Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C2C(C)(C)/C(=C\C=C(/C3C=CC=C(CCCCC(O[N:70]4[C:74](=[O:75])[CH2:73][CH2:72][C:71]4=[O:76])=O)C=3)\C=C\C3C(C)(C)C4C5C=C(S([O-])(=O)=O)C=C(S([O-])(=O)=O)C=5C=CC=4[N+]=3CCCCS([O-])(=O)=O)/N=C2N(CCCCS([O-])(=O)=O)C=1.[Na+:77].[Na+].[Na+].[C:80]([CH2:83][CH2:84][CH2:85][CH2:86][C:87]1[CH:88]=[C:89](/[C:93](=[CH:119]\[CH:120]=[C:121]2/[C:122]([CH3:140])([CH3:139])[C:123]3[C:124](=[N:138]/2)[N:125]([CH2:130][CH2:131][CH2:132][CH2:133][S:134]([O-:137])(=[O:136])=[O:135])[CH:126]=[C:127]([Cl:129])[CH:128]=3)/[CH:94]=[CH:95]/[C:96]2[C:104]([CH3:106])([CH3:105])[C:103]3[C:98](=[CH:99][CH:100]=[C:101]([S:107]([O-:110])(=[O:109])=[O:108])[CH:102]=3)[N+:97]=2[CH2:111][CH2:112][CH2:113][CH2:114][S:115]([O-:118])(=[O:117])=[O:116])[CH:90]=[CH:91][CH:92]=1)([OH:82])=[O:81].[Na+].[Na+]>>[Cl:129][C:127]1[CH:128]=[C:123]2[C:122]([CH3:140])([CH3:139])/[C:121](=[CH:120]\[CH:119]=[C:93](/[C:89]3[CH:90]=[CH:91][CH:92]=[C:87]([CH2:86][CH2:85][CH2:84][CH2:83][C:80]([O:82][N:70]4[C:74](=[O:75])[CH2:73][CH2:72][C:71]4=[O:76])=[O:81])[CH:88]=3)\[CH:94]=[CH:95]\[C:96]3[C:104]([CH3:105])([CH3:106])[C:103]4[C:98](=[CH:99][CH:100]=[C:101]([S:107]([O-:110])(=[O:108])=[O:109])[CH:102]=4)[N+:97]=3[CH2:111][CH2:112][CH2:113][CH2:114][S:115]([O-:118])(=[O:116])=[O:117])/[N:138]=[C:124]2[N:125]([CH2:130][CH2:131][CH2:132][CH2:133][S:134]([O-:137])(=[O:136])=[O:135])[CH:126]=1.[Na+:77].[Na+:77]
Reactant: CC1(C)C2=CC(Cl)=CN(CCCCS(=O)(=O)[O-])C2=N/C1=C/C=C(/C=C/C1=[N+](CCCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c2C1(C)C)c1cccc(CCCCC(=O)ON2C(=O)CCC2=O)c1
Reactant: CC1(C)C2=CC(Cl)=CN(CCCCS(=O)(=O)[O-])C2=N/C1=C/C=C(/C=C/C1=[N+](CCCCS(=O)(=O)[O-])c2ccc(S(=O)(=O)[O-])cc2C1(C)C)c1cccc(CCCCC(=O)O)c1
Agent: [Na+]
Product: CC1(C)C2=CC(Cl)=CN(CCCCS(=O)(=O)[O-])C2=N/C1=C/C=C(/C=C/C1=[N+](CCCCS(=O)(=O)[O-])c2ccc(S(=O)(=O)[O-])cc2C1(C)C)c1cccc(CCCCC(=O)ON2C(=O)CCC2=O)c1

Procedure:
Compound 50 is prepared analogously to compound 29 (Example 38), except that compound 49 is used as a starting material.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:30])[CH:7]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]=1[N+:27]([O-:29])=[O:28])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:4].[CH3:31]I.O>CN(C)C=O>[CH2:11]([O:10][C:8](=[O:9])[C:7]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]=1[N+:27]([O-:29])=[O:28])([CH3:31])[C:6]([O:5][CH2:3][CH3:4])=[O:30])[CH3:12]
Reactant: CCOC(=O)C(C(=O)OCC)c1cccc(C(=O)c2ccccc2)c1[N+](=O)[O-]
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C(=O)OCC)c1cccc(C(=O)c2ccccc2)c1[N+](=O)[O-]
Reaction time: 0.08 h

Procedure:
A slurry of 0.6 g (0.012 mole) of 50% sodium hydride/oil (washed, petroleum ether) in a 10 ml dimethylformamide was treated dropwise with a solution of 3.6 g (0.009 mole) of 2-(3-benzoyl-2-nitrophenyl)propanedioic acid diethyl ester in 20 ml of dimethylformamide. The mixtue was stirred for 5 min and the 4 ml (9.1 g, 0.065 mole) of methyliodide was added and the solution stirred at ambient temperature overnight. The solution was poured into 500 ml of cold water and let stand overnight. The aqueous layer was decanted and the gummy residue was dissolved in diethylether. The ether solution was washed with water and saturated sodium chloride solution, dried over sodium sulfate and concentrated to give 3.5 g (95%) of a gray solid, m.p. 102°-104° C. (recrystallized from 2-propanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:18][CH3:19])=[CH:5][C:6]2[C:15]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[C:9](=[O:16])[NH:8][C:7]=2[CH:17]=1.[CH3:20][N:21]([CH2:23][CH2:24]Cl)[CH3:22]>>[CH3:20][N:21]([CH3:22])[CH2:23][CH2:24][N:12]1[CH2:11][C:10]2[C:9](=[O:16])[NH:8][C:7]3[CH:17]=[C:3]([O:2][CH3:1])[C:4]([O:18][CH3:19])=[CH:5][C:6]=3[C:15]=2[CH2:14][CH2:13]1
Reactant: CN(C)CCCl
Reactant: COc1cc2[nH]c(=O)c3c(c2cc1OC)CCNC3
Product: COc1cc2[nH]c(=O)c3c(c2cc1OC)CCN(CCN(C)C)C3

Procedure:
In the same way as described in example 10, 0.02 m of 1,2,3,4-tetrahydro-8,9-dimethoxybenzo[c][2,7]naphthyridin-5(6H)-one was alkylated with dimethylamino ethyl chloride. Crystallization from acetonitrile gave analytical material, mp 160°-164° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([OH:13])(=O)[CH2:8][CH2:9][C:10]#[CH:11].[Cl:14][C:15]1[CH:16]=[C:17]([NH:21][CH3:22])[CH:18]=[CH:19][CH:20]=1>C(Cl)Cl>[Cl:14][C:15]1[CH:16]=[C:17]([N:21]([CH3:22])[C:7](=[O:13])[CH2:8][CH2:9][C:10]#[CH:11])[CH:18]=[CH:19][CH:20]=1
Reactant: CNc1cccc(Cl)c1
Reactant: C#CCCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: C#CCCC(=O)N(C)c1cccc(Cl)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
Oxalyl chloride (89 μL, 1.02 mmol) was added to a solution of pent-4-ynoic acid (50 mg, 0.51 mmol) in DCM (3 mL). The reaction mixture was stirred at 50° C. for 1 hour, was cooled to 0° C. and was added dropwise to a solution of (3-chloro-phenyl)-methyl-amine (62 μL, 0.51 mmol). The reaction mixture was stirred for 2 hours at room temperature. After evaporation of the solvent, the crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 100 mg (0.45 mmol, 88%) of pent-4-ynoic acid (3-chloro-phenyl)-methyl-amide.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([NH:20][CH3:21])=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:22]=1.[C:23]([C:25]1([OH:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)#[CH:24]>>[OH:31][C:25]1([C:23]#[C:24][C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][N:8]4[C:12]([C:18]([NH:20][CH3:21])=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]4[C:6]=3[CH:22]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CNC(=O)c1c(C(N)=O)nc2n1CCOc1ccc(Br)cc1-2
Reactant: C#CC1(O)CCCCC1
Product: CNC(=O)c1c(C(N)=O)nc2n1CCOc1ccc(C#CC3(O)CCCCC3)cc1-2

Procedure:
Similar to as described in General Procedure E, reaction of 10-bromo-N3-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2,3-dicarboxamide with 1-ethynylcyclohexanol gave the titled compound. M+H=409.2.
Reaction SMILES: [N:1]([C@H:4]1[CH2:9][O:8][C@@H:7]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][C@@H:5]1[OH:23])=[N+]=[N-]>CO>[NH2:1][C@H:4]1[CH2:9][O:8][C@@H:7]([CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:6][C@@H:5]1[OH:23]
Reactant: [N-]=[N+]=N[C@H]1CO[C@@H](C(c2ccccc2)c2ccccc2)C[C@@H]1O
Solvent: CO
Product: N[C@H]1CO[C@@H](C(c2ccccc2)c2ccccc2)C[C@@H]1O
Yield: 100.8 %

Procedure:
(2R,4S,5S)-5-Azido-2-benzhydryl-tetrahydropyran-4-ol (0.05 g, 0.14 mmol) was hydrogenated (Procedure G) to yield (2R,4S,5S)-5-amino-2-benzhydryl-tetrahydropyran-4-ol 0.04 g (97%, [α]D=(+) 66.2, c=1, MeOH).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:13](=[O:15])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[BH4-].[Na+]>C(O)C>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:4]=[C:5]([CH:13]([OH:15])[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: CC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 1.5 h
Yield: 93.3 %

Procedure:
To a solution of 17.8 g of 3',5'-bis(trifluoromethyl) acetophenone in 300 mL of absolute ethanol was added 1.32 g of NaBH4 while stirring in an ice bath. After 30 min the ice bath was removed and stirring was continued for an additional 1.5 h. The reaction was quenched using excess 2N HCl and the solvent was mostly evaporated in vacuo. The residue was partitioned between ethyl acetate and aq. HCl and the aqueous layer was extracted again with ethyl acetate. The separate organic layers were sequentially washed with brine, then combined, dried over MgSO4 and evaporated to provide 16.74 g of the title compound as a white solid after vacuum drying.
Reaction SMILES: C([O:8][C:9](=[O:37])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=1[N:18]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20])C1C=CC=CC=1>C(Cl)Cl.CCCCCC>[CH2:30]([N:18]([S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[C:11]1[C:12]([O:16][CH3:17])=[CH:13][CH:14]=[CH:15][C:10]=1[C:9]([OH:37])=[O:8])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccccc2)c2c(OC)cccc2C(=O)OCc2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCCC
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)c2c(OC)cccc2C(=O)O)cc1
Yield: 90.3 %

Procedure:
In the same manner as described in Example 19, 1.86 g (3.6 mmol) of the product of Example 97 provided 1.39 g (90%) of the desired carboxylic acid as a white solid after trituration with CH2Cl2 :hexane (1:4). CI Mass Spec 428.1 (M+H).
Reaction SMILES: [OH-].[Na+].[CH:3]([N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10])=[CH2:4].[C:11](OC=C)(=[O:13])[CH3:12]>CO>[CH:3]([N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10])=[CH2:4].[CH:11]([OH:13])=[CH2:12]
Reactant: C=COC(C)=O
Agent: C=CN1CCCC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=CO
Temperature: 25 °C
Reaction time: 48 h

Procedure:
0.19 g (4.8 mmole) of sodium hydroxide was dissolved in 4.7 ml of methanol. The resultant solution was added to 800 mg of 1-vinylpyrrolidone/vinyl acetate copolymer (V). The mixture was stirred at room temperature for 48 hours. The hydrolyzed product, 1-vinyl pyrrolidone/vinyl alcohol copolymer was precipitated out in 10-fold excess of diethyl ether three times. The solid was then dried under vacuum at 60° C. overnight to yield 320 mg of 1-vinyl pyrrolidone/vinyl alcohol copolymer (VI). IR (KBr pellet): 3467.7, 2949.0, 1654.0, 1441.0, 1291.5, 649.9 cm-1: C-13 NMR, (D20) :17.6, 31.3, 33.6-35.1, 38.0-40.0, 42.6-45.9, 64.5-65.8.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17](Br)[CH:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[CH2:26][CH2:27]OC.[Cl-].[Li+].C([Sn](CCCC)(CCCC)C=C)CCC.[OH-].[Na+]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([CH:26]=[CH2:27])[CH:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCOC
Reactant: COc1ccc(C[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1Br
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Li+]
Product: C=Cc1cc(C[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)ccc1OC
Temperature: 25 °C
Yield: 83 %

Procedure:
To the solution of 0.5 g (1.3 mmol) (R)-2-(3-bromo-4-methoxy-benzyl)-morpholine-4-carboxylic acid tert-butyl ester (see Example 9) in 15 mL 1,2-dimethoxyethane 45 mg (39 μmol) tetrakis(triphenylphosphine)palladium(0) and 0.17 g (3.9 mmol) lithium chloride were added. After the addition of 0.45 mL tributyl(vinyl)tin the reaction was stirred under reflux for 23 h. After cooling down to room temperature the reaction suspension was poured on 1N aqueous sodium hydroxide solution and was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was chromatographed using MPLC and tert-butyl methyl ether: n-heptane (1:1 v/v) as eluant to give the compound as a colorless oil (83%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:16](Cl)(=[O:19])[CH2:17][CH3:18]>CN(C)C1C=CN=CC=1.ClCCl>[C:16]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:19])[CH2:17][CH3:18]
Reactant: Oc1ccc(Br)cc1
Reactant: CCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)Oc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Bromophenol (259 g) and 4-dimethylaminopyridine (1.5 g) were dissolved in dichloromethane (1000 ml), the solution was cooled in an ice bath and triethylamine (219 ml) was added portionwise such that the reaction temperature was kept below 20° C. Propionyl chloride (137 ml) was then added over 1 hour and the resulting mixture was stirred at room temperature for 2 hours. The mixture was washed with water followed by brine, then dried (anhydrous magnesium sulphate) and the solvent removed under reduced pressure to yield 4-bromophenyl propionate (344 g) as a green oil.
Reaction SMILES: C(ON1CC1C(OCC)=O)C=C.[CH2:13]([O:16][N:17]1[CH2:19][CH:18]1[C:20]([NH2:22])=[O:21])[CH:14]=C>>[CH2:13]([O:16][N:17]1[CH2:19][CH:18]1[C:20]([NH2:22])=[O:21])[CH3:14]
Reactant: C=CCON1CC1C(N)=O
Agent: C=CCON1CC1C(=O)OCC
Product: CCON1CC1C(N)=O

Procedure:
ethyl 1-allyloxyaziridine-2-carboxylate (see Example 5e) 1-allyloxyaziridine-2-carboxamide; m.p. 57°-60° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:16][CH2:17][OH:18]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([S:8][CH2:16][CH2:17][OH:18])[CH:5]=[CH:6][CH:7]=1
Reactant: OCCBr
Reactant: Sc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: OCCSc1cccc(Br)c1
Temperature: 50 °C
Yield: 89.4 %

Procedure:
A solution of 3-bromobenzenethiol (5.00 g, 26.4 mmol) in anhydrous DMF (30 mL) was treated with Cs2CO3 (17.2 g, 52.8 mmol) and 2-bromoethanol (3.90 g, 31.7 mol) and heated to about 50° C. under nitrogen for 12 h. DMF was distilled out completely and the residue was dissolved in DCM and washed with water and brine. Organic layer was dried over Na2SO4, evaporated and purified by column chromatography (silica) to afford 5.5 g (90%) of the title compound as pale yellow solid.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][N:7]1[C:11]([CH3:12])=[CH:10][C:9]([CH:13]=O)=[C:8]1[CH3:15])(=[O:3])[CH3:2].Cl.NO.[N:19]1C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([NH:4][CH2:5][CH2:6][N:7]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]#[N:19])=[C:8]1[CH3:15])(=[O:3])[CH3:2]
Reactant: c1ccncc1
Reactant: CC(=O)NCCn1c(C)cc(C=O)c1C
Agent: Cl
Agent: NO
Solvent: Cc1ccccc1
Product: CC(=O)NCCn1c(C)cc(C#N)c1C

Procedure:
5.2 g (0.025 mol) of 1-(2-acetylaminoethyl)-2,5-dimethylpyrrole-3-aldehyde, 1.75 g (0.025 mol) of hydroxylamine hydrochloride and 2 ml (0.025 mol) of pyridine are heated under reflux in 25 ml of toluene for 1.5 hours. After the mixture has been concentrated, the residue is taken up in water, the mixture is extracted with methylene chloride and the product is recrystallized from toluene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([CH:8]2[CH2:17][C:16]3[N:15]=[N:14][CH:13]=[C:12]([CH3:18])[C:11]=3[C:10](=O)[CH2:9]2)[CH:7]=1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].Cl.Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([CH:8]2[CH2:17][C:16]3[N:15]=[N:14][CH:13]=[C:12]([CH3:18])[C:11]=3[C:10](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:9]2)[CH:7]=1
Reactant: Cc1cnnc2c1C(=O)CC(c1cc(Cl)ccc1F)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Product: Cc1cnnc2c1C(=NNC(=N)N)CC(c1cc(Cl)ccc1F)C2
Temperature: 110 °C
Reaction time: 2 h
Yield: 158.6 %

Procedure:
To a mixture of 7-(5-chloro-2-fluorophenyl)-4-methyl-5,6,7,8-tetrahydrocinnolin-5-one (0.33 g) and aminoguanidine hydrochloride (0.133 g) in ethanol (4 ml) was added concentrated hydrochloric acid (0.1 ml), and the mixture was stirred at 110° C. (bath) for 2 hours. The reaction solution was cooled to room temperature, and the crystals were filtered and dried to give 7-(5-chloro-2-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydrocinnoline hydrochloride (Compound 175) (0.345 g) as blue gray crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH:16]([CH3:18])[CH3:17])=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[CH:8][CH:7]([CH3:15])[CH2:6]2.[Br:19]Br>ClCCl>[Br:19][C:8]1[CH:7]([CH3:15])[CH2:6][C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[C:4]=2[CH:16]([CH3:18])[CH3:17])[CH:9]=1
Reactant: COc1cc2c(c(C(C)C)c1OC)CC(C)C=C2
Reactant: BrBr
Solvent: ClCCl
Product: COc1cc2c(c(C(C)C)c1OC)CC(C)C(Br)=C2
Temperature: 55 °C
Reaction time: 0.25 h
Yield: 91 %

Procedure:
Compound 12 (3.00 g, 12.2 mmol) was dissolved in 20 mL of dichloromethane and bromine (1.95 g, 12.2 mmol) in 5 ml of dichloromethane was added dropwise with stirring over a period of 15 min. The solvent was evaporation and the residue was taken up in 15 ml of DMF. The DMF solution was warmed to 50-60° C. for 1 h. The reaction mixture was poured onto ice and stirred. The solid product was filtered, dried and recrystallized from a concentrated petroleum ether solution to give 3.60 g (11.1 mmol, 91%) of 13 as nearly colorless microcrystalline plates: mp 71-72° C.; 1H NMR 1.09 (d, J=6.95, 3H), 1.32 (d, J=7.2 Hz, 6H), 2.4-3.2 (m, 3H), 3.49 (m, 1H), 3.80 (s, 3H), 3.82 (s, 3H), 6.43 (s, 1H), 6.64 (s, 1H). Anal. (C16H21BrO2) C, H.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Cl[C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][N:22]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[CH:13]=[C:14]([CH:20]=[CH:21][N:22]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1
Reactant: Cc1ccc(B(O)O)cc1
Product: CCOC(=O)c1ccnc(-c2ccc(C)cc2)c1

Procedure:
4-Methylphenylboronic acid (161 mg) and ethyl 2-chloroisonicotinate (200 mg) were treated in the same manner as in Preparation Example 1 to obtain the title compound.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][CH:8]([C@H:10]1[CH2:15][N:14]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13](=O)[C:12](=O)[NH:11]1)[CH3:9]>C1COCC1>[CH3:9][CH:8]([C@@H:10]1[NH:11][CH2:12][CH2:13][N:14]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15]1)[CH3:7]
Reactant: CC(C)[C@H]1CN(Cc2ccccc2)C(=O)C(=O)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)[C@H]1CN(Cc2ccccc2)CCN1
Temperature: 0 °C
Yield: 77.9 %

Procedure:
LAH (1.87 g, 49.3 mmol) was suspended in 60 mL of THF with stirring and cooled to 0° C. under an inert atmosphere. (5S)-5-(1-methylethyl)-1-(phenylmethyl)-2,3-piperazinedione (2.43 g, 9.87 mmol) was dissolved in 50 mL of THF and added dropwise via addition funnel over 20 min. The funnel was rinsed with an additional 10 mL of THF. The reaction was warmed to rt and stirred for 2 days. The reaction was quenched by the careful sequential addition of 1.9 mL of H2O, 1.9 mL of 1N NaOH (aq.), and 5.7 mL of H2O. The slurry was stirred for 30 min and filtered. The solids were washed with DCM. The filtrate was concentrated in vacuo. Purification by flash chromatography afforded the title compound of step B (1.68 g, 7.69 mmol, 78%). 1H NMR (400 MHz, DMSO-d6) δ 7.33-7.18 (m, 5H), 3.40 (AB, ΔνAB=34.5 Hz, JAB=13.2 Hz, 2H), 2.78 (m, 1H), 2.71-2.51 (m, 3H), 2.28 (m, 1H), 1.88-1.72 (m, 2H), 1.63 (t, J=10.3 Hz, 1H), 1.45 (m, 1H), 0.83 (d, J=6.8 Hz, 3H), 0.79 (d, J=6.8 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:16])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[N:8]([CH2:13][CH3:14])[C:7]2=[O:15].[C:17]([NH2:21])([CH3:20])([CH3:19])[CH3:18]>CN1C(=O)CCC1>[Br:1][C:2]1[C:3]([F:16])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:21][C:17]([CH3:20])([CH3:19])[CH3:18])[N:8]([CH2:13][CH3:14])[C:7]2=[O:15]
Reactant: CCn1c(Cl)nc2c(Br)c(F)ccc2c1=O
Reactant: CC(C)(C)N
Solvent: CN1CCCC1=O
Product: CCn1c(NC(C)(C)C)nc2c(Br)c(F)ccc2c1=O
Yield: 92.6 %

Procedure:
A solution of 8-bromo-2-chloro-3-ethyl-7-fluoroquinazolin-4(3H)-one (512c, 197 mg, 0.645 mmol), tert-butylamine (Aldrich; 1.5 mL, 14.27 mmol), and NMP (0.5 mL) was heated in a sealed microwave vial at 100° C. for 30 min. The reaction mixture was then partitioned between EtOAc (60 mL) and water (40 mL). The organic layer was separated and sequentially washed water (40 mL) and brine (40 mL), then dried over Na2SO4, filtered, and concentrated in vacuo to give as a yellow solid. The combined aqueous layers were subsequently extracted with DCM (2×30 mL), and the combined organic extracts were then sequentially washed with water (2×40 mL) and brine (40 mL), dried over Na2SO4, filtered, and concentrated in vacuo to provide a yellow solid. Combination of the two batches of isolated solids afforded 8-bromo-2-(tert-butylamino)-3-ethyl-7-fluoroquinazolin-4(3H)-one (204.3 mg, 0.597 mmol, 93% yield) as a light-yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.05 (1H, dd, J=8.8, 6.1 Hz), 6.89 (1H, t, J=8.5 Hz), 4.56 (1H, br. s.), 4.05 (2H, q, J=7.2 Hz), 1.62 (9H, s), 1.33 (3H, t, J=7.2 Hz). 19F NMR (376 MHz, CDCl3) δ ppm −96.81 (1F, s). m/z (ESI, +ve) 341.9/343.9 (M+H)+.
Reaction SMILES: [OH-].[Na+].[CH:3](=O)[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[OH:6].[ClH:12].Cl.[O:14]([CH2:16][CH:17]([F:21])[CH2:18][NH:19][CH3:20])[NH2:15]>C(O)C>[ClH:12].[OH:6][C:5]1[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=1[CH:3]=[N:15][O:14][CH2:16][CH:17]([F:21])[CH2:18][NH:19][CH3:20]
Reactant: CNCC(F)CON
Reactant: O=Cc1ccccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CNCC(F)CON=Cc1ccccc1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2.5 ml of 1N sodium hydroxide solution and 305 mg (2.5 mmol) of salicylaldehyde are added to a solution of 488 mg (2.5 mmol) of N-(3-aminoxy-2-fluoropropyl)-methylamine dihydrochloride in 10 ml of ethanol and the mixture is stirred for 24 hours at room temperature. The reaction mixture is then concentrated to dryness by evaporation and the residue is crystallised from ethanol/ether.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[NH:25][N:24]=[C:23]([CH:26]([OH:28])[CH3:27])[CH:22]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:29][N:30]([CH3:35])[CH2:31][C:32](O)=[O:33].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:29][N:30]([CH3:35])[CH2:31][C:32]([O:28][CH:26]([C:23]1[CH:22]=[C:21]([C:19](=[O:20])[NH:18][C@@H:16]([CH3:17])[CH2:15][N:12]2[CH:13]=[CH:14][C:10]([C:4]3[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[CH:3]=3)=[N:11]2)[NH:25][N:24]=1)[CH3:27])=[O:33]
Reactant: CC(O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)[nH]n1
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(OC(=O)CN(C)C)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)[nH]n1
Temperature: 25 °C
Yield: 23.9 %

Procedure:
A solution of N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(1-hydroxyethyl)-1H-pyrazole-5-carboxamide of Example 56 (90 mg, 0.225 mmol) in 2 ml of DCM was added to a suspension of N,N-dimethylglycine (47 mg, 0.45 mmol), DIPEA (0.13 ml; 0.75 mmol), anhydrous HOBt (61 mg, 0.45 mmol) and EDCI (87 mg, 0.45 mmol) in 2 ml of DCM. The reaction mixture was stirred at RT over three nights. The mixture was diluted with DCM and washed with water. Organic phase was dried over Na2SO4, filtered and evaporated. Crude product was purified twice by CombiFlash (1st column: silica, eluent: 0-10% MeOH in DCM; 2nd column: alumina, eluent: 0-10% MeOH in DCM) to obtain 26 mg (36%) of the title compound. 1H-NMR (400 MHz; CDCl3): δ 1.22 (d, 3H), 1.66 (d, 3H), 2.35 (d, 6H), 3.20 (d, 2H), 4.25-4.33 (m, 1H), 4.37-4.45 (m, 1H), 4.52-4.64 (m, 1H), 6.00 (q, 1H), 6.60 (m, 1H), 6.80 (s, 1H), 7.50 (dd, 1H), 7.67 (m, 1H), 7.74-7.87 (m, 2H), 8.09 (d, 1H), 11.6 (bs, 1H).
Reaction SMILES: FC1C=C2C(=CC=1)NC(=O)C2.N1C=CN=C1C(N)=O.[NH2:20][CH2:21][C@@H:22]([OH:30])[CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C(N(CC)CC)C>C(#N)C.O1CCCC1>[NH2:20][CH2:21][C@H:22]([OH:30])[CH2:23][N:24]1[CH2:25][CH2:26][O:27][CH2:28][CH2:29]1
Reactant: NC[C@@H](O)CN1CCOCC1
Agent: NC(=O)c1ncc[nH]1
Agent: O=C1Cc2cc(F)ccc2N1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NC[C@H](O)CN1CCOCC1
Temperature: 60 °C

Procedure:
A 0.25 L flask fitted with a thermometer, condenser, magnetic stirring, and nitrogen inlet was charged with 4.92 g 5-Fluorooxindole, 7.0 g Imidazole amide, 15.5 g (R)-1-Amino-3-(4-morpholinyl)-2-propanol, 9.78 g Triethylamine and 88 ml Tetrahydrofuran. The mixture was heated to 60° C. for 16.5 hours. The reaction is cooled to ambient temperature and filtered. The solids obtained are slurried (3) three successive times in acetonitrile at 11 ml/g, dried in vacuo for 3.6 g (25.25%). [HPLC, Hypersil BDS, C-18, 5μ, (6:4), Acetonitrile: 0.1M Ammonium Chloride, PHA-571437=4.05 min.] H1NMR (DMSO): δ 10.86 (1H,bs); 7.75 (1H,d); 7.70 (1H,s); 7.50 (1H,m); 6.88 (2H,m); 4.72 (1H,bs); 3.78 (1H,bs); 3.56 (4H,m) 3.32 (6H,m); 3.15 (1H,m); 2.43 (8H,bm).