Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:20][NH:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:33][CH2:32][NH:31][CH2:30]2)=[CH:25][CH:24]=1>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:31]4[CH2:32][CH2:33][CH:29]([C:26]5[CH:27]=[CH:28][C:23]([CH2:22][NH:21][CH3:20])=[CH:24][CH:25]=5)[CH2:30]4)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CNCc1ccc(C2CCNC2)cc1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Product: CNCc1ccc(C2CCN(c3cc4c(cc3F)c(=O)c(C(=O)O)cn4C3CC3)C2)cc1
Yield: 85 %

Procedure:
Starting from 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.80 g, 3.0 mmol) and N-methyl-4-(3-pyrrolidinyl)benzenemethanamine, a procedure analogous to that given in Example 1 provided the title compound (1.11 g, 85%) as an off-white solid, mp 235°-237° C.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:6]=1[C:15](=[O:17])[CH3:16])(=O)C.[OH-].[K+].O>C(O)C>[NH2:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:6]=1[C:15](=[O:17])[CH3:16]
Reactant: COc1cc(NC(C)=O)c(C(C)=O)c(OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(N)c(C(C)=O)c(OC)c1
Yield: 58.4 %

Procedure:
A mixture of (2'-acetylamino-4',6'-dimethoxyphenyl)ethanone (compound 75-3, prepared in Preparation 75) (0.237 g, 1.0 mmol), potassium hydroxide (0.2 g, 3.57 mmol), water (0.2 ml), and ethanol (2 ml) is heated to reflux for one hour. The solvent is distilled under reduced pressure, and the residue is extracted with dichloromethane. The extract is washed with water, dried, and the solvent is removed to yield a crystalline residue. Recrystallization from ethyl acetate gives (2'-amino-4',6'-dimethoxyphenyl)ethanone as a crystalline solid (0.114 g, 58%, m.p.=104°-105° C.).
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([C:11]([C:13]2[CH:14]=[N:15][O:16][C:17]=2[C:18]2[CH:23]=[CH:22][C:21]([S:24]([F:29])([F:28])([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[O:12])[CH2:10][CH2:9]1.Cl>ClCCl>[C:14]([CH:13]([C:11]([CH:8]1[CH2:9][CH2:10]1)=[O:12])[C:17]([C:18]1[CH:19]=[CH:20][C:21]([S:24]([F:27])([F:29])([F:25])([F:26])[F:28])=[CH:22][CH:23]=1)=[O:16])#[N:15]
Reactant: O=C(c1cnoc1-c1ccc(S(F)(F)(F)(F)F)cc1)C1CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CC(C(=O)c1ccc(S(F)(F)(F)(F)F)cc1)C(=O)C1CC1

Procedure:
Triethylamine (0.73 g) was added to a stirred solution of 4-cyclopropylcarbonyl-5-(4-pentafluorosulphanylphenyl)isoxazole (Compound 2, 0.4 g) in dichloromethane. After 16 hours the solution was washed (2M hydrochloric acid), dried (magnesium sulphate) and evaporated to dryness. The residue was purified by chromatography eluting with ethyl acetate/hexane to give a residue which was suspended in dichloromethane and shaken with hydrochloric acid until dissolved. The organic phase was evaporated and triturated with hexane to give 2-cyano-3-cyclopropyl-1-(4-pentafluorosulphanylphenyl)propan-1,3-dione as a white solid (Compound 3, m.p.108-110° C.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][CH2:21][CH2:22][C:23]1[O:24][C:25]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:26]([C:28](O)=[O:29])[N:27]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:28]([C:26]3[N:27]=[C:23]([CH2:22][CH2:21][O:20][CH3:19])[O:24][C:25]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:29])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Reactant: COCCc1nc(C(=O)O)c(-c2ccccc2)o1
Product: COCCc1nc(C(=O)Nc2cnn(Cc3ccc(C(C)=O)o3)n2)c(-c2ccccc2)o1

Procedure:
Following general procedure A followed by B, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-(2-methoxy-ethyl)-5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH:36]([CH3:38])[CH3:37])[N:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH:36]([CH3:38])[CH3:37])[N:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(C)Oc1cccc(Br)n1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(OC(C)C)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 290, Step 1, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-6-isopropoxy-pyridine.
Reaction SMILES: Cl.O.N[CH:4]([CH2:8]C1C=CC=CC=1)[C:5](O)=O.[CH2:15]([O:18][C:19]1[CH:30]=[CH:29][C:22]([CH2:23][C@@H:24]([C:26]([OH:28])=[O:27])[NH2:25])=[CH:21][CH:20]=1)[C:16]#[CH:17]>[OH-].[Na+].CO>[CH2:8]([O:27][C:26](=[O:28])[CH:24]([NH2:25])[CH2:23][C:22]1[CH:29]=[CH:30][C:19]([O:18][CH2:15][C:16]#[CH:17])=[CH:20][CH:21]=1)[C:4]#[CH:5]
Reactant: NC(Cc1ccccc1)C(=O)O
Reactant: C#CCOc1ccc(C[C@H](N)C(=O)O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C#CCOC(=O)C(N)Cc1ccc(OCC#C)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The propargyl ester (1.6 g, 5.5 mmol) from the previous step was dissolved in a mixture of aqueous 2 N NaOH (14 mL) and MeOH (10 mL). After stirring for 1.5 h at room temperature, the pH was adjusted to 7 by adding conc. HCl. Water (20 mL) was added and the mixture was kept at 4° C. overnight. The precipitate was filtered, washed with ice-cold H2O, and dried under vacuum yielding, 1.23 g (90%) of 1 in FIG. 11 (2-Amino-3-phenylpropionic acid (1) (also known as p-propargyloxyphenylalanine) as a white solid. 1H NMR (400 MHz, D2O) (as the potassium salt in D2O) δ 7.20 (d, J=8.8 Hz, 2H), 6.99 (d, J=8.8 Hz, 2H), 4.75 (s, 2H), 3.50 (dd, J=5.6, 7.2 Hz, 1H), 2.95 (dd, J=5.6, 13.6 Hz, 1H), 2.82 (dd, J=7.2, 13.6 Hz, 1H); 13C NMR (100 MHz, D2O) δ 181.3, 164.9, 155.6, 131.4, 130.7, 115.3, 57.3, 56.1, 39.3, HRMS (CI) m/z 220.0969 [C12H13NO3 (M+1) requires 220.0968].
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH2:17][OH:18])[CH2:15][OH:16])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH2:15][O:16][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:17][O:18][S:28]([CH3:27])(=[O:30])=[O:29])=[CH:10][CH:9]=1)=[O:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(CO)CO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccc(C(COS(C)(=O)=O)COS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of [4-(2-hydroxy-1-hydroxymethyl-ethyl)-phenyl]-carbamic acid tert-butyl ester (267 mg, 1.00 mmol, as prepared in the previous step) in DCM (10 mL) and Et3N (0.35 mL, 2.5 mmol), methanesulfonyl chloride (MsCl) (0.15 mL, 2.0 mmol) was added dropwise at 0° C. The resulting mixture was stirred at RT for 30 min, diluted with DCM (10 mL) and washed with satd NaHCO3 (20 mL). The organic layer was separated, dried (Na2SO4) and concentrated to afford methanesulfonic acid 2-(4-tert-butoxycarbonylamino-phenyl)-3-methanesulfonyloxy-propyl ester, which was dried in vacuo and directly used in next step: Mass spectrum, (ESI, m/z): Calcd. for C16H25NO8S2, 446.1 (M+Na). found 446.0.
Reaction SMILES: C(O)CCC#C.IC1SC=CC=1.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]#[C:19][CH2:20][CH2:21][CH:22]=[O:23]>>[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]#[C:19][CH2:20][CH2:21][CH2:22][OH:23]
Reactant: O=CCCC#Cc1cccs1
Agent: C#CCCCO
Agent: Ic1cccs1
Product: OCCCC#Cc1cccs1

Procedure:
5-thienyl-4-pentyn-1-ol was prepared from 4-pentyn-1-ol and 2-iodothiophene as in Example 15 and converted into 5-thienyl-4-pentyn-1-al as in Example 9.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[CH:5]=[CH:4][N:3]1[C:9]([O:11][CH2:12][C:13]1[CH:18]=CC=C[CH:14]=1)=[O:10].C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C.[H][H]>[Pd].C(OCC)(=O)C>[CH3:14][CH:13]([CH3:18])[CH2:12][O:11][C:9]([N:3]1[CH2:4][CH2:5][C:6](=[O:8])[CH2:7][CH:2]1[CH3:1])=[O:10]
Reactant: CC1CC(=O)C=CN1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Product: CC(C)COC(=O)N1CCC(=O)CC1C
Yield: 20.9 %

Procedure:
A mixture of 1.1 g of the crude 2(R,S)-methyl-1(benzyloxycarbonyl)-2,3-dihydro-4-pyridone, 200 mL of ethyl acetate, 1 g of di-tert-butyldicarbonate and 1 g of 10% palladium on carbon was shaken under 55 psi of hydrogen for 24 h. The mixture was filtered, concentrated under reduced pressure, and purified by low pressure chromatography on silica gel eluting with 40% ethyl acetate in hexane. There was obtained first 0.20 g of (±)-1-(2,2-dimethylethoxycarbonyl)-2-methyl-4-oxopiperidine: 1H NMR (400 MHz, CDCl3) 4.65 (m, 1H), 4.2 (m, 1H), 3.3 (m, 1H), 2.65 (dd, 1H), 2.45 (m, 1H), 2.3 (m, 1H), 2.2 (dd, 1H), 1.45 (s, 9H), 1.14 (d, 3H). Later fractions gave 0.50 g of the (±)-1-(2,2-dimethylethoxycarbonyl)-2-methyl-4-hydroxypiperidine: 1H NMR (400 MHz, CDCl3) 4.3 (m, 1H), 4.15 (t, 1H), 3.8 (m, 1H), 3.25 (m, 1H), 2.15 (s, 1H), 2.8 (m, 1H), 1.65 (m, 3H), 1.42 (s, 3H), 1.25 (d, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[CH:45][N:44]=[C:43]([CH:47]3[CH2:51][CH2:50][CH2:49][CH2:48]3)[CH:42]=2)[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[CH:45][N:44]=[C:43]([CH:47]3[CH2:48][CH2:49][CH2:50][CH2:51]3)[CH:42]=2)[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(C3CCCC3)c2)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Product: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccnc(C3CCCC3)c2)c1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (281 mg, 0.75 mmol) and 3-[3-(2-cyclopentyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K61) (274 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow foam (410 mg, 82%).
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]([CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])=[CH:5][CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:21])=[CH:15][C:16]([O:18]CC)=[O:17])=[CH:10][CH:9]=1>C(O)(C)C>[CH3:3][C:4]([CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])=[CH:5][CH:6]=[CH:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]([CH3:21])=[CH:15][C:16]([OH:18])=[O:17])=[CH:12][CH:13]=1
Reactant: CCOC(=O)C=C(C)c1ccc(C=CC=C(C)CCC=C(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC(C)=CCCC(C)=CC=Cc1ccc(C(C)=CC(=O)O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62.3 %

Procedure:
5.4 g of potassium hydroxide was dissolved in 100 ml of isopropanol. 14 g of ethyl 3-[4-(4,8-dimethyl-1,3,7-nonatrienyl)phenyl]-2-butenoate was added to the solution under heating, reflux and stirring. After 30 min, the resulting solution was poured into ice/water and extracted with 100 ml of n-hexane. The aqueous layer was made acidic with dilute hydrochloric acid, extracted with ethyl ether and washed with water. After drying over magnesium sulfate, the product was concentrated and the resulting concentrate was crystallized from n-hexane to obtain 8 g of intended 3-[4-(4,8-dimethyl-1,3,7-nonatrienyl)phenyl]-2-butenoic acid as light yellow crystals.
Reaction SMILES: [CH3:1][C:2]([C:5]1[NH:9][C:8]2[CH2:10][CH2:11][C:12](=[O:13])[C:7]=2[N:6]=1)([CH3:4])[CH3:3].[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1.C1(C)C=CC=CC=1.[NH4+].[Cl-]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+]>[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][N:6]2[C:7]3[C:12](=[O:13])[CH2:11][CH2:10][C:8]=3[N:9]=[C:5]2[C:2]([CH3:1])([CH3:3])[CH3:4])=[CH:17][CH:16]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: CC(C)(C)c1nc2c([nH]1)CCC2=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CC(C)(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(=O)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.8 %

Procedure:
Tetrabutylammonium bromide (317 mg) was added to a stirred mixture of Intermediate 32 (350 mg), 4-chlorobenzyl bromide (444 mg) in sodium hydroxide 15% aq. (10 mL) and toluene (15 mL). The RM was stirred at room temp under nitrogen atm. for 16 hours. Sat. NH4Cl aq. solution (10 mL) was added and the mixture was extracted with EtOAc (2×50 ml). The organics were combined, dried (hydrophobic frit) and concentrated under vacuum The residue was purified on silica (50 g) using a cyclohexane:ethyl acetate 0-100% gradient. The desired fractions were combined and concentrated under vacuum to give the title compound (421 mg). LC/MS MH+ 303, Rt 2.51 min (5 minute run).
Reaction SMILES: [CH2:1]([N:3]([CH2:23][CH3:24])[CH2:4][CH:5]([N:7]1[C:20]2[CH:19]=[C:18]([C:21]#[N:22])[CH:17]=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:6])[CH3:2].C(N(CC)CC)C.[SH2:32]>N1C=CC=CC=1>[CH2:23]([N:3]([CH2:1][CH3:2])[CH2:4][CH:5]([N:7]1[C:20]2[CH:19]=[C:18]([C:21](=[S:32])[NH2:22])[CH:17]=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:6])[CH3:24]
Reactant: S
Reactant: CCN(CC)CC(C)N1c2ccccc2Sc2ccc(C#N)cc21
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCN(CC)CC(C)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 10-[(2RS)-1-diethylamino-2-propyl]-2-phenothiazinecarbonitrile (8.44 g) and triethylamine (3.5 cc) in anhydrous pyridine (60 cc) is saturated by bubblin9 in hydrogen sulphide for 5 hours at 25° C. The clear solution obtained is kept stirred for 12 hours at 25° C., and the mixture is then outgassed by bubbling through nitrogen for 90 minutes. The reaction mixture i diluted with ethyl acetate (500 cc) and washed with distilled water (8×200 cc). The organic phase is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa). The residue is purified by chromatography on a column of basic alumina (0.05-0.16 mm) (height: 31 cm; diameter: 2.6 cm), eluting with mixtures of cyclohexane and ethyl acetate in proportions (by volume) of 80:20 (5 liters) and 50:50 (5 liters) and collecting 100-cc fractions. Fractions 4 to 90 are combined and concentrated under reduced pressure (30 mm Hg; 4 kPa) to give 10-[(2RS)-1-diethylamino-2-propyl]-2-phenothiazinecarbothioamide (8.54 g) in the form of an orange-yellow product of honey-like consistency.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][Si](C)(C)C)[CH:5]=[CH:4][N:3]=1.I[C:15]1[NH:19][C:18]([CH:20]([CH3:22])[CH3:21])=[N:17][CH:16]=1>>[CH:20]([C:18]1[NH:17][CH:16]=[C:15]([C:9]#[C:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)[N:19]=1)([CH3:22])[CH3:21]
Reactant: CC(C)c1ncc(I)[nH]1
Reactant: Cc1cc(C#C[Si](C)(C)C)ccn1
Product: Cc1cc(C#Cc2c[nH]c(C(C)C)n2)ccn1

Procedure:
4-(2-Isopropyl-1H-imidazol-4-ylethynyl)-2-methyl-pyridine (II-2) [MS: m/e=226.4 (M+H+)] was prepared in analogy to the method as described in example II-1, method A2, step 3 from 2-methyl-4-trimethylsilanylethynyl-pyridine and 5-iodo-2-isopropyl-1H-imidazole.
Reaction SMILES: C[CH2:2][N:3](C(C)C)C(C)C.[C:10]([C:14]1[N:18]([CH2:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:17]2[CH:26]=[CH:27][C:28]([S:30]([N:33]3[CH:37]=[CH:36][C:35]([C:38]([OH:40])=O)=[CH:34]3)(=[O:32])=[O:31])=[CH:29][C:16]=2[N:15]=1)([CH3:13])([CH3:12])[CH3:11].Cl.CN.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:10]([C:14]1[N:18]([CH2:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:17]2[CH:26]=[CH:27][C:28]([S:30]([N:33]3[CH:37]=[CH:36][C:35]([C:38]([NH:3][CH3:2])=[O:40])=[CH:34]3)(=[O:32])=[O:31])=[CH:29][C:16]=2[N:15]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C(=O)O)c3)ccc2n1CC1CCOCC1
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)c1ccn(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCOCC2)c1

Procedure:
Following the same procedure in Example 33, step A, using DIPEA (0.37 mL, 274 mg, 2.2 mmol), 1-{[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrrole-3-carboxylic acid (0.12 mmol) (see the step B in example 33 for preparation), methylamine hydrochloride (100 mg, 1.45 mmol) and HATU (150 mg, 0.40 mmol) in DMF (5 mL). The crude product was purified by MPLC using Hex/EtOAc (3:7) on silica gel to 25 mg (45%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.41-1.58 (m, 4 H), 1.61 (s, 9 H), 2.21-2.41 (m, 1 H), 2.79 (s, 3 H), 3.23-3.35 (m, 2 H), 3.83-3.96 (m, 2 H), 4.44 (d, J=7.62 Hz, 2 H), 6.63 (dd, J=3.32, 1.76 Hz, 1 H), 7.30 (dd, J=3.32, 2.34 Hz, 1H), 7.75-7.80 (m, 1 H), 7.95 (d, J=8.7 Hz, 1 H), 7.98 (dd, J=8.7, 1.5 Hz, 1 H), 8.27 (d, J=0.98 Hz, 1 H); MS (ESI) (M+H)+=458.8; Anal. Calcd for C23H30N4O4S+1.50 TFA (629.62): C, 49.60; H, 5.04; N, 8.90. Found: C, 49.53; H, 5.00; N, 9.10.
Reaction SMILES: [CH3:1][N:2]([CH3:38])[CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[S:18][C:17]3[C:16]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[N:15][C:14]([Sn](CCCC)(CCCC)CCCC)=[N:13][C:12]=3[CH:11]=2)[CH2:5][CH2:4]1.Br[C:40]1[N:45]2[CH:46]=[CH:47][N:48]=[C:44]2[CH:43]=[CH:42][CH:41]=1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[N:48]1[CH:47]=[CH:46][N:45]2[C:40]([C:14]3[N:15]=[C:16]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[C:17]4[S:18][C:10]([CH2:9][N:6]5[CH2:5][CH2:4][CH:3]([N:2]([CH3:38])[CH3:1])[CH2:8][CH2:7]5)=[CH:11][C:12]=4[N:13]=3)=[CH:41][CH:42]=[CH:43][C:44]=12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2sc(CN3CCC(N(C)C)CC3)cc2n1
Reactant: Brc1cccc2nccn12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)C1CCN(Cc2cc3nc(-c4cccc5nccn45)nc(N4CCOCC4)c3s2)CC1
Temperature: 140 °C
Yield: 62.8 %

Procedure:
A mixture of dimethyl-[1-(4-morpholin-4-yl-2-(tributylstannanyl)thieno[3,2-d]pyrimidin-6-ylmethyl)piperidin-4-yl]amine (156 mg, 0.24 mmol), 5-bromoimidazo[1,2-a]pyridine (56 mg, 0.29 mmol), Pd(PPh3)4 (28 mg, 0.02 mmol) and copper(I) iodide (55 mg, 0.29 mmol) in THF (2.5 mL) was purged with argon gas then heated at 140° C., for 20 min, in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (5 g), washed with MeOH then eluted with 2 M NH3 in MeOH. The resulting residue was purified by flash chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 10:90) to give 688 as a white solid (72 mg, 63%). LCMS (Method F): RT 3.89 min; [M+H]+ 478. 1H NMR (400 MHz, CHCl3-d): δ 9.23 (s, 1 H); 7.95 (dd, J=8.6, 1.3 Hz, 1 H); 7.77 (d, J=8.6 Hz, 1 H); 7.75 (d, J=1.3 Hz, 1 H); 7.35 (s, 1 H); 7.32-7.29 (m, 1 H); 4.07 (t, J=4.8 Hz, 4 H); 3.91 (t, J=4.8 Hz, 4 H); 3.84 (s, 2 H); 3.04 (d, J=11.25 Hz, 2 H); 2.33-2.25 (m, 6 H); 2.21-2.10 (m, 3 H); 1.84 (d, J=12.5 Hz, 2 H); 1.61 (m, 2 H)
Reaction SMILES: [N:1]([C@@H:4]1[CH2:10][CH2:9][C@@H:8]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])[O:7][CH2:6][C@H:5]1[OH:20])=[N+:2]=[N-:3].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[N:1]([C@@H:4]1[CH2:10][CH2:9][C@@H:8]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])[O:7][CH2:6][C:5]1=[O:20])=[N+:2]=[N-:3]
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](N=[N+]=[N-])[C@H](O)CO1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](N=[N+]=[N-])C(=O)CO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.1 %

Procedure:
To a solution of (3S,4R,7S)-4-azido-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-3-ol (1.4 g, 4.96 mmol, intermediate 90) in DCM (35 mL) was added Dess-Martin peridionane (2.52 g, 5.96 mmol) and the mixture stirred at room temperature for 2 hr. Aqueous saturated NaHCO3 (60 mL) and 20% sodium thiosulfate solution (50 mL) were added and the reaction mixture was stirred for 30 min until full dissolution of salts was observed. The organic layer was separated, dried over MgSO4 and solvents removed under reduced pressure. Purification via silica gel column chromatography (0-40% EtOAc/isoHexane) gave (4R,7S)-4-azido-7-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-3-one as an off-white solid (1.1 g, 82%). 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 5.38 (dd, J=10.2, 2.7 Hz, 1H), 4.62-4.49 (m, 2H), 4.31-4.22 (m, 1H), 4.08 (s, 3H), 2.31-2.17 (m, 3H), 2.15-2.04 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[N+:13]([O-])=O>C1COCC1.CCO.[Pd]>[NH2:13][C:3]1[CH:4]=[C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH:6]=[CH:7][C:2]=1[OH:1]
Reactant: CC(C(=O)O)c1ccc(O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C(=O)O)c1ccc(O)c(N)c1
Reaction time: 3 h

Procedure:
A mixture of (1) (810 mg, 1 mmol) in THF (20 ml) and EtOH (20 ml) is slowly added to 10% Pd/C (90 mg) at room temperature. The reaction mixture is hydrogenated for 3 h with H2 balloon at 45 psi. The mixture is filtered through celite pad and washed with EtOH. The filtrate is concentrated in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:36])=[C:6]([CH:35]=1)[O:7][CH2:8][C:9]1[C:10]([C:23]2[CH:28]=[CH:27][C:26]([O:29]COC)=[CH:25][C:24]=2[O:33][CH3:34])=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]([CH3:19])[C:16](=[O:20])[C:15]([CH3:22])([CH3:21])[NH:14]2.Cl.O1CCOCC1>O1CCOCC1.CO.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:36])=[C:6]([CH:35]=1)[O:7][CH2:8][C:9]1[C:10]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:24]=2[O:33][CH3:34])=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]([CH3:19])[C:16](=[O:20])[C:15]([CH3:22])([CH3:21])[NH:14]2
Reactant: COCOc1ccc(-c2ccc3c(c2COc2cc(F)ccc2C)N(C)C(=O)C(C)(C)N3)c(OC)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cc(O)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
8-(5-Fluoro-2-methylphenoxymethyl)-7-(2-methoxy-4-methoxymethoxyphenyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 8-1, 2.73 g, 5.52 mmol) was dissolved in a mixed solution of 1,4-dioxane (25 mL) and methanol (5 mL), and 4N hydrochloride/1,4-dioxane solution (7.0 mL, 28 mmol) was added thereto. After the reaction mixture was stirred at room temperature for 1 hour, the mixture was diluted with ethyl acetate (130 mL). The mixture was washed with aqueous sodium hydrogen carbonate solution (130 mL) and saturated brine (100 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure to give the titled reference compound (2.41 g) as a pale yellow solid. (Yield 97%)