
6,7-Dichloro-2-[4-(2-morpholin-4-ylethoxy)phenyl]-3H-imidazo[4,5-b]pyridine (Example 206) (0.030 g, 0.072 mmol) was dissolved in l-phenylethylamine (1 ml, 7.83 mmol) and heated in a sealed vial at 200° C. for 2 h. The excess amine was removed under reduced pressure, and the solid residue was washed with diethyl ether, NH3 (28% in water) and CH3CN, giving the title product (0.018 g, 52%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[C:30]([O:31][CH3:32])=[C:29]4[C:24]([C:25](=[O:39])[C:26]([C:36]([OH:38])=[O:37])=[CH:27][N:28]4[CH:33]4[CH2:35][CH2:34]4)=[CH:23][C:22]=3[F:40])[CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+].C(O)(=O)C>ClC(Cl)C>[CH:33]1([N:28]2[C:29]3[C:24](=[CH:23][C:22]([F:40])=[C:21]([N:18]4[CH2:19][CH2:20][CH:15]([NH:14][CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)[CH2:16][CH2:17]4)[C:30]=3[O:31][CH3:32])[C:25](=[O:39])[C:26]([C:36]([OH:38])=[O:37])=[CH:27]2)[CH2:34][CH2:35]1
Reactant: COc1c(N2CCC(NC3CCN(C(=O)OC(C)(C)C)CC3)CC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: COc1c(N2CCC(NC3CCNCC3)CC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reaction time: 3 h

Procedure:
To a stirred solution of 7-[4-(1-tert-Butoxycarbonyl-piperidin-4-ylamino)-piperidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (113 mg, 0.2 mmol) in dichloroethane (1.5 mL) was added trifluoroacetic acid (692 mg, 6.07 mmol). The resulting mixture was stirred for 3 hours before condensed to dryness. To this residue was added saturated aqueous sodium carbonate followed by the addition of acetic acid to pH around 6. This aqueous solution was extracted with 20% (v/v) isopropanol/dichloromethane. The combined organic layers were dried over sodium sulfate and condensed to give product as slightly yellow syrup, which was used directly for next reaction. ESI MS m/z 459 (M+H+); 1H NMR (400 MHz, CDCl3) δ 8.74 (s, 1H), 7.78 (d, J=11.6 Hz, 1H), 3.98 (m, 3H), 3.71 (s, 3H), 3.54 (d, J=13.2 Hz, 2H), 3.33 (t, J=13.3 Hz, 2H), 3.14 (m, 1H), 2.91 (d, J=12.5 Hz, 2H), 2.11 (d, J=11.7 Hz, 2H), 2.00 (m, 2H), 1.78 (m, 4H), 1.16 (d, J=7.0 Hz, 2H), 0.93 (d, J=3.3 Hz, 2H).
Reaction SMILES: [CH3:1][CH:2]([C:8]([CH3:10])=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[CH2:11]([NH:18]/[C:8](/[CH3:10])=[C:2](/[CH3:1])\[C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)C(C)C(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)/C(C)=C(/C)NCc1ccccc1
Reaction time: 6 h

Procedure:
A solution of ethyl 2-methylacetoaceate (1-004-01) (115.34 g) and benzylamine (85.73 g) in toluene (1.6 L) was azeotropically dehydrated in an oil bath at 145° C. for 8 h under nitrogen atmosphere. Benzylamine was added to the reaction mixture and the reaction mixture was dehydrated again. After 6 h, the reaction mixture was distilled under atmospheric pressure to remove about 600 mL of the solvent, and evaporated under reduced pressure to give ethyl 3-benzylamino-2-methylcrotonate (1-004-02). (195.66 g).