Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH2:11]([NH2:14])[CH2:12][CH3:13]>CCO>[N+:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[NH:14][CH2:11][CH2:12][CH3:13])([O-:10])=[O:9]
Reactant: CCCN
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: CCO
Product: CCCNc1ccncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-chloro-3-nitro-pyridine (18.0 g, 114 mmol) in EtOH(300 ml) is added n-propylamine (46.9 ml, 568 mmol) slowly at 0° C. and the resulting yellow mixture is warmed to room temp. After stirring for 2 h, the reaction is concentrated in vacuo. The residue is purified by flash chromatography (eluent 50% Hex/EtOAc) to give (3-nitro-pyridin-4-yl)-propyl-amine as a yellow solid. 1H NMR (CDCl3) δ 9.16 (s, 1H), 8.25 (d, J=6 Hz, 1H), 8.15 (br s, 1H), 6.68 (d, J=6 Hz, 1H), 3.29 (q, J=6.8 Hz, 2H), 1.74 (sextet, J=7.2 Hz, 2H), 1.02 (t, J=7.6 Hz, 3H). LRMS calcd 181.19. found 182.5 (MH+).
Reaction SMILES: [CH3:1][C:2]([NH2:25])([CH3:24])[CH2:3][C:4]1[C:12]2[C:7](=[C:8]([O:13][C@@H:14]([CH3:23])[C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.O.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C@@H:33]2[CH2:35][O:34]2)[CH:28]=1>C(O)C>[CH3:1][C:2]([NH:25][CH2:35][C@@H:33]([C:29]1[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=1)[OH:34])([CH3:24])[CH2:3][C:4]1[C:12]2[C:7](=[C:8]([O:13][C@@H:14]([CH3:23])[C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: C[C@H](Oc1cccc2c(CC(C)(C)N)c[nH]c12)C(=O)N1CCOCC1
Reactant: c1cncc([C@@H]2CO2)c1
Solvent: O
Solvent: CCO
Product: C[C@H](Oc1cccc2c(CC(C)(C)NC[C@H](O)c3cccnc3)c[nH]c12)C(=O)N1CCOCC1
Temperature: 10 °C
Reaction time: 18 h
Yield: 25 %

Procedure:
To a solution of 2-methyl-1-{7-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethoxy]-1H-indol-3-yl}propan-2-amine (68.4 mg, 0.198 mmol) in ethanol (4 mL)- water (0.4 mL) is added (R)-(pyridin-3-yl)oxirane (36.0 mg, 0.297 mmol), and the mixture is refluxed for 8 hours. To the reaction solution is added (R)-(pyridin-3-yl)oxirane (144.0 mg, 1.19 mmol) in 4 portions, and the mixture is heated with stirring at 100 to 1 10° C. in a sealed tube for 18 hours. After the reaction is completed, the solvent is evaporated under reduced pressure, and the obtained residue is purified by silica gel column chromatography (chloroform/methanol=20/1→10/1→chloroform/a saturated ammonia methanol=10/1) to give (1R)-2-[(1,1-dimethyl-2-{7-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethoxy]-1H-indol-3-yl}ethyl)amino]-1-pyridin-3-ylethanol (23.1 mg).
Reaction SMILES: C[O:2][C:3]1[CH:21]=[CH:20][C:6]2[C:7]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)=[N:8][S:9][C:5]=2[CH:4]=1>C(O)(=O)C.Br>[F:19][C:16]([F:17])([F:18])[C:13]1[CH:12]=[CH:11][C:10]([C:7]2[C:6]3[CH:20]=[CH:21][C:3]([OH:2])=[CH:4][C:5]=3[S:9][N:8]=2)=[CH:15][CH:14]=1
Reactant: COc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Agent: Br
Solvent: CC(=O)O
Product: Oc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Temperature: 3 °C
Yield: 82.8 %

Procedure:
A solution of 20 g (64.66 mmol) of 6-Methoxy-3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazole in 150 ml of acetic acid and 75 ml 62% aqueous HBr solution was heated to reflux for 70 h, subsequently cooled and taken up in ice water and extracted with tert-butylmethyleter (3×). The organic phases were washed with saturated sodium hydrogen carbonate solution (3×) and dried (Na2SO4). The residue was suspended in 350 ml boiling CH2Cl2, cooled to 3° C. and filtered to yield 15.8 g (83%) of 3-(4-Trifluoromethyl-phenyl)-benzo[d]isothiazol-6-ol, MS: 295 (M).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([S:28]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)(=[O:30])=[O:29])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH:20]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]>[C].[Pd].CO>[CH2:1]([O:3][C:4]([C:6]1[N:7]([S:28]([C:31]2[CH:32]=[CH:33][C:34]([CH3:37])=[CH:35][CH:36]=2)(=[O:30])=[O:29])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH:15]1[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])[CH2:19][CH2:20]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(C3=CCN(C(=O)OC(C)(C)C)CC3)ccc2n1S(=O)(=O)c1ccc(C)cc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1cc2cc(C3CCN(C(=O)OC(C)(C)C)CC3)ccc2n1S(=O)(=O)c1ccc(C)cc1
Reaction time: 13 h

Procedure:
A mixture of 5-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-(toluene-4-sulfonyl)-1H-indole-2-carboxylic acid ethyl ester (495 mg, 0.9 mmol), 5% palladium carbon (100 mg), and methanol (20 ml) was stirred under a hydrogen atmosphere for 13 hours. The reaction mixture was filtered through Celite, and washed with ethyl acetate, and the filtrate was concentrated. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography. Thus, 5-(1-tert-butoxycarbonyl-piperidin-4-yl)-1-(toluene-4-sulfonyl)-1H-indole-2-carboxylic acid ethyl ester was obtained as a colorless amorphous material (315.9 mg, 64%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]([CH3:10])[CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][OH:12].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22].CN(C1C=CC=CN=1)C>ClCCl>[Cl:1][C:2]1[C:7]([N:8]([CH3:9])[CH3:10])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][O:12][S:21]([CH3:20])(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C)c1cccc(CO)c1Cl
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)c1cccc(COS(C)(=O)=O)c1Cl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
(2-Chloro-3-dimethylamino-phenyl)-methanol (0.50 g, 2.69 mmol) was placed in a round bottomed flask with dichloromethane (10 mL) and cooled to 0° C. Triethylamine (0.68 g, 6.73 mmol), methanesulfonylchloride (0.23 mL, 2.97 mmol), and dimethylaminopyridine (0.02 g) were added and the reaction was allowed to warm and stir at rt over 3 h. The reaction was diluted with dichloromethane (20 mL) and washed with 1N Hydrochloric acid (10 mL), 10% aqueous sodium bicarbonate (10 mL), and water (10 mL). The organics were dried (MgSO4) and concentrated to afford methanesulfonic acid 2-chloro-3-dimethylamino-benzyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C@H:11]2[CH2:15][NH:14][C@H:13]([C:16]([NH:18][C:19]3([C:22]#[N:23])[CH2:21][CH2:20]3)=[O:17])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([N:35]2[CH2:38][CH2:37][CH:36]2[C:39]([O-])=[O:40])[CH2:31][CH2:30]1)=[O:28])[CH3:25].[Li+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C@H:11]2[CH2:15][N:14]([C:39]([CH:36]3[CH2:37][CH2:38][N:35]3[CH:32]3[CH2:31][CH2:30][N:29]([C:27]([O:26][CH2:24][CH3:25])=[O:28])[CH2:34][CH2:33]3)=[O:40])[C@H:13]([C:16](=[O:17])[NH:18][C:19]3([C:22]#[N:23])[CH2:21][CH2:20]3)[CH2:12]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)N1CCC(N2CCC2C(=O)[O-])CC1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(Cl)cc3)CN2)CC1
Agent: [Li+]
Product: CCOC(=O)N1CCC(N2CCC2C(=O)N2C[C@H](S(=O)(=O)c3ccc(Cl)cc3)C[C@H]2C(=O)NC2(C#N)CC2)CC1

Procedure:
The reaction of (2S,4R)-4-(4-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide 7B and lithium 1-(1-(ethoxycarbonyl)piperidin-4-yl)azetidine-2-carboxylate 20J carried out according to the general procedure L yielded ethyl 4-(2-((2S,4R)-4-(4-chlorophenylsulfonyl)-2-(1-cyanocyclopropylcarbamoyl)pyrrolidine-1-carbonyl)azetidin-1-yl)piperidine-1-carboxylate 1:1 epimers as a white solid (73%). MS ISP (m/e): 592.3/594.2 (100/40) [(M+H)]+.
Reaction SMILES: [F:1][C:2]([F:15])([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1)[C:3]([F:6])([F:5])[F:4].C(N(CC)CC)C.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>ClCCl>[CH3:33][C:23]1[CH:28]=[CH:27][C:26]([S:29]([O:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([C:2]([F:15])([F:1])[C:3]([F:5])([F:4])[F:6])=[CH:8][CH:9]=2)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: OCc1ccc(C(F)(F)C(F)(F)F)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCc2ccc(C(F)(F)C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.7 %

Procedure:
To a stirred solution of (4-(perfluoroethyl)phenyl)methanol (0.60 g, 2.65 mmol) and triethylamine (0.53 g, 5.30 mmol) in dichloromethane (30 mL) was added p-toluenesulfonyl chloride (1.00 g, 5.30 mmol). The resulting mixture was allowed to stir at room temperature. After 2 h, the mixture was concentrated. Chromatographic purification of the residue (silica gel, 10% ethyl acetate in petroleum ether elute) afforded 0.400 g (40%) of 4-(perfluoroethyl)benzyl 4-methylbenzenesulfonate as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:12]([C:17](=[O:20])[CH2:18][CH3:19])C(OC)=O)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Cl-].[Na+]>O.CS(C)=O>[Cl:1][C:2]1[C:3]([CH2:12][C:17](=[O:20])[CH2:18][CH3:19])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: CCC(=O)C(C(=O)OC)c1ncc(C(F)(F)F)cc1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCC(=O)Cc1ncc(C(F)(F)F)cc1Cl
Temperature: 130 °C
Reaction time: 8 h

Procedure:
2.08 g of methyl 2-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]-3-oxopentanoate (0.00677 mol) and 0.12 g of sodium chloride are dissolved in a mixture of water (0.25 mL) and dimethylsulfoxyde (20 mL). The reaction medium is stirred at a temperature of 130° C. for 8 hours. After cooling, 100 mL of water are added to the reaction mixture which is extracted twice with 150 mL of ethyl acetate.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.[C:21](=O)([O-])[O-:22].[K+].[K+].CO>O>[CH3:21][O:22][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2s1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1cnccc1-c1nc2cc(C(F)(F)F)ccc2s1
Temperature: 25 °C

Procedure:
A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzothiazole, 0.28 g of potassium carbonate and 3 ml of methanol was refluxed with heating for 1.5 hours. The reaction mixture was cooled down to room temperature. To the reaction mixture was added water, and the resultant mixture was extracted with ethyl acetate twice. The combined organic layers were washed with water and saturated saline, dried over magnesium sulfate, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, to obtain 2-(3-methoxypyridin-4-yl)-5-(trifluoromethyl)benzothiazole (hereinafter, referred to as the present compound 4).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:13]=[C:12]([F:14])[C:11]([Cl:15])=[C:10]([F:16])[C:8]=1[NH2:9].CN(C)[CH:19]=[O:20].[Cl-].[NH4+]>O1CCCC1>[NH2:9][C:8]1[C:10]([F:16])=[C:11]([Cl:15])[C:12]([F:14])=[CH:13][C:7]=1[CH:19]=[O:20]
Reactant: Nc1c(Br)cc(F)c(Cl)c1F
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Nc1c(C=O)cc(F)c(Cl)c1F
Temperature: -75 °C
Reaction time: 3 h

Procedure:
66 cm3 of a 2 N butyllithium solution (in hexane) was added dropwise over 30 minutes to a stirred solution of 13.4 g of 2-bromo-5-chloro-4,6-difluoroaniline in 150 cm3 of anhydrous tetrahydrofuran (THF) cooled to a temperature in the region of −75° C. After stirring for 1 hour at this temperature, 12.8 cm3 of dimethylformamide was added. After the addition, the mixture was again stirred for 3 hours at a temperature in the region of −70° C. The mixture was brought to a temperature in the region of −5° C., and then an aqueous ammonium chloride solution (18 g dissolved in 180 cm3) was added. The reaction mixture was extracted twice with 200 cm of diethyl ether. The combined ethereal extracts were washed once with 150 cm3 of water and once with 150 cm3 of a saturated aqueous sodium chloride solution. After drying over magnesium sulphate, the solution was concentrated under reduced pressure (5 kPa), at a temperature in the region of 40° C. After taking up the solid residue obtained in 80 cm3 of hexane and then filtration, 6.2 g of 2-amino-4-chloro-3,5-difluorobenzaldehyde was obtained in the form of a yellow solid.
Reaction SMILES: [CH2:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[O-].[Na+].[C:14](OCC)(=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[C:2]1([CH:1]([C:8]#[N:9])[C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: N#CCc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C(=O)C(C#N)c1ccccc1
Yield: 90 %

Procedure:
Reaction of benzyl cyanide, sodium ethylate and diethyl oxalate according to the method described in Org. Synth. Coll. Vol. II (1943) 287 and Chem. Ber. 107 (1974) 2794-2795 in alcohol, acidification with conc. (37%) hydrochloric acid to pH 2 and subsequent recrystallization of the separated precipitate from ethanol yielded ethyl phenylcyanopyruvate in 90% yield as yellow crystals, melting point 127°-128°.
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([CH3:8])=[C:5]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=O)[C:4]=1[CH3:18])=[O:2].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[CH3:18][C:4]1[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:11]([C:12]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:14])[CH:10]=2)=[C:6]([CH3:8])[NH:7][C:3]=1[CH:1]=[O:2]
Reactant: C1COCCN1
Reactant: Cc1[nH]c(C=O)c(C)c1-c1cccc(C(=O)O)c1
Product: Cc1[nH]c(C=O)c(C)c1-c1cccc(C(=O)N2CCOCC2)c1

Procedure:
3-(5-Formyl-2,4-dimethyl-1H-pyrrol-3-yl)-benzoic acid was reacted with morpholine using General Amidation Procedure 1 to give 3,5-dimethyl-4-[3-(morpholine-4-carbonyl)-phenyl]-1H-pyrrole-carbaldehyde. MS m/z 326 [M+1].
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH:9]1(B(O)O)[CH2:11][CH2:10]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH:9]2[CH2:11][CH2:10]2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: OB(O)C1CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Clc1nccc(C2CC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.7 %

Procedure:
2,4-Dichloropyrimidine (15 g, 101 mmol), cyclopropylboronic acid (8.65 g, 101 mmol), Pda2(dppf)-CH2Cl2 adduct (8.22 g, 10.07 mmol), and potassium phosphate (53.4 g, 252 mmol) were combined in a 1 L round-bottom flask. THF (503 mL) was added and the suspension was heated to reflux with stirring overnight. The reaction was then cooled to room temperature, concentrated to ˜100 mL under reduced pressure, extracted with ethyl acetate, washed with saturated aqueous NaHCO3, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with ethyl acetate in hexanes to give 2-chloro-4-cyclopropylpyrimidine (10.124 g, 58.3 mmol, 57.9%) as an 89:11 mixture of regioisomers.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].I[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>[Cu]Br>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:6]=[CH:5]2
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: Ic1ccccc1
Agent: [Cu]Br
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Brc1ccc2c(ccn2-c2ccccc2)c1
Temperature: 100 °C
Reaction time: 9 h
Yield: 33.1 %

Procedure:
A mixture of 5-bromoindole (10 g), potassium carbonate (27 g), copper (I) bromide (0.73 g) and iodobenzene (135 g) was heated to 100° C., then was removed once from the oil bath, sodium hydroxide (1.58 g) and copper (II) acetate (50 mg) were added and the mixture was stirred at 140° C. for 9 hours. From the reaction solution, the insolubles were filtered off, the filtrate was distilled off in vacuo, and the residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate=19:1 to 3:2) to afford the above-identified compound (4.6 g).
Reaction SMILES: [BH4-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:19]2[N:20]=[CH:21][N:22](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:23]=2)[O:12][CH2:13][C:14](OCC)=[O:15])=[CH:7][CH:6]=1)#[N:4]>C(O)C>[OH:15][CH2:14][CH2:13][O:12][CH:11]([C:19]1[NH:20][CH:21]=[N:22][CH:23]=1)[C:8]1[CH:9]=[CH:10][C:5]([C:3]#[N:4])=[CH:6][CH:7]=1
Reactant: CCOC(=O)COC(c1ccc(C#N)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1ccc(C(OCCO)c2cnc[nH]2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2.45 mmol of sodium borohydride are added to a solution of 1.63 mmol of ethyl [(4-cyanophenyl)-1-(trityl-1H-imidazol-4-yl)methoxy]acetate in 10 ml of ethanol at room temperature. The reaction mixture is stirred at room temperature for 16 hours and then evaporated. The residue is taken up in dichloromethane and saturated aqueous sodium bicarbonate solution, the phases are separated, and the aqueous phase is back-extracted with dichloromethane. The combined organic phases are dried with sodium sulphate and evaporated. The title compound is obtained as a white solid from the residue by flash chromatography (SiO2 60F). Rf=0.10 (ethyl acetate-heptane 1:2); Rt=7.39.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[CH:5]([C:9]1[C:14]([F:15])=[CH:13][C:12]([O:16][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:11][C:10]=1[F:34])[O:6][CH2:7][CH3:8])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[CH2:1]([O:3][C:4](=[O:35])[CH:5]([C:9]1[C:14]([F:15])=[CH:13][C:12]([OH:16])=[CH:11][C:10]=1[F:34])[O:6][CH2:7][CH3:8])[CH3:2]
Reactant: CCOC(=O)C(OCC)c1c(F)cc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(OCC)c1c(F)cc(O)cc1F
Yield: 86.2 %

Procedure:
(RS)-[4-(tert-Butyl-diphenyl-silanyloxy)-2,6-difluoro-phenyl]-ethoxy-acetic acid ethyl ester (6.85 g) was dissolved in THF (135 ml) and a 1 M TBAF sol. in THF (15.1 ml) was added. After 3 h the reaction mixture was poured on AcOEt (300 ml) and H2O (300 ml). The aqueous layer was extracted with two more portions of AcOEt (100 ml). The combined organic layers were washed with brine and dried (MgSO4) and the solvent was evaporated. Crystallization from ice cold CH2Cl2 afforded 3.08 g (86%) of (RS)-(2,6-difluoro-4-hydroxy-phenyl)-ethoxy-acetic acid ethyl ester. White crystals. MS 258.9 ([M−H]+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[CH:3]=1.[CH2:10]([O:12][C:13]1[CH:14]=[CH:15][C:16]([F:22])=[C:17](B(O)O)[CH:18]=1)[CH3:11].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:10]([O:12][C:13]1[CH:14]=[CH:15][C:16]([F:22])=[C:17]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[CH:3]=2)[CH:18]=1)[CH3:11]
Reactant: N#Cc1cc(Cl)ccn1
Reactant: CCOc1ccc(F)c(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOc1ccc(F)c(-c2ccnc(C#N)c2)c1
Yield: 85.5 %

Procedure:
A mixture of 4-chloropyridine-2-carbonitrile (4.1 g, 29.56 mmol) and (5-ethoxy-2-fluoro-phenyl)boronic acid (5982.6 mg, 32.52 mmol) in monoglyme (150 mL) was treated with sodium carbonate (29.56 mL, 59.13 mmol) and then PdCl2(PPh3)2 (1037.5 mg, 1.48 mmol) and the mixture was refluxed under argon. After 2 hrs the DME was evaporated and ethyl acetate (200 ml) and water were added and the product was extracted into ethyl acetate (3 times). The extracts were dried (Na2SO4) and concentrated. Chromatography on silica gel (0-50% ethyl acetate in isohexane, using a SNAP340 cartidge on a Biotage SP4) gave 4-(5-ethoxy-2-fluoro-phenyl)pyridine-2-carbonitrile (D111) (6.12 g) as an off white solid;
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[CH:24][CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42](B3OC(C)(C)C(C)(C)O3)[CH:41]=2)(=[O:38])=[O:37])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[NH2:1][C:2]1[C:3]([C:42]2[CH:41]=[C:40]([NH:39][S:36]([C:33]3[CH:34]=[CH:35][C:30]([O:29][CH3:28])=[CH:31][CH:32]=3)(=[O:38])=[O:37])[CH:45]=[CH:44][CH:43]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[CH:24][CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: COc1ccc(S(=O)(=O)Nc2cccc(B3OC(C)(C)C(C)(C)O3)c2)cc1
Reactant: C[C@H](Nc1ncnc(N)c1Br)c1nn2cccc2c(=O)n1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(S(=O)(=O)Nc2cccc(-c3c(N)ncnc3N[C@@H](C)c3nn4cccc4c(=O)n3-c3ccccc3)c2)cc1
Yield: 59.1 %

Procedure:
(S)-2-(1-((6-Amino-5-bromopyrimidin-4-yl)amino)ethyl)-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (150 mg, 0.35 mmol) was treated with 4-methoxy-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzenesulfonamide (205 mg, 0.53 mmol), 2M cesium carbonate (360 μl, 0.72 mmol) and bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (28 mg, 0.03 mmol) according to the method described in Example 3 to give 126 mg (59% yield) of the title compound as a solid. Purity 100%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([NH:7][C:8]2[S:9][C:10]3[N:18]=[CH:17][CH:16]=[CH:15][C:11]=3[C:12](=[O:14])[N:13]=2)=[CH:5][CH:4]=1.[H-].[Li+].[CH2:23](I)[CH2:24][CH2:25][CH3:26]>>[CH2:23]([N:13]1[C:12](=[O:14])[C:11]2[CH:15]=[CH:16][CH:17]=[N:18][C:10]=2[S:9][C:8]1=[N:7][C:6]1[CH:19]=[CH:20][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH2:24][CH2:25][CH3:26]
Reactant: COc1ccc(Nc2nc(=O)c3cccnc3s2)cc1
Reactant: CCCCI
Agent: [H-]
Agent: [Li+]
Product: CCCCn1c(=Nc2ccc(OC)cc2)sc2ncccc2c1=O

Procedure:
The reaction procedure of Example 11 was followed except that 428 mg of 2-(4-methoxyanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 14 mg of lithium hydride and 0.17 ml of butyl iodide were used. As a result, 295 mg of 3-butyl-2-[(4-methoxyphenyl)imino]-2,3-dihydro-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained as a low polarity substance, and 55 mg of 2-[N-butyl-N-(4-methoxyphenyl)amino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained as a high polarity substance.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.O[CH:9]1[CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]1>>[NH:11]1[CH2:10][CH:9]([O:5][C:3]2[CH:2]=[CH:12][CH:9]=[CH:10][N:11]=2)[CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: O=C(O)C(F)(F)F
Product: c1ccc(OC2CNC2)nc1

Procedure:
Preparation of compound P21. Compound P21 was prepared by deprotection of C73 with trifluoroacetic acid as described for t-butyl 3-hydroxyazetidine-1-carboxylate in the preparation of C19 in Example 3, before being used in the coupling step.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6]/[C:7](=[CH:9]/[CH2:10][OH:11])/[CH3:8])[CH3:3]>[O-2].[O-2].[Mn+4].ClCCl>[CH3:3][C:2](=[CH:4][CH2:5][CH2:6]/[C:7](=[CH:9]/[CH:10]=[O:11])/[CH3:8])[CH3:1]
Reactant: CC(C)=CCC/C(C)=C/CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(C)=CCC/C(C)=C/C=O
Yield: 79.1 %

Procedure:
Geraniol (7.0 g, 0.045 mol, 1 equiv.), manganese (IV) dioxide (100.0 g) and dichloromethane (500 ml) were stirred together at ambient temperature overnight. The mixture was filtered through Celite™, and the filtrate concentrated in vacuo to yield geranial (5.42 g, 80%). A cooled (−15° C.), stirred suspension of methyltriphenyl-phosphonium iodide (16.0 g, 0.039 mol, 1.1 equiv.) in tetrahydrofuran (50 ml) and diethyl ether (50 ml) was treated with n-butyllithium (2.5 M; 16 ml, 0.039 mol, 1.1 equiv.). After 0.25 hours, geranial (5.42 g, 0.036 mol, 1 equiv.) was added and the mixture allowed to stir at ambient temperature for 1 hour. The mixture was partitioned between diethyl ether (200 ml), water (200 ml) and petroleum ether b.p. 40-60° C. (200 ml), and the organic layer dried (MgSO4) and concentrated in vacuo to yield a crude oil which was subjected to column chromatography over Florisil (100% hexane) to give the nonatriene as a colourless oil (3.42 g, 64%).