Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8]([CH3:15])=[N:9]2)([O-])=O.[OH-].[Na+]>Cl>[NH2:1][C:4]1[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8]([CH3:15])=[N:9]2
Reactant: Cc1ccc2c([N+](=O)[O-])c(Cl)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc2c(N)c(Cl)ccc2n1
Yield: 77.6 %

Procedure:
To 50 ml of concentrated hydrochloric acid having dissolved therein 25 g of stannous chloride was added 6.7 g of 5-nitro-6-chloroquinaldine and the mixture was allowed to react on a water bath at a temperature of 80° to 90° C. for 30 minutes. The reaction mixture was ice-cooled, rendered alkaline (pH 10) with 30% sodium hydroxide and filtered and extracted with 500 ml of chloroform and Celite (diatomaceous earth). After drying over anhydrous sodium sulfate the chloroform fraction was concentrated and recrystallized from a mixture of benzene and hexane to obtain 4.5 g of 5-amino-6-chloroquinaldine as colorless plates having a melting point of 196° to 197° C.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][N:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:18])[C:13]=2[NH2:17])[C:8]1=[O:19])(=[O:3])[CH3:2].[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](O)=[O:29])=[CH:23][C:22]=1[C:31]([F:34])([F:33])[F:32].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.C(Cl)Cl>>[C:1]([O:4][CH2:5][CH2:6][N:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:18])[C:13]=2[NH:17][C:28](=[O:29])[CH2:27][C:24]2[CH:25]=[CH:26][C:21]([F:20])=[C:22]([C:31]([F:32])([F:34])[F:33])[CH:23]=2)[C:8]1=[O:19])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCn1ccc2c(N)c(Cl)ccc2c1=O
Reactant: O=C(O)Cc1ccc(F)c(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OCCn1ccc2c(NC(=O)Cc3ccc(F)c(C(F)(F)F)c3)c(Cl)ccc2c1=O
Temperature: 45 °C
Reaction time: 96 h

Procedure:
A reaction vial was charged with 2-(5-amino-6-chloro-1-oxoisoquinolin-2(1H)-yl)ethyl acetate (60.0 mg, 0.000214 mol), 2-(4-fluoro-3-(trifluoromethyl)phenyl)acetic acid (57.0 mg, 0.000256 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (203 mg, 0.000534 mol), N,N-diisopropylethylamine (0.093 mL, 0.00053 mol) and methylene chloride (3 mL, 0.05 mol) and the reaction stirred at 45° C. for 4 days. The reaction did not go to completion and a polar by product started increasing and so the reaction was stopped and solvent removed and the residue purified by flash chromatography to obtain the product as a light yellow solid. MS m/z=485.2 (M+H)
Reaction SMILES: Cl[Si](C)(C)C.[F:6][C:7]1[CH:8]=[C:9]([CH:16]=[C:17]([F:19])[CH:18]=1)[CH2:10][CH:11]([C:13]([OH:15])=[O:14])[NH2:12].C(N(C(C)C)C(C)C)C.[CH:29]1(/[CH:35]=[CH:36]/[C:37](Cl)=[O:38])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>ClCCl>[CH:29]1(/[CH:35]=[CH:36]/[C:37]([NH:12][C@H:11]([C:13]([OH:15])=[O:14])[CH2:10][C:9]2[CH:8]=[C:7]([F:6])[CH:18]=[C:17]([F:19])[CH:16]=2)=[O:38])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: NC(Cc1cc(F)cc(F)c1)C(=O)O
Reactant: O=C(Cl)/C=C/C1CCCCC1
Agent: C[Si](C)(C)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(/C=C/C1CCCCC1)N[C@@H](Cc1cc(F)cc(F)c1)C(=O)O
Temperature: 0 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
6.3 ml (49.7 mmol) of chlorotrimethylsilane are added to a solution of 5.0 g (24.9 mmol) of 3,5-difluoro-DL-phenylalanine in dichloromethane (150 ml) and the reaction mixture is heated to reflux for 1 h. After cooling to 0° C., 9.7 ml (55.9 mmol) of ethyldiisopropylamine are slowly added and then, dropwise, 4.29 g (24.9 mmol) of trans-3-cyclohexyl-2-propenoyl chloride. The reaction mixture is stirred overnight with slow warming to RT and remains standing at RT for two days. For working up, the mixture is evaporated to dryness in vacuo, the residue is taken up using diethyl ether and extracted with 2.5 pc. aq. sodium hydrogencarbonate solution (250 ml). The aqueous phase is extracted twice with diethyl ether. The combined organic phases are extracted a further three times with sodium hydrogencarbonate solution. The combined aqueous phases are brought to pH=2 using 1N aqueous hydrochloric acid and extracted three times with ethyl acetate. The combined ethyl acetate phases are dried over sodium sulfate, filtered, and the solvent is concentrated in vacuo. The residue (4.63 g) is washed by stirring with diethyl ether and filtered. 3.64 g (43% of th.) of colorless solid are obtained. The residue from the concentrated mother liquor and the residue from the concentrated diethyl ether phase of the alkaline extraction (see above), are taken up together in ethyl acetate and extracted with 1N hydrochloric acid. The organic phase is dried over sodium sulfate, filtered and concentrated. The residue is washed by stirring with diethyl ether and filtered off with suction. A further 2.18 g (26%) of product are isolated.
Reaction SMILES: [CH3:1][CH:2]([OH:6])[CH2:3][C:4]#[CH:5].Br[C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH:11]=[CH:12][CH:13]=1>>[F:20][C:19]([F:21])([F:22])[C:18]([NH:17][CH2:16][CH2:15][CH2:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:5]#[C:4][CH2:3][CH:2]([OH:6])[CH3:1])[CH:9]=1)=[O:23]
Reactant: C#CCC(C)O
Reactant: O=C(NCCCc1cccc(Br)c1)C(F)(F)F
Product: CC(O)CC#Cc1cccc(CCCNC(=O)C(F)(F)F)c1

Procedure:
Coupling of pent-4-yn-2-ol with bromide 10 following the method used in Example 13 except the reaction was conducted at room temperature gave 2,2,2-trifluoro-N-(3-(3-(4-hydroxypent-1-ynyl)phenyl)propyl)acetamide as a pale yellow oil. Yield (0.95 g, 63%): 1H NMR (400 MHz, DMSO-d6) δ 9.40 (br s, 1H), 7.14-7.26 (m, 4H), 4.80 (s, 1H), 3.81 (q, J=5.6 Hz, 1H), 3.16 (q, J=6.8 Hz, 2H), 2.54 (t, J=5.6 Hz, 2H), 2.39 (dd, J=16.8, 6.8 Hz, 2H), 1.76 (quint, J=7.2 Hz, 2H), 1.17 (d, J=5.6 Hz, 3H).
Reaction SMILES: [NH2:1][C@H:2]([CH3:22])[C@@H:3]([OH:21])[CH2:4][N:5]([CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH2:6][C:7]([F:10])([F:9])[F:8].[CH3:23][N:24]1[C:28]([C:29]2[CH:30]=[C:31]([NH:35][C:36](=O)[O:37]C3C=CC=CC=3)[CH:32]=[CH:33][CH:34]=2)=[N:27][N:26]=[N:25]1>C(#N)C>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][CH2:11][N:5]([CH2:6][C:7]([F:8])([F:9])[F:10])[CH2:4][C@H:3]([OH:21])[C@H:2]([NH:1][C:36]([NH:35][C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([C:28]3[N:24]([CH3:23])[N:25]=[N:26][N:27]=3)[CH:30]=2)=[O:37])[CH3:22])=[CH:19][CH:18]=1
Reactant: C[C@@H](N)[C@@H](O)CN(CCCc1ccc(F)cc1)CC(F)(F)F
Reactant: Cn1nnnc1-c1cccc(NC(=O)Oc2ccccc2)c1
Solvent: CC#N
Product: C[C@@H](NC(=O)Nc1cccc(-c2nnnn2C)c1)[C@@H](O)CN(CCCc1ccc(F)cc1)CC(F)(F)F
Yield: 6.7 %

Procedure:
The product of Step e (192 mg, 0.60 mmol, 1 eq.), phenyl 3-(1-methyl-1H-tetraazol-5-yl)phenylcarbamate (176 mg, 0.60 mmol, 1 eq.) and acetonitrile (4 mL) were mixed at 25° C. under N2 overnight. Worked up by stripping off the solvents then purifying the residue over silica gel in 9:1 Hexanes/EtOAc to 100% EtOAc. Obtained 21 mg of a viscous oil. NMR (300 MHz, CDCl3) δ 8.35-8.20 (M, 1H); 7.79 (s, 1H); 7.70 (d, 1H, J=7 Hz); 7.45-7.20 (m, 2H); 7.10 (t, 2H, J=7 Hz); 6.93 (t, 2H, J=7 Hz); 6.20-5.80 (m, 1H); 4.05 (s, 3H); 3.93 (m, 1H); 3.80-3.40 (m, 2H); 3.25-3.05 (m, 2H); 2.85-2.40 (m, 4H); 1.85-1.60 (m, 2H); 1.20 (d, 3H, J=7 Hz); 1.00-0.70 (m, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[C:8]2[C:9]([O:11][C:12](=O)[NH:13][C:7]2=[CH:6][CH:5]=1)=[O:10])([O-:3])=[O:2].C[O-].[Na+].[CH:19]1([C:22](Cl)=[O:23])[CH2:21][CH2:20]1.O>CO>[CH3:12][O:11][C:9](=[O:10])[C:8]1[CH:15]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=1[NH:13][C:22]([CH:19]1[CH2:21][CH2:20]1)=[O:23]
Reactant: O=C(Cl)C1CC1
Reactant: O=c1[nH]c2ccc([N+](=O)[O-])cc2c(=O)o1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1NC(=O)C1CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
5-nitroisatoic anhydride (20.8 g, 0.1 mol) ) was heated to reflux with sodium methoxide (0.5 g, 0.01 mol) in methanol (600 mL). After 1 h, the solvent was evaporated under vacuum and the residue dissolved in 1,2-dichloroethane (400 mL), washed with cold water and dried over MgSO4. Cyclopropanecarbonyl chloride (20.9 g, 0.2 mol) was added to the solution and then heated at 80° C. for 4.5 h. The mixture was allowed to cool and water (200 mL) was added under vigorous stirring. After 0.5 h, the stirring was interrupted and the phases separated, the C2H4Cl2 layer washed with sodium bicarbonate solution and dried over MgSO4. Evaporation of the solvent afforded 2-(cyclopropanecarbonyl-amino)-5-nitro-benzoic acid methyl ester (21.7 g, 0.082 mmol). This material was dissolved in methanol (500 mL) and 10% Pd/C (2.2 g) was added. The flask was then flushed with H2 and stirred at room temperature and at 1 atm. After 5 h reduction, the catalyst was removed by filtration through Celite. The catalyst was carefully washed and the combined filtrate evaporated to dryness to give the pure title compound as a grey solid (18.0 g, 0.077 mol).
Reaction SMILES: [C:1]1([OH:12])[C:10]2[CH2:9][CH2:8][CH:7]([OH:11])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C[O-].[Na+].[CH2:16]([CH:18]1[O:20][CH2:19]1)Cl>CO>[O:20]1[CH2:19][CH:18]1[CH2:16][O:12][C:1]1[CH:2]=[CH:3][CH:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH:7]([OH:11])[CH2:6]2
Reactant: Oc1cccc2c1CCC(O)C2
Reactant: ClCC1CO1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: OC1CCc2c(cccc2OCC2CO2)C1
Reaction time: 8 h

Procedure:
A solution of 2.46 g. (0.015 mole) of 5,6,7,8-tetrahydro-1,6-naphthalenediol and 810 mg. (0.015 mole) of sodium methoxide in 30 ml. of methanol is prepared under nitrogen and the solvent removed in vacuo. The resulting foam is stirred overnight with 20 ml. of dimethylsulfoxide and 1.40 g. (0.015 mole) of epichlorohydrin, poured into 200 ml. of water and extracted with four 125 ml. portions of ether. Drying and solvent removal gives 3.06 g. of oil which is purified by chromatography on silica gel (75 g.). Elution with hexane-chloroform mixtures gives a total of 1.56 g. (49%) of material with one spot on TLC.
Reaction SMILES: CO[C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[CH3:23][CH:24]([NH2:27])[CH2:25][OH:26]>>[CH2:18]([C:13]1[C:12](/[CH:11]=[CH:10]/[C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH:27][CH:24]([CH3:23])[CH2:25][OH:26])=[O:22])=[CH:5][N:6]=2)=[C:16]([CH3:17])[O:15][N:14]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CC(N)CO
Reactant: CCCCc1noc(C)c1/C=C/c1ccc(C(=O)OC)cn1
Product: CCCCc1noc(C)c1/C=C/c1ccc(C(=O)NC(C)CO)cn1
Yield: 87 %

Procedure:
As described in example 4, 6-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-nicotinic acid methyl ester (100 mg, 0.28 mmol) instead of 6-[2-(5-methyl-3-phenyl-isoxazol-4-yl)-ethyl]-nicotinic acid methyl ester, and DL-2-amino-1-propanol instead of ethanolamine, was converted to the title compound (85 mg, 87%) which was obtained as a light yellow oil after purification by chromatography (silica, dichloromethane:methanol 100:0 to 94:6). MS: m/e=364.4 [M+H]+.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[CH:5]([CH2:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[Br:12]Br.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[Br:12][C:4]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:1](=[O:11])[NH:2][CH:3]=1
Reactant: O=C1NCCC2CC=CC=C12
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=c1[nH]cc(Br)c2c1CCCC2
Yield: 96.4 %

Procedure:
32.4 g (217 mmol) of tetrahydroisoquinolinone (compound 5) is dissolved in 300 ml of chloroform at 5° C. and then 11.2 ml (34.7 g, 217 mmol) of bromine, dissolved in 150 ml of chloroform, are added dropwise over the course of 1 h. The mixture is stirred while cooling in ice for a further hour and then neutralized with 150 ml of saturated NaHCO3 solution and filtered with suction. The organic phase of the filtrate is extracted with dichloromethane and concentrated. The residue is mixed with ethyl acetate, filtered off with suction and dried together with the first residue in a vacuum drying oven at 45° C. 47.7 g (96%) of colorless bromide are obtained.
Reaction SMILES: C(OC([N:8]1[C:12]2=[C:13]([Cl:25])[N:14]=[CH:15][C:16]([C:17]([N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])=[C:11]2[C:10]([CH3:26])=[CH:9]1)=O)(C)(C)C.[C:27]([C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32])#[N:28].C(OCC)C.Cl>C(OCC)(=O)C.C(OCC)C>[ClH:25].[C:27]([C:29]1[CH:30]=[C:31]([NH:32][C:13]2[N:14]=[CH:15][C:16]([C:17]([N:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)=[O:18])=[C:11]3[C:10]([CH3:26])=[CH:9][NH:8][C:12]=23)[CH:33]=[CH:34][CH:35]=1)#[N:28]
Reactant: Cc1cn(C(=O)OC(C)(C)C)c2c(Cl)ncc(C(=O)N3CCCCC3)c12
Reactant: N#Cc1cccc(N)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Cc1c[nH]c2c(Nc3cccc(C#N)c3)ncc(C(=O)N3CCCCC3)c12
Yield: 26.5 %

Procedure:
Prepared in a similar manner to Example 4(d) from 7-chloro-3-methyl-4-(1-piperidin-1-yl-methanoyl)-pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester (90 mg) and using 3-cyanoaniline (56 mg) instead of 3-bromoaniline and heating for 15 rather than 30 minutes. Isolated by MDAP rather than trituration with diethyl ether and then suspended in ethyl acetate (10 ml) and treated with a solution of 1M hydrochloric acid in diethyl ether (10 drops). The mixture was evaporated and dried at 40° C. under vacuum to afford the title compound (25 mg).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[N:5]=[C:4]([NH:15][CH2:16][CH2:17][OH:18])[N:3]=1.Cl.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH2:28][CH2:29][NH:30][CH2:31][CH:32]=2)=[CH:23][CH:22]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[CH:12]1([CH2:11][NH:10][C:6]2[C:7]([C:8]#[N:9])=[C:2]([N:30]3[CH2:29][CH:28]=[C:27]([C:24]4[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=4)[CH2:32][CH2:31]3)[N:3]=[C:4]([NH:15][CH2:16][CH2:17][OH:18])[N:5]=2)[CH2:14][CH2:13]1
Reactant: Fc1ccc(C2=CCNCC2)cc1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NCC1CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1c(NCC2CC2)nc(NCCO)nc1N1CC=C(c2ccc(F)cc2)CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-6-(cyclopropylmethyl-amino)-2-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile (example 41b) was treated with 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride in dioxane in the presence of N-ethyl-diisopropylamine at 90° C. to yield 4-(cyclopropylmethyl-amino)-6-[4-(4-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile as an amorphous, white solid; MS: [M+H]+=409.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[Cl:11])=[N+:2]=[N-:3].[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([O:22][CH3:23])=[C:17]([CH2:19][C:20]#[N:21])[CH:18]=1.C[O-].[Na+]>C(O)C.C(OCC)(=O)C>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([O:22][CH3:23])=[C:17]([C:19]2[N:3]=[N:2][N:1]([C:4]3[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=3[Cl:11])[C:20]=2[NH2:21])[CH:18]=1
Reactant: COc1ccc(Cl)cc1CC#N
Reactant: [N-]=[N+]=Nc1ccc(Cl)cc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(Cl)cc1-c1nnn(-c2ccc(Cl)cc2Cl)c1N
Temperature: 0 °C
Reaction time: 8 h
Yield: 27.1 %

Procedure:
To an ice-cooled and stirred mixture of 1-azido-2,4-dichloro-benzene (0.9 g, 1 eq) and commercial (5-chloro-2-methoxy-phenyl)-acetonitrile (1.04 g, 1.2 eq) in ethanol (10 ml) kept under nitrogen, a solution of sodium methoxide (0.388 g, 1.5 eq) in ethanol (10 ml) is added drop-wise (20 min). After the addition, the reaction mixture is allowed to reach room temperature spontaneously and stirring is then continued overnight at room temperature. The resulting reaction mixture is diluted with ethyl acetate (40 ml), washed with water (2×50 ml), dried over MgSO4 and evaporated to dryness. The yellow solid residue (0.820 g) is purified by crystallization from a mixture of dichloromethane and hexane (1:1), to afford the title compound as white solid (0.480 g, 28% yield). M.p. 153.5-154.7° C.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:14][C:13]([CH2:15]Br)=[C:12]([CH2:17]Br)[CH2:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:20][NH2:21].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:20][N:21]1[CH2:15][C:13]2[CH2:14][N:10]([S:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:19])=[CH:2][CH:3]=3)(=[O:9])=[O:8])[CH2:11][C:12]=2[CH2:17]1
Reactant: Cc1ccc(S(=O)(=O)N2CC(CBr)=C(CBr)C2)cc1
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)N2CC3=C(CN(C)C3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
To a solution of 1-p-toluenesulfonyl-3,4-bis(bromomethyl)-3-pyrroline (6.1 g) was dissolved in acetonitrile (70 ml), 40% methylamine aqueous solution (1.5 ml) and anhydrous potassium carbonate powder (16 g) were added and stirred for 2 hours at room temperature. The solid was filtered off and the filtrate was purified by silicagel column chromatography to yield 3-methyl-7-p-toluenesulfonyl-3,7-diazabicyclo[3.3.0]oct-1(5)-ene (0.82 g, yield 20%). 0.8 g of this compound and 0.8 g of phenol were refluxed in 48% hydrobromic acid (15 ml) for 5 hours. The reaction mixture was washed with chloroform (20 ml×3), decolorized with active charcoal. The solvent was distilled off and washed with ethanol-ethylether (1:1) to give the title compound (0.5 g, yield 60%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17]O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:43]I>C1COCC1>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][I:43])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: II
Reactant: CC(C)(C)OC(=O)N1CCC(CCCCO)CC1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCCCI)CC1
Yield: 61.9 %

Procedure:
A mixture of 4-2 (3.4 g, 13.2 mmol), Ph3P (5.2 g, 19.8 mmol), imidazole (2.7 g, 39.6 mmol), and THF (30 mL) at ambient temperature was treated with iodine (5.0 g, 19.8 mmol) in three portions. After 1 h most of the THF was evaporated and the residue partitioned between EtOAc and H2O. The EtOAc layer was washed with H2O, 10% Na2S2O3, and brine, dried (MgSO4) and concentrated to give a solid. Flash chromatography (silica, 10% EtOAc/hexanes) gave 4-3 (3.0 g) as a light yellow oil. Rf 0.27 (silica, 10% EtOAc/hexanes).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][CH:8]=2)[NH:4][C:3]=1[C:18]([O:20]CC)=O.C(O)(=O)C.[CH:27](N)=[NH:28]>C(O)C>[O:20]=[C:18]1[NH:28][CH:27]=[N:1][C:2]2[CH:6]=[C:5]([C:7]3[CH:8]=[CH:9][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:12]=3)[NH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(-c2cc(N)c(C(=O)OCC)[nH]2)cc1
Reactant: N=CN
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(-c2cc3nc[nH]c(=O)c3[nH]2)cc1
Temperature: 25 °C
Yield: 94.3 %

Procedure:
A mixture of ethyl 3-amino-5-[4-(ethoxycarbonyl)phenyl]-1H-pyrrole-2-carboxylate (3.36 g), formamidine acetate (1.74 g) and ethanol (60 mL) was heated under reflux for 15 hrs. After cooling to room temperature, the precipitated solid was collected by filtration, washed with ethanol, and dried under reduced pressure at 60° C. to give the title compound (2.97 g).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1([CH2:20][CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])[O:13][C:12]2=[N:14][C:15]([N+:17]([O-:19])=[O:18])=[CH:16][N:11]2[CH2:10]1>C(Cl)Cl>[CH3:8][C:9]1([CH2:20][CH2:21][C:22]([OH:24])=[O:23])[O:13][C:12]2=[N:14][C:15]([N+:17]([O-:19])=[O:18])=[CH:16][N:11]2[CH2:10]1
Reactant: CC(C)(C)OC(=O)CCC1(C)Cn2cc([N+](=O)[O-])nc2O1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(CCC(=O)O)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.4 %

Procedure:
Trifluoroacetic acid (2 ml) was added to a solution of tert-butyl 3-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-yl) propionate prepared in Example 44 (0.72 g, 2.42 mmol) in methylene chloride (14 ml) followed by stirring at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was crystallized from ethanol-methylene chloride to afford 3-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-yl)propionic acid (0.30 g, 51%) as a light yellow solid.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].Cl[C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([O:25][CH2:26][C:27]2[CH:31]=[CH:30][S:29][CH:28]=2)[N:16]=1>CN(C)C=O>[S:29]1[CH:30]=[CH:31][C:27]([CH2:26][O:25][C:17]2[CH:18]=[C:19]([C:21]([F:24])([F:22])[F:23])[CH:20]=[C:15]([O:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=3)[N:16]=2)=[CH:28]1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: FC(F)(F)c1cc(Cl)nc(OCc2ccsc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(Oc2cc(C(F)(F)F)cc(OCc3ccsc3)n2)c1

Procedure:
To a mixture prepared by adding to meta-trifluoromethylphenol (1.1 g, 0.0034×2.0 mol) successively dimethylformamide and sodium hydride (0.20 g, (ca.60% in mineral oil), 0.0034×1.5 mol), 2-chloro-6-(3-thienylmethyloxy)-4-trifluoromethylpyridine (1.0 g, 0.0034 mol) was added, and the resultant solution was refluxed for about 2 hours.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.[NH2:17][C:18]1[C:19]([OH:31])=[N:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[CH:22][CH:23]=1.C(N(CC)CC)C>CN(C)C=O>[OH:31][C:19]1[C:18]([NH:17]/[CH:14]=[C:5]2\[C:6](=[O:13])[NH:7][C:8](=[O:12])[C:9]3[C:4]\2=[CH:3][C:2]([I:1])=[CH:11][CH:10]=3)=[CH:23][CH:22]=[C:21]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)[N:20]=1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(I)cc21
Reactant: CN1CCN(c2ccc(N)c(O)n2)CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(I)cc43)c(O)n2)CC1
Temperature: 100 °C

Procedure:
(4E)-6-iodo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (0.12 g, 0.35 mmol), 3-amino-6-(4-methyl-piperazin-1-yl)-pyridin-2-ol (0.15 g, contaminated with triethylammonium trifluoroacetate) were coupled in N,N-dimethylformamide (3 mL) with triethylamine (0.27 mL). The mixture is heated in a 100° C. oil bath for three hours. The reaction mixture is purified by reverse phase HPLC to give (4Z)-4-({[2-hydroxy-6-(4-methylpiperazin-1-yl)pyridin-3-yl]amino}methylene)-6-iodoisoquinoline-1,3(2H,4H)-dione.2 trifluoroacetic acid salt (18 mg, 7.0%).
Reaction SMILES: [Na].C(O)C.Cl.[CH:6]1([NH:11][C:12]([NH2:14])=[NH:13])[CH2:10][CH2:9][CH2:8][CH2:7]1.[Cl:15][C:16]1[N:21]2[N:22]=[C:23]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[C:24]([C:25](=O)[C:26]#[C:27][CH3:28])=[C:20]2[CH:19]=[CH:18][CH:17]=1>O>[Cl:15][C:16]1[N:21]2[N:22]=[C:23]([C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)[C:24]([C:25]3[CH:26]=[C:27]([CH3:28])[N:14]=[C:12]([NH:11][CH:6]4[CH2:10][CH2:9][CH2:8][CH2:7]4)[N:13]=3)=[C:20]2[CH:19]=[CH:18][CH:17]=1
Reactant: N=C(N)NC1CCCC1
Reactant: CC#CC(=O)c1c(-c2ccc(F)cc2)nn2c(Cl)cccc12
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Product: Cc1cc(-c2c(-c3ccc(F)cc3)nn3c(Cl)cccc23)nc(NC2CCCC2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.8 %

Procedure:
To a dry round bottom flask was added sodium metal (81 mg, 3.5 mmol). Ethanol (20 mL) was added and allowed to react with sodium at room temperature until completely dissolved. N-Cyclopentylguanidine hydrochloride (572 mg, 3.5 mmol) was added and the mixture was allowed to stir at room temperature for 10 minutes. To the resultant mixture was added 1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-butyn-1-one (842 mg, 2.69 mmol) and the reaction mixture was allowed to stir at room temperature for 72 hours, then heated to 70° C. for 12 hours. The reaction mixture was cooled to room temperature and diluted with water. The mixture was extracted with ethyl acetate, and the combined extracts were washed with water and brine. The organic layer was dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (4:1 hexanes:ether to 3:2 hexanes:ether) provided 4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-cyclopentyl-6-methyl-2-pyrimidinamine (1.11 g, 98%) as a yellow foam. Rf 0.45 (3:1 hexanes:ethyl acetate). 1H NMR (CDCl3) δ 8.35 (d, 1H), 7.64 (m, 2H), 7.24 (m, 1H), 7.13 (m, 2H), 7.03 (d, 1H), 6.22 (s, 1H), 5.10 (m, 1H), 4.35 (m, 1H), 2.19 (s, 3H), 2.03 (m, 2H), 1.60 (m, 6H); MS m/z 422 (M+1).