Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10].[CH2:20]([C:22]1[CH:27]=[CH:26][C:25]([C:28]2[S:32][C:31]([CH3:33])=[N:30][C:29]=2[C:34](O)=[O:35])=[CH:24][CH:23]=1)[CH3:21]>>[CH2:20]([C:22]1[CH:23]=[CH:24][C:25]([C:28]2[S:32][C:31]([CH3:33])=[N:30][C:29]=2[C:34]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:6]3)[C@H:2]2[CH2:7][NH:8][C:9]([C:11]2[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=2[CH3:19])=[O:10])=[O:35])=[CH:26][CH:27]=1)[CH3:21]
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2C[C@@H]21
Reactant: CCc1ccc(-c2sc(C)nc2C(=O)O)cc1
Product: CCc1ccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)cc1

Procedure:
prepared by reaction of 6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid [(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 5-(4-Ethyl-phenyl)-2-methyl-thiazole-4-carboxylic acid. LC-MS (basic): tR=1.37 min; [M+H]+=506.1.
Reaction SMILES: C1C=CC=CC=1.[CH2:7]([OH:10])[CH2:8][OH:9].[CH3:11][C:12]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](=[N:25][O:26][CH3:27])[CH:23]=O>[Cl-].[Na+].O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:27][O:26][N:25]=[C:22]([CH:23]1[O:10][CH2:7][CH2:8][O:9]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][O:14][C:13]1[CH:28]=[C:29]([CH3:32])[CH:30]=[CH:31][C:12]=1[CH3:11]
Reactant: CON=C(C=O)c1ccccc1COc1cc(C)ccc1C
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CON=C(c1ccccc1COc1cc(C)ccc1C)C1OCCO1
Reaction time: 2 h
Yield: 87.9 %

Procedure:
Benzene (4 ml), ethylene glycol (0.12 g, 2.0 mmol) and p-toluenesulfonic acid monohydrate (0.01 g, 0.05 mmol) were added to 2-(2,5-dimethylphenoxymethyl)-α-methoxyiminophenylacetaldehyde (0.3 g, 1.0 mmol), and the mixture was subjected to azeotropic dehydration for 2 hours. After completion of the reaction, half-saturated brine (100 ml) was added, and the mixture was extracted with dichloromethane (50 ml) twice. The extracts were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetatein-hexane) to give 2-(2,5-dimethylphenoxymethyl)phenyl 1,3-dioxolan-2-yl ketone O-methyloxime (0.30 g, yield 87.9%) as colorless crystals. mp 136-137° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:18][C:19]([O:21]C)=[O:20].[OH-].[K+]>O.C1COCC1>[Br:1][C:2]1[C:3]2[O:10][C:18]([C:19]([OH:21])=[O:20])=[CH:5][C:4]=2[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)CCl
Reactant: O=Cc1cccc(Br)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc2cccc(Br)c2o1
Temperature: 130 °C
Reaction time: 4 h

Procedure:
10 g (49.75 mmol) of 3-bromo-2-hydroxybenzaldehyde and 1.84 g (4.97 mmol) of tetra-N-butylammonium iodide are, together with 27.5 g (199.0 mmol) of anhydrous potassium carbonate, initially charged. 24.3 g (223.86 mmol) of methyl chloroacetate are added. The reaction mixture is heated at 130° C. for 4 h and then cooled to 0° C. using an ice bath. 100 ml of THF and 16.75 g (298.5 mmol) of potassium hydroxide in 100 ml of water are added, the mixture is then stirred at 40° C. for 4 h. The solvent is removed under reduced pressure. The residue is diluted with water and acidified with conc. hydrochloric acid. The product is purified on silica gel 60 (mobile phase: toluene/ethyl acetate/acetic acid 40:10:1). The solvent is removed under reduced pressure. Any last solvent residues are finally removed under high vacuum. Fine purification is carried out by preparative HPLC. 303 mg (2.5% of theory) of the title compound are isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:13][CH2:14][C:15]2([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:20][CH2:19][N:18]([C:21](OC(C)(C)C)=O)[CH2:17][CH2:16]2)[CH3:12])[C:8]2[C:4](=[CH:5][N:6]([CH:35]3[CH2:37][CH2:36]3)[N:7]=2)[CH:3]=1.C([BH3-])#N.[Na+].C=O>FC(F)(F)C(O)=O.C(O)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:13][CH2:14][C:15]2([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]2)[CH3:12])[C:8]2[C:4](=[CH:5][N:6]([CH:35]3[CH2:37][CH2:36]3)[N:7]=2)[CH:3]=1
Reactant: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cn(C3CC3)nc12
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: CC(OCC1(c2ccc(F)cc2)CCN(C)CC1)c1cc(Cl)cc2cn(C3CC3)nc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(±)-tert-Butyl 4-((1-(5-chloro-2-cyclopropyl-2H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (65 mg, 0.12 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 2 mL) and stirred at room temperature for 1 h. The reaction was concentrated, loaded onto a strong cation exchange cartridge in methanol, and flushed with several volumes of methanol which were discarded. The crude secondary amine was eluted in 2 M ammonia in methanol and concentrated. The resulting residue was dissolved in acetonitrile (2 mL), cooled to 0° C., and treated with sodium cyanoborohydride (38.7 mg, 0.62 mmol) and formalin (0.45 mL). After 5 min, the reaction was treated with a few drops of acetic acid. The ice bath was removed and stirring continued for 1 h. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated to give 16 mg (29%) as a clear oil. 1H-NMR (CDCl3, 500 MHz) δ 7.86 (s, 1H), 7.41 (m, 1H), 7.30-7.33 (m, 2H), 6.99-7.03 (m, 2H), 6.78 (m, 1H), 4.92 (q, J=6.4 Hz, 1H), 3.86-3.90 (m, 2H), 3.33-3.38 (m, 2H), 2.52-2.53 (m, 2H), 2.20 (s, 3H), 1.97-2.24(m, 6H), 1.41 (d, J=6.4 Hz, 3H), 1.25-1.28 (m, 2H), 1.13-1.17 (m, 2H); 13C-NMR (CDCl3, 126 MHz) δ 161.3 (d, J=243.8 Hz), 145.4 135.2, 129.0, 128.9, 127.9, 122.3, 122.1, 117.0, 115.0, 114.9, 73.8, 52.1, 50.8, 46.4, 40.5, 34.7, 32.8, 22.8. Mass spec.: 442.44 (MH)+.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].CCN(C(C)C)C(C)C.C[Al](C)C.[F:19][C:20]1[CH:25]=[C:24]([I:26])[CH:23]=[CH:22][C:21]=1[N:27]1[CH:32]=[C:31]([O:33][CH3:34])[C:30](=[O:35])[C:29]([C:36]([O:38]C)=O)=[N:28]1>C(Cl)Cl>[F:19][C:20]1[CH:25]=[C:24]([I:26])[CH:23]=[CH:22][C:21]=1[N:27]1[CH:32]=[C:31]([O:33][CH3:34])[C:30](=[O:35])[C:29]([C:36]([N:3]([O:4][CH3:5])[CH3:2])=[O:38])=[N:28]1
Reactant: CNOC
Reactant: COC(=O)c1nn(-c2ccc(I)cc2F)cc(OC)c1=O
Agent: C[Al](C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cn(-c2ccc(I)cc2F)nc(C(=O)N(C)OC)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
To a solution of N,O-dimethylhydroxylamine hydrochloride (8.78 g, 90 mmol) and iPr2NEt (15.7 mL, 90 mmol) in CH2Cl2 (100 mL) was added AlMe3 (1.8 M solution in toluene, 50 mL, 90 mmol) slowly at 0° C. under Ar atmosphere. After stirring for 1 h, a solution of methyl 1-(2-fluoro-4-iodophenyl)-5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate (12.1 g, 30 mmol) in CH2Cl2 (100 mL) was added slowly, and the mixture was stirred for 1 h at 0° C. The reaction mixture was poured into ice-water and the organic layer was separated. The aqueous layer was extracted with AcOEt. The combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with AcOEt to give the title compound (9.96 g, 77% yield) as a white amorphous solid: 1H NMR (300 MHz, CDCl3): δ ppm 3.39 (3H, s), 3.70 (3H, s), 3.90 (3H, s), 7.39 (1H, t, J=8.1 Hz), 7.63-7.67 (2H, m), 7.77 (1H, d, J=2.3 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[C:14]2C(=O)OC(C)(C)[O:16][C:15]2=[O:23])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(O)=O>C(N(CC)CC)C>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([CH2:13][CH2:14][C:15]([OH:23])=[O:16])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(C=C2C(=O)OC(C)(C)OC2=O)cc(OC)c1OC
Solvent: O=CO
Solvent: CCN(CC)CC
Product: COc1cc(CCC(=O)O)cc(OC)c1OC

Procedure:
16.1 g (0.05 mol) of 5-(3,4,5-trimethoxyphenylmethylene)- 2,2-dimethyl-1,3-dioxane-4,6-dione (m.p.: 159°-160° C.) were added to 50 ml of the mixture of formic acid and triethylamine prepared as described in Example 1, then the procedure described in Example 2 was followed.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9](=[O:12])[CH2:10]Cl)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].O1CCOCC1.[CH:21]([NH2:24])([CH3:23])[CH3:22]>O>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9](=[O:12])[CH2:10][NH:24][CH:21]([CH3:23])[CH3:22])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(C)N
Reactant: CC(=O)Nc1ccc(C(=O)CCl)cc1
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc(C(=O)CNC(C)C)cc1
Reaction time: 2 h
Yield: 89.6 %

Procedure:
In a reactor, 21 g (0.1 mol) of 4-acetylaminophenacyl chloride are introduced into a mixture comprising 100 ml of dioxane, 26 ml (0.3 mol) of isopropylamine and 20 ml of water. The reaction medium is stirred at 30°-40° C. for 2 hours. After the addition of 500 ml of iced water, a precipitate is collected, washed and dried. Recrystallization from ethyl acetate gives 21 g of N-(4-acetylaminophenacyl)isopropylamine, which is in the form of a white powder. Melting point (inst.)=156° C.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:29]=[CH:28][C:8]2[N:9]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:10]([CH2:12][N:13]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[NH:15][C:14]3=[O:22])=[N:11][C:7]=2[CH:6]=1)=[NH:4].[C:30](Cl)(Cl)=[O:31]>>[CH3:27][CH:25]([CH3:26])[CH2:24][CH2:23][N:9]1[C:8]2[CH:28]=[CH:29][C:5]([C:3]3[NH:4][C:30](=[O:31])[O:1][N:2]=3)=[CH:6][C:7]=2[N:11]=[C:10]1[CH2:12][N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][C:14]1=[O:22]
Reactant: CC(C)CCn1c(Cn2c(=O)[nH]c3ccccc32)nc2cc(C(=N)NO)ccc21
Reactant: O=C(Cl)Cl
Product: CC(C)CCn1c(Cn2c(=O)[nH]c3ccccc32)nc2cc(-c3noc(=O)[nH]3)ccc21
Reaction time: 48 h
Yield: 26.3 %

Procedure:
N-Hydroxy-1-(3-methyl-butyl)-2-(2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1H-benzoimidazole-5-carboxamidine (75 mg, 0.191 mmol) was treated with phosgene (1 ml, 1.91 mmol, 1.92 M in toluene) and heated to reflux for 2.5 h. The mixture was cooled and stirred for 48 h. A white precipitate was isolated by filtration to give 21 mg (26%) of 1-[1-(3-Methyl-butyl)-5-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-1H-benzoimidazol-2-ylmethyl]-1,3-dihydro-benzoimidazol-2-one.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[C:7]([Cl:13])[CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([F:21])[CH:15]=2)[CH:3]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>>[Cl:13][C:7]1[CH:8]=[C:9]([OH:12])[CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([F:21])[CH:15]=1)[CH:3]=[C:2]2[C:27]1[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Oc1cc(Cl)c2nc(-c3ccc(O)c(F)c3)cc(Br)c2c1
Product: COc1ccc(-c2cc(-c3ccc(O)c(F)c3)nc3c(Cl)cc(O)cc23)cc1
Yield: 97 %

Procedure:
This compound was prepared from 45a using 4-methoxyphenylboronic acid according to method P. Orange solid; Yield: 97%; mp 140–142° C.; 1H-NMR (400 MHz, DMSO-d6) δ 3.87 (s, 3H), 7.09 (dd, J=8.8, 8.8 Hz, 1H), 7.11 (d, J=2.7 Hz, 1H), 7.16 (d, J=8.8 Hz, 2H), 7.51 (d, J=2.6 Hz, 1H), 7.53 (d, J=8.8 Hz, 2H), 7.93(s, 1H), 8.02 (dd, J=8.5, 1.7 Hz, 1H), 8.14 (dd, J=13.1, 2.1 Hz, 1H), 10.21 (s, 1H), 10.27 (s, 1H); 19F-NMR (400 MHz, DMSO-d6) δ −136.48 (dd, J=13.0, 9.7 Hz); MS (ESI) m/z 394/396 ([M−H]−), 396/398 ([M+H]+); Anal. Calcd for C22H15ClFNO3: C: 66.76, H: 3.82, N: 3.54. Found: C: 66.05, H: 4.01, N: 3.19.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[C:11]1[S:10][C:9]([C:15]3[O:19][N:18]=[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:16]=3[C:26]([F:29])([F:28])[F:27])=[N:8][C:7]=1[CH2:6][CH2:5]2.[CH2:30]([Sn](CCCC)(CCCC)C=C)[CH2:31]CC>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:20]1([C:17]2[C:16]([C:26]([F:27])([F:28])[F:29])=[C:15]([C:9]3[S:10][C:11]4[C:12]5[C:4](=[CH:3][C:2]([CH:30]=[CH2:31])=[CH:14][CH:13]=5)[CH2:5][CH2:6][C:7]=4[N:8]=3)[O:19][N:18]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: FC(F)(F)c1c(-c2ccccc2)noc1-c1nc2c(s1)-c1ccc(Br)cc1CC2
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc2c(c1)CCc1nc(-c3onc(-c4ccccc4)c3C(F)(F)F)sc1-2
Temperature: 110 °C

Procedure:
To 5-(7-bromo-4,5-dihydronaphtho[2,1-d]thiazol-2-yl)-3-phenyl-4-(trifluoromethyl)isoxazole (Preparation 82D), 0.4 g, 0.838 mmol) in toluene (2 mL) was added tributyl(vinyl)stannane (0.294 mL, 1.00 mmol), followed by bis(triphenylphosphine)palladium(II)chloride (0.029 g, 0.042 mmol) at room temperature. The reaction mixture was heated at 110° C. for 3 h. The reaction mixture was loaded onto a silica gel column and purified using hexane/EtOAc (9.25:0.75, 300 mL). The desired fractions were collected and concentrated to yield 0.35 mgs of a yellow solid. The solid was triturated with acetonitrile (5 mL), filtered and washed with acetonitrile (2×5 mL) to yield 200 mgs of a pale yellow solid (I crop). The mother liquor was concentrated to yield another 100 mgs of greenish-yellow solid (II crop). LC/MS M+1=425.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([CH2:7][CH:8]([C:11]#[N:12])[C:9]#[N:10])=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:18][CH2:19][C:20]([F:23])([F:22])[F:21]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([CH2:7][C:8]([CH2:18][CH2:19][C:20]([F:23])([F:22])[F:21])([C:11]#[N:12])[C:9]#[N:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(CC(C#N)C#N)cc1
Reactant: FC(F)(F)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CC(C#N)(C#N)CCC(F)(F)F)cc1
Yield: 27.7 %

Procedure:
Using 0.39 g of 2-(4-methoxybenzyl)malononitrile, 5 ml of N,N-dimethylformamide, 0.12 g of sodium hydride (60% in oil), and 0.34 g of 1-bromo-3,3,3-trifluoropropane, and according to the process described in the Production Example 1, there was obtained 0.15 g of 2-(4-methoxybenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (89)).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:6])[O-:5])[CH3:2].[OH:7][C:8]1[C:9]([Cl:21])=[CH:10][C:11]2[CH:12]([CH3:20])[CH:13]3[CH2:17][NH:16][CH2:15][CH:14]3[C:18]=2[CH:19]=1.[F:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Br>>[CH2:1]([NH:3][C:4](=[O:5])[O-:6])[CH3:2].[F:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][O:7][C:8]1[C:9]([Cl:21])=[CH:10][C:11]2[CH:12]([CH3:20])[CH:13]3[CH2:17][NH:16][CH2:15][CH:14]3[C:18]=2[CH:19]=1
Reactant: Fc1ccccc1CBr
Reactant: CC1c2cc(Cl)c(O)cc2C2CNCC12
Agent: CCNC(=O)[O-]
Product: CC1c2cc(Cl)c(OCc3ccccc3F)cc2C2CNCC12

Procedure:
The subtitle compound was prepared by the method of Example 6, Step A utilizing N-ethylcarbamate-5-hydroxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 5, Step A) and 2-fluorobenzyl bromide. The crude product was obtained without further purification. MS calculated for C22H23ClFNO3+H: 404, observed: 404.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:12][C:13]#[N:14])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].O.Cl.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:12][CH2:13][NH2:14])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(CC#N)ccc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(CCN)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.9 %

Procedure:
Under ice cooling, 17.0 g of 2-(3-methoxy-4-nitrophenyl)acetonitrile in 50 ml of tetrahydrofuran is combined with 180 ml of 1-molar borane-tetrahydrofuran complex in tetrahydrofuran, stirred for 16 hours at room temperature, and mixed with water. The mixture is agitated at 0° C. for 0.5 hour, 200 ml of 2N hydrochloric acid is added dropwise, and the mixture is again stirred for 2 hours at 0° C. and for 2 hours at room temperature. A pH of 9.5°-10.5 is set with sodium hydroxide solution, and the mixture is extracted four times with ethyl acetate/butanol 10:1. The product is chromatographed on silica gel with methanol/dichloromethane 1:1, thus obtaining 9.0 g of 2-(3-methoxy-4-nitrophenyl)ethylamine as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13](S(C)=O)[N:12]=2)[N:8]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:7]1=[O:27])#[N:2].[NH2:32][CH2:33][CH2:34][CH2:35][OH:36]>O1CCOCC1>[C:1]([C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:32][CH2:33][CH2:34][CH2:35][OH:36])[N:12]=2)[N:8]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:7]1=[O:27])#[N:2]
Reactant: CS(=O)c1nccc(-c2cn(Cc3ccccc3C#N)c(=O)n2-c2ccc(F)cc2)n1
Reactant: NCCCO
Solvent: C1COCCO1
Product: N#Cc1ccccc1Cn1cc(-c2ccnc(NCCCO)n2)n(-c2ccc(F)cc2)c1=O
Temperature: 80 °C
Reaction time: 5 h
Yield: 62.1 %

Procedure:
A mixture of 70 mg of 1-(2-cyanobenzyl)-3-(4-fluorophenyl)-4-(2-methylsulfinylpyrimidin-4-yl)-4-imidazolin-2-one (Compound of Reference example 6(2) or Reference example 7(2)), 60.6 mg of 3-aminopropanol and 2 ml of dioxane was stirred at 80° C. for 5 hours. The reaction mixture was concentrated and then purified by silica gel column chromatography (chloroform: methanol=19:1) and crystallized from ether to give 44.6 mg of the title compound. Melting point: 166-167° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([N+:16]([O-:18])=[O:17])[C:14]=1F)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.CN(C=O)C.[CH3:24][S-:25].[Na+].C(=O)(O)[O-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([N+:16]([O-:18])=[O:17])[C:14]=1[S:25][CH3:24])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: C[S-]
Reactant: O=[N+]([O-])c1c(F)c(Cl)cc2c1[nH]c1cnccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1c(Cl)cc2c([nH]c3cnccc32)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
A 250 ml round-bottom flask with magnetic stirrer was charged with 6-chloro-7-fluoro-8-nitro-β-carboline (Intermediate 5, 3.959 g, 14.9 mmol) and 100 ml anhydrous DMF. The resulting orange mixture was cooled to 0° C. (ice and water bath) and sodium thiomethoxide (1.809 g, 25.8 mmol) in powder form was added slowly thereto. The reaction mixture was stirred for 1 hr at 0° C., warmed to RT, and added slowly to a stirring mixture of 4:1H2O/saturated aqueous sodium bicarbonate (500 ml). The precipitated solid was collected via suction filtration and air-dried to afford 4.017 g of 6-chloro-7-methylsulfanyl-8-nitro-9H-β-carboline as an orange powder. The crude material was used directly in subsequent steps. 1H-NMR (300 MHz, Methanol-d4): δ 8.91 (1H, d) 8.63 (1H, s) 8.42 (1H, d) 8.17 (1H, dd) 2.54 (3H, s). LCMS (formic acid standard method) retention time=1.43 min. MS (M+H+): 294.
Reaction SMILES: S(C1C=CC(C)=CC=1)([O-])(=O)=O.[Cl:12][C:13]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:14]=1[O:15][CH:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[Cl:31])[CH:17](O)[C:18]([CH3:21])([CH3:20])[CH3:19].O>CS(C)=O>[Cl:12][C:13]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:14]=1[O:15][C:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[Cl:31])=[CH:17][C:18]([CH3:20])([CH3:21])[CH3:19]
Reactant: CC(C)(C)C(O)C(Oc1ccc(Cl)cc1Cl)Oc1ccc(Cl)cc1Cl
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)C=C(Oc1ccc(Cl)cc1Cl)Oc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
An equimolar amount of potassium tert.-butylate is added to 54.6 g (0.1 mole) of the tosylate of 1,1-bis-(2,4-dichlorophenoxy)-3,3-dimethylbutan-2-ol in 200 ml of dry dimethylsulfoxide. The mixture is stirred for 30 minutes at room temperature, after which it is hydrolyzed with water and then extracted twice with the same volume of ethyl acetate, the organic phase is dried and the solvent is distilled off under reduced pressure.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>C1COCC1.C(OCC)(=O)C>[O:14]1[CH2:15][CH2:16][N:11]([C:2]2[S:3][CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=2)[CH2:12][CH2:13]1
Reactant: COC(=O)c1csc(Br)n1
Reactant: C1COCCN1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1csc(N2CCOCC2)n1
Yield: 93.4 %

Procedure:
A solution of methyl 2-bromothiazole-4-carboxylate (0.20 g, 0.901 mmol) in THF (10 mL) was treated with morpholine (0.17 mL, 1.94 mmol) and refluxed for 18 h. The reaction was then diluted with ethyl acetate and washed with sat. NaHCO3 (1×), brine (1×) and dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (2.5×10 cm, 50% AcOEt/CH2Cl2) to give the title material (0.192 g, 92%) as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ ppm: 7.44 (s, 1H) 3.82 (s, 3H) 3.75 (m, 4H) 3.45 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[C:18]3[C:17]([NH2:19])=[N:16][CH:15]=[N:14][C:13]=3[N:12]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>ClCCl.N1C=CC=CC=1>[NH2:19][C:17]1[C:18]2[C:10]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([NH:1][C:26](=[O:27])[O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:3]=3)=[CH:11][N:12]([CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24]3)[C:13]=2[N:14]=[CH:15][N:16]=1
Reactant: COc1ccc(-c2cn(C3CCCC3)c3ncnc(N)c23)cc1N
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(-c2cn(C3CCCC3)c3ncnc(N)c23)cc1NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 44.1 %

Procedure:
A solution of 5-(3-amino-4-methoxyphenyl)-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (40 mg, 0.124 mmol) in dichloromethane (1 ml) and pyridine (1 ml) was cooled to 0° C. and then treated with benzyl chloroformate (32 mg, 0.186 mmol) while maintaining a temperature of less than 5° C. The solution was stirred for another 1 hour at 0° C. then the solvents were removed under reduced pressure. Purification by preparative C-18 RP-HPLC then lyophilization provided benzyl N-[5-(4-amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (25 mg) as a white powder: 1H NMR (DMSO-d6, 400 MHz) δ 8.75 (s, 1H), 8.11 (s, 1H), 7.75 (s, 1H), 7.1-7.4 (m, 8H), 6.2 (bs, 2H), 5.15 (s, 2H), 5.07 (m, 1H), 3.8 (s 3H), 1.6-2.2 (m, 8H), RP-HPLC (Hypersil HyPurity Elite C18, 5 μm, 200 A, 250×4.6 mm; 25-100% acetonitrile-0.1 M ammonium acetate over 25 min, 1 ml/min) tr=18.63 min.; MS: MH+458.
Reaction SMILES: [C:1]([C:5]1[C:13]2[O:12][C:11](=[O:14])[CH:10](O)[C:9]=2[CH:8]=[C:7]([CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:19])=O>CN(C)C=O>[C:1]([C:5]1[C:13]2[O:12][C:11](=[O:14])[CH:10]([Cl:19])[C:9]=2[CH:8]=[C:7]([CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: Cc1cc2c(c(C(C)(C)C)c1)OC(=O)C2O
Solvent: CN(C)C=O
Product: Cc1cc2c(c(C(C)(C)C)c1)OC(=O)C2Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 13 %

Procedure:
To a suspension of 2.2 g (10.0 mmol) of 7-tert-butyl-3-hydroxy-5-methyl-3H-benzofuran-2-one (compound (202), Example 1a, Table 2) in 2.4 ml) 55.0 mmol) of thionyl chloride is added one drop of dimethyl formamide and the mixture is stirred for 2 hours at room temperature. Excess thionyl chloride is afterwards distilled off on a vacuum rotary evaporator. Chromatography of the residue on silica gel with the solvent system dichloromethane/hexane=1:1 and crystallisation of the pure fractions from methanol yields 0.30 g (13%) of 7-tert-butyl-3-chloro-5-methyl-3H-benzofuran-2-one, m.p. 81-86° C. (compound (208), Table 2).