Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:31]=[CH:32][CH:33]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[CH:21]=[C:20]([O:22]CC3C=CC=CC=3)[CH:19]=[CH:18][N+:17]=2[O-:30])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C)C.C(O)(C)C.CC(C)=O>C(O)C.[Pd]>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:31]=[CH:32][CH:33]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][N+:17]=2[O-:30])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [O-][n+]1ccc(OCc2ccccc2)cc1NCCCOc1cccc(CN2CCCCC2)c1
Agent: [Pd]
Solvent: CC(C)O
Solvent: CCO
Solvent: CC(C)=O
Product: [O-][n+]1ccc(O)cc1NCCCOc1cccc(CN2CCCCC2)c1
Yield: 78.6 %

Procedure:
2-[3-[3-(Piperidinomethyl)phenoxy]propylamino]-4-benzyloxypyridine-N-oxide (0.94 g) in ethanol (100 ml) was hydrogenated at 344 KPa (50 p.s.i.), for 5 hours in the presence of 10% palladium on charcoal (0.1 g). The reaction mixture was filtered and the filtrate evaporated under reduced pressure to give an oil. Trituration under diethyl ether containing a little isopropanol gave as a buff solid 2-[3-[3-(piperidinomethyl)phenoxy]propylamino]-4-hydroxypyridine-N-oxide (0.59 g), m.p. 140°-142.5° C. (recrystallised from isopropanol-acetone).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].Cl.[CH:23]1([N:29]([CH3:37])[CH2:30][CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(NC(C)C)(C)C>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:34]3[CH2:35][CH2:36][CH:31]([CH2:30][N:29]([CH:23]4[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]4)[CH3:37])[CH2:32][CH2:33]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: CN(CC1CCNCC1)C1CCCCC1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: Cl
Solvent: CC(C)NC(C)C
Product: CN(CC1CCN(C(=O)Oc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)CC1)C1CCCCC1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and cyclohexyl-methyl-piperidine-4-ylmethyl-amine, hydrochloride, 5 equivalent of diisopropylamine was added, praeparative HPLC (Method C) (43%, white crystals). HPLC-MS m/z=492.3 (M+1), Rt: 3.22 min.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]([Cl:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1.CO.[BH3-]C#N.[Na+]>CCOC(C)=O.C(O)(=O)C>[Cl:14][C:12]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:5]([NH:4][CH2:3][CH2:2][NH:1][CH2:25][C:24]2[CH:27]=[CH:28][C:21]([Cl:20])=[CH:22][CH:23]=2)[N:13]=1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Reactant: O=Cc1ccc(Cl)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Clc1ccc(CNCCNc2nc(Cl)nc3c2ncn3C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 63.8 %

Procedure:
The operation is carried out as in Stage 2 of Example 7 starting from 280 mg of the product obtained in Stage 1 of Example 7, 197 mg of 4-chlorobenzaldehyde in place of the benzaldehyde, 4 ml of methanol and 0.2 ml of acetic acid then the reaction medium is agitated at ambient temperature for 5 hours. Then 100 mg of NaBH3CN is added and the reaction medium is agitated at ambient temperature for approximately 1 hour. 10 ml AcOEt is added, followed by washing with 2×5 ml of H2O, then 5 ml of a saturated aqueous solution of NaCl, drying and evaporating the solvent. After purification by chromatography on silica eluting with methylene chloride/methanol/ammonium hydroxide in a proportion of 95/05/0.33, 258 mg of expected product is obtained.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][O:7][C:8]2[C:9]([CH3:20])=[CH:10][C:11]([C:14](N(OC)C)=[O:15])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][O:7][C:8]2[C:9]([CH3:20])=[CH:10][C:11]([CH:14]=[O:15])=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CON(C)C(=O)c1cc(C)c(OCc2ccc(F)cc2)cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1cc(C=O)ncc1OCc1ccc(F)cc1
Yield: 97 %

Procedure:
The title compound is prepared in 97% yield (1.03 g, pale red solid) from 5-((4-fluorobenzyl)oxy)-N-methoxy-N,4-dimethylpicolinamide (1.32 g, 4.33 mmol, Step-4) and lithium aluminum hydride (82 mg, 2.2 mmol) in a similar manner to Step-2 of Amine-3.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[S:30][C:29]([CH:31]=O)=[CH:28][C:9]=3[N:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][SiH2:20][C:21]([CH3:27])([CH3:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH:14]=3)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:33][N:34]1[CH2:39][CH2:38][N:37]([CH2:31][C:29]2[S:30][C:8]3[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[N:12][C:11]([C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([O:19][SiH2:20][C:21]([CH3:26])([CH3:27])[C:22]([CH3:25])([CH3:23])[CH3:24])[CH:14]=4)=[N:10][C:9]=3[CH:28]=2)[CH2:36][CH2:35]1
Reactant: CN1CCNCC1
Reactant: CC(C)(C)C(C)(C)[SiH2]Oc1cccc(-c2nc(N3CCOCC3)c3sc(C=O)cc3n2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN1CCN(Cc2cc3nc(-c4cccc(O[SiH2]C(C)(C)C(C)(C)C)c4)nc(N4CCOCC4)c3s2)CC1
Reaction time: 72 h
Yield: 88 %

Procedure:
A mixture of 4-morpholin-4-yl-2-[3-(1,1,2,2-tetramethyl-propylsilanyloxy)-phenyl]-thieno[3,2-d]pyrimidine-6-carbaldehyde (6.67 g, 14.66 mmol), N-methylpiperazine (2.11 mL, 1.3 equivalents) and acetic acid (838 μL, 1.0 eq.) was stirred in 1,2-dichloroethane (70 mL) at room temperature. To this was added sodium triacetoxyborohydride (3.42 g, 1.1 equivalents) and the reaction mixture was stirred for 3 days. The reaction mixture was then quenched with aqueous sodium bicarbonate solution, extracted exhaustively with chloroform, dried (MgSO4), and the solvent removed in vacuo to yield a yellow oil. This was purified using flash chromatography (silica, ethyl acetate to ethyl acetate/methanol) to yield 6-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-2-[3-(1,1,2,2-tetramethyl-propylsilanyloxy)-phenyl]-thieno[3,2-d]pyrimidine (6.95 g, 88%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.Cl/[C:10](/[CH:16]=O)=[C:11](\[O:13][CH2:14][CH3:15])/[O-:12].[K+].S(=O)(=O)(O)O>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][N:8]=[C:4]2[CH:3]=1
Reactant: Nc1cc(Br)ccn1
Reactant: CCO/C([O-])=C(\Cl)C=O
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1cnc2cc(Br)ccn12
Temperature: 90 °C
Reaction time: 18 h

Procedure:
A solution of 4-bromopyridin-2-amine (10 g, 57.8 mmol) and potassium (Z)-2-chloro-1-ethoxy-3-oxoprop-1-en-1-olate (step 1) (23.4 g, 124 mmol) in ethanol (200 ml) was cooled to 5° C. Sulfuric acid (7.70 ml, 144 mmol) was added dropwise and the reaction heated to reflux at 90° C. for 3 hrs. The mixture was cooled to RT and TEA (20.03 ml, 144 mmol) was slowly added and heating continued at 90° C. for 18 hrs. After cooling to RT, the mixture was filtered and the solid was partitioned between EtOAc and aqueous 2M HCl. The aqueous layer was basified (NaOH, solid pellets) and extracted using EtOAc. The combined organic extracts were dried (MgSO4) and concentrated in vacuo to afford the title compound;
Reaction SMILES: N1C2C=CC=CC=2N=C1.[CH3:10][Si:11]([CH3:26])([CH3:25])[CH2:12][CH2:13][O:14][CH2:15][N:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[CH:17]1.C([Li])CCC.[I:32]I>C1COCC1>[I:32][C:17]1[N:16]([CH2:15][O:14][CH2:13][CH2:12][Si:11]([CH3:26])([CH3:25])[CH3:10])[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=1
Reactant: II
Reactant: C[Si](C)(C)CCOCn1cnc2ccccc21
Agent: [Li]CCCC
Agent: c1ccc2[nH]cnc2c1
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(I)nc2ccccc21
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 63.2 %

Procedure:
Preparation of 2-iodo-1-[2-trimethyl-silanyl)-ethoxymethyl]-1H-benzoimidazole. A solution of 1-(2-(trimethyl-silanyl)-ethoxymethyl]-1H-benzoimidazole (5.029 g, 20.25 mmol) (see Witten et al., J. Org. Chem, 51, 1891-1894 (1986)) in THF (50 mL) was cooled to −78° C. and added dropwise over 12 min via cannula to a flask containing n-butyllithium (2.5 M in hexanes, 12.2 mL) in THF (30 mL) at −78° C. under argon. After stirring for 25 min at −78° C., the flask was warmed to 0° C. for 10 min, then cooled again to −78° C. This solution was then added via cannula to a second flask containing iodine (25.7 g, 101 mmol) in THF (50 mL) at −78° C. Once the addition was complete (˜5 min), the cooling bath was removed, and stirring was continued for 30 min. The reaction mixture was partitioned between ethyl acetate (500 mL) and water (100 mL). The organic layer was washed with saturated aqueous sodium metabisulfite (2×100 mL) to remove the dark iodine color, dried (MgSO4), and concentrated in vacuo. Purification by flash chromatography (10% to 50% ethyl acetate/hexanes) yielded 4.79 g (63%) of pure 2-iodo-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-benzoimidazole as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.76-7.72 (m, 1H), 7.54-7.51 (m, 1H), 7.29-7.25 (m, 2H), 5.54 (s, 2H), 3.59 (t, 2H, J=8.1 Hz), 0.92 (t, 2H, J=8.1 Hz), −0.03 (s, 9H). Anal. (C13H19IN2OS) C, H. Calculated: C, 41.71; H, 5.12; I, 33.90; N, 7.48. Found: C, 41.90; H, 5.09; I, 34.00; N, 7.37.
Reaction SMILES: [Cl:1][CH:2]([Cl:18])[C:3]1[O:8][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[C:13]([C:14]([F:17])([F:16])[F:15])[C:5]=2[N:4]=1.[S:19]1[CH:23]=[CH:22][N:21]=[C:20]1[NH:24][C:25](=[O:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].[OH-].[Na+].Cl>O.O1CCCC1>[Cl:1][CH:2]([Cl:18])[C:3]([NH:4][C:5]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](=[O:9])[CH:26]([C:25]([NH:24][C:20]1[S:19][CH:23]=[CH:22][N:21]=1)=[O:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:8]
Reactant: CCOC(=O)CC(=O)Nc1nccs1
Reactant: O=c1oc(C(Cl)Cl)nc2c(C(F)(F)F)cccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)Nc1nccs1)C(=O)c1cccc(C(F)(F)F)c1NC(=O)C(Cl)Cl
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
At 20° C., 150 g of 2-dichloromethyl-8-trifluoromethyl-4H-3,1-benzoxazine-4-one, 120 g of ethyl 3-(2-thiazolylamino)-3-oxo-propanoate and 1.5 liters of tetrahydrofuran were mixed together and stirred for 30 minutes and then, while maintaining the temperature at 20° C., 40 g of sodium hydroxide in flakes were added thereto. After stirring the mixture at 20° C. for two hours, it was poured into a mixture of 4.5 liters of water and 150 ml of concentrated hydrochloric acid and the mixture was stirred at 0° to +5° C. for 30 minutes. The crystals formed were separated, rinsed with water and dried to obtain 255 g of ethyl 2-[(2,2-dichloro-1-oxoethyl)-amino]-β-oxo-α-[(2-thiazolylamino)-carbonyl]-3-(trifluoromethyl)-benzene-propanoate melting at 90° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([N:13]2[CH:17]=[CH:16][CH:15]=[C:14]2[C:18](=[O:23])[C:19]([Cl:22])([Cl:21])[Cl:20])[CH2:11][C:10](=[O:12])[NH:9][C:7]1=[O:8])=[O:5])[CH3:2].[Br:24]Br.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Br:24][C:16]1[CH:15]=[C:14]([C:18](=[O:23])[C:19]([Cl:22])([Cl:20])[Cl:21])[N:13]([C:6]2([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][C:10](=[O:12])[NH:9][C:7]2=[O:8])[CH:17]=1
Reactant: CCOC(=O)C1(n2cccc2C(=O)C(Cl)(Cl)Cl)CC(=O)NC1=O
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1(n2cc(Br)cc2C(=O)C(Cl)(Cl)Cl)CC(=O)NC1=O
Reaction time: 0.5 h
Yield: 33.1 %

Procedure:
To a stirred solution of 2-ethoxycarbonyl-2-(2-trichloroacetylpyrrol-1-yl)succinimide (6.0 g) in chloroform (30 ml) was added dropwise a solution of bromine (6.9 g) in chloroform (18 ml) under ice cooling. The resulting mixture was stirred under ice cooling for 30 minutes, poured into aqueous sodium bicarbonate solution, and extracted with chloroform. The extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel using chloroform/methanol (2000:1) as the eluent. Fractions containing the title compound were pooled and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give the title compound (2.4 g, 36.4%) as colorless crystals, mp 196°-198° C.
Reaction SMILES: [F:1][C:2]1[C:3]2[C:4]3[N:5]([C:13]([C:16]4[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=4)=[N:14][CH:15]=2)[CH2:6][CH2:7][C:8]=3[NH:9][C:10](=[O:12])[CH:11]=1.[CH3:24][NH2:25]>>[F:1][C:2]1[C:3]2[C:4]3[N:5]([C:13]([C:16]4[CH:17]=[CH:18][C:19]([CH2:20][NH:25][CH3:24])=[CH:22][CH:23]=4)=[N:14][CH:15]=2)[CH2:6][CH2:7][C:8]=3[NH:9][C:10](=[O:12])[CH:11]=1
Reactant: O=Cc1ccc(C2=NC=C3C(F)=CC(=O)NC4=C3N2CC4)cc1
Reactant: CN
Product: CNCc1ccc(C2=NC=C3C(F)=CC(=O)NC4=C3N2CC4)cc1

Procedure:
The title compound was prepared following the procedure described in Example 32 from aldehyde 97a and methylamine (2M/MeOH) to give 0.069 g (42%) of a white solid: mp=204-208° C. (dec); Rf=0.03 (7% methanolic ammonia/CHCl3); IR (KBr) 1655, 1609, 1470, 1437 cm−1; 1H NMR (DMSO-d6) δ 2.30 (s, 3H), 3.54-3.55 (m, 2H), 3.75 (s, 2H), 4.45-4.46 (m, 2H), 7.52 (d, 2H, J=8.2 Hz), 7.57-7.61 (m, 1H), 7.73-7.76 (m, 1H), 7.80 (d, 2H, J=8.2 Hz), 8.59-8.63 (m, 1H). HRMS calcd for C18H17N4OF 324.1386 (M+), found 324.1378. Anal. (C18H17N4OF.0.3H2O) C, H, N.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[S:15][C:14]3C[CH2:17][CH2:18][CH2:19][C:13]=3[C:12]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1SC2CCCC=2C=1C(OCC)=O.C1(S(Cl)(=O)=O)C=CC=CC=1>>[C:1]1([S:7]([NH:10][C:11]2[S:15][C:14]3[CH2:17][CH2:18][CH2:19][C:13]=3[C:12]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2)sc2c1CCCC2
Agent: CCOC(=O)c1c(N)sc2c1CCC2
Agent: O=S(=O)(Cl)c1ccccc1
Product: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2)sc2c1CCC2

Procedure:
Prepared by proceeding in a similar manner to Intermediate 1, starting from ethyl 2-amino-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxylate and benzenesulphonyl chloride.
Reaction SMILES: [CH2:1]([N:5]([CH2:19][CH2:20][CH2:21][CH3:22])[C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[N:10]=1)[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)(Cl)=O.[C:28](=O)([O-])[O-:29].[Na+].[Na+]>CN(C=O)C.O>[CH2:1]([N:5]([CH2:19][CH2:20][CH2:21][CH3:22])[C:6]1[S:7][C:8]([CH:28]=[O:29])=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCCC)c1nc(-c2cccc(OC)c2)cs1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCN(CCCC)c1nc(-c2cccc(OC)c2)c(C=O)s1
Reaction time: 8 h

Procedure:
To a solution of 100.8 g (316.5 mmol) of crude 2-di-n-butylamino-4-(3-methoxyphenyl)thiazole (compound 2-12) and 630 ml of DMF was added, over about 30 mins, a solution of 55.81 g (364 mmol) of phosphorus oxychloride in 188 ml of DMF. The mixture was stirred overnight and poured into a solution of 158.1 g of sodium carbonate in 3.5 l of water. The oily precipitate was extracted with methylene chloride, and the extract was washed with water, dried over magnesium sulfate, and concentrated. The yield of brown oil was 88.77 g and was used without further purification. Anal. Calcd. For C19H26N2O2S: C, 65.9; H, 7.6; N, 8.1; S, 9.3. Found: C, 66.20; H, 7.85; N, 8.60; S, 7.93.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:17]=[C:16]([N:27]3[CH2:31][CH2:30][CH2:29][C@H:28]3[CH3:32])[N:15]=2)[C@H:10]([CH3:33])[CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[F:26][C:23]1[CH:22]=[CH:21][C:20]([C:18]2[CH:19]=[C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]3[CH3:33])[N:15]=[C:16]([N:27]3[CH2:31][CH2:30][CH2:29][C@H:28]3[CH3:32])[N:17]=2)=[CH:25][CH:24]=1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1cc(-c2ccc(F)cc2)nc(N2CCC[C@H]2C)n1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1CNCCN1c1cc(-c2ccc(F)cc2)nc(N2CCC[C@H]2C)n1

Procedure:
Stir 4-[6-(4-fluoro-phenyl)-2-(2-(R)-methyl-pyrrolidin-1-yl)-pyrimidin-4-yl]-3-(R)-methyl-piperazine-1-carboxylic acid tert-butyl ester (4.5 g, 9.88 mmol) in 4M HCl-dioxane (50 mL) for 40 min. Concentrate and partition between EtOAc and sat. NaHCO3. Dry the organic layer (Na2SO4) and concentrate under reduced pressure to yield the title compond.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][C:12]1([C:18]([OH:20])=[O:19])[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]1.CCN(C(C)C)C(C)C>CC(O)C>[CH3:11][C:12]1([C:18]([OH:20])=[O:19])[CH2:17][CH2:16][CH2:15][N:14]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:13]1
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CC1(C(=O)O)CCCNC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C(=O)O)CCCN(c2ccncc2[N+](=O)[O-])C1
Temperature: 60 °C

Procedure:
4-chloro-3-nitropyridine (1.1 eq) was added to a solution of 3-methylpiperidine-3-carboxylic acid (1 eq) and DIEA (3 eq) in iPrOH (0.1 M). The reaction mixture was heated in a 60° C. oil bath for 3 h then concentrated in vacuo. The crude residue was diluted with EtOAc and washed with 1.0 N NaOH. The combined aqueous washes were acidified to pH=4 with 1.0 N HCl and extracted with CH2Cl2. The combined organic phases were dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give 3-methyl-(3-nitropyridin-4-yl)piperidine-3-carboxylic acid. LC/MS (m/z): 266.2 (MH+).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH:11]([OH:24])[C:12](=[NH:23])[NH:13][O:14][C:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:9][CH3:10])(C)(C)C.O.C(O)(C(F)(F)F)=O>C(O)C.[OH-].[OH-].[Pd+2]>[NH2:7][CH:8]([CH2:9][CH3:10])[CH:11]([C:12]1[N:23]=[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:14][N:13]=1)[OH:24]
Reactant: CCC(NC(=O)OC(C)(C)C)C(O)C(=N)NOC(=O)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCC(N)C(O)c1noc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Compound 3 (9.0 g, 39 mmol) was dissolved in ethanol (100 ml) and water (20 ml) followed by the addition of 9 grams of Pd(OH)2 and TFA (4 ml). The mixture was hydrogenated at 50 psi for 48 hours, then the reaction was filtered through celite which was concentrated to give 9 grams of crude material 4 which was used without further purification. Compound 4 was dissolved in dry methanol (300 ml) and HCl gas was bubbled through for 15 minutes. The reaction was stirred at room temperature for three days and was concentrated. The crude product was purified on silica eluting With 1:1 heptane/ethyl acetate to give 3.9 grains of compound 5.
Reaction SMILES: [Br:1]C1C=CC(O)=CC=1CCO.Br[CH:13]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH2:29][O:30][CH3:31])[CH:23]=1)[O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18].BrC1C=CC(OCOCC[Si](C)(C)C)=CC=1CCO.[OH-].[K+].IC>CS(C)=O.O>[Br:1][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])=[CH:23][C:24]=1[CH2:28][CH2:29][O:30][CH3:31]
Reactant: OCCc1cc(O)ccc1Br
Reactant: COCCc1cccc(OC(Br)OCC[Si](C)(C)C)c1
Agent: C[Si](C)(C)CCOCOc1ccc(Br)c(CCO)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Solvent: CI
Product: COCCc1cc(OCOCC[Si](C)(C)C)ccc1Br
Reaction time: 16 h

Procedure:
Preparation of 2-[2-Bromo-5-(2-trimethylsilanyl-ethoxymethoxy)-phenyl] was prepared in 65% yield by the substitution of 4-bromo-3-(2-hydroxy-ethyl)-phenol in the procedure described in Example 24(a), step (vi). 1H NMR (300 MHz, CDCl3) δ 7.43 (d, 1H, J=8.7 Hz), 6.97 (d, 1H, J=3.0 Hz), 6.82 (dd, 1H, J=8.7, 3.0 Hz), 5.19 (s, 2H), 3.88 (q, 2H, J=6.6 Hz), 3.74 (t, 2H, J=8.4 Hz), 2.99 (t, 2H, J=6.6 Hz), 1.42 (t, 1H, J=6.6 Hz), 0.94 (t, 2H, 1=8.4 Hz), −0.01 (s, 9H). {(2-[Bromo-3-(2-methoxy-ethyl)phenoxymethoxy]-ethyl}-trimethyl-silane: 2-[2-Bromo-5-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-ethanol (1.9 g, 6.0 mmol) was added to a solution of potassium hydroxide (1.35 g, 24 mmol) in DMSO (16 mL). Iodomethane (1.12 mL, 18 mmol) was added, and the solution stirred for 16 h. The reaction was diluted with water (50 mL) and extracted with ether (2×40 mL). Organics were washed with brine (40 mL), dried (Na2SO4) and concentrated in vacuo. Purification by silica gel chromatography (10% ether/hexanes) gave 1.28 g of (2-[4-bromo-3-(2-methoxy-ethyl)-phenoxymethoxy]-ethyl)-trimethyl-silane as a clear oil. 1H NMR (300 MHz, CDCl3) δ 7.40 (d, 1H, J=8.7 Hz), 6.96 (d, 1H, J=3.0 Hz), 6.80 (dd, 1H, J=8.7, 3.0 Hz), 5.18 (s, 2H), 3.74 (t, 2H, J=8.4 Hz), 3.60 (t, 2H, J=7.2 Hz), 3.37 (s, 3H), 2.98 (t, 2H, J=7.2 Hz), 0.95 (t, 2H, J=8.4 Hz), −0.01 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]12[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH:14]C(=O)O[C:10]2=[O:11]>CN(C)C=O.C(OCC)(=O)C>[NH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=1[C:10]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=1)=[O:11]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: Nc1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1ccccc1C(=O)Nc1ccc(F)cc1
Temperature: 115 °C

Procedure:
To a solution of 4-fluoroaniline (2.40 mL, 24.5 mmol) in N,N-dimethylformamide (30 mL) was added isatoic anhydride (4.00 g, 24.5 mmol), and the reaction mixture was heated at 115° C. for 14 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (100 mL). The organic layer was washed with 1 N NaOH (200 mL), water (100 mL), then brine, and dried over Na2SO4. The solvent was removed under reduced pressure to give crude product, which was purified by column chromatography (silica gel 230-400 mesh; 10% EtOAc/hexane as eluent) to give 2-amino-N-(4-fluoro-phenyl)-benzamide as white solid. Yield: 2.00 g (35%).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][C:5]2=[CH:9][S:10][CH:11]=[C:4]2[S:3]1(=[O:13])=[O:12].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1.C(N(CC)CC)C.Cl>CS(C)=O>[OH:8][C:7]1[N:2]([CH3:1])[S:3](=[O:13])(=[O:12])[C:4]2[C:5](=[CH:9][S:10][CH:11]=2)[C:6]=1[C:22](=[O:23])[NH:21][C:18]1[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=1
Reactant: CN1C(=O)Cc2cscc2S1(=O)=O
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN1C(O)=C(C(=O)Nc2ccc(Cl)cc2)c2cscc2S1(=O)=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
1 g (4.6 mmol) of 3,4-dihydro-2-methyl-3-oxo-2H-thieno[3,4-e]-1,2-thiazine 1,1-dioxide are stirred at room temperature under nitrogen for 3 hours with 0.71 g (4.6 mmol) of p-chlorophenylisocyanate and 0.47 g (4.6 mmol) of triethylamine in 10 ml of absolute dimethylsulfoxide. Thereafter, the mixture is poured into 40 ml of 2-N hydrochloric acid and 25 g of ice and stirred for 20 minutes. The separated precipitate is filtered off under suction and washed neutral with water. The precipitate is dissolved in 200 ml of methylene chloride, the turbid solution is dried over sodium sulfate, stirred with 0.3 g of active carbon and filtered. The filtrate is extracted with five 100 ml portions of saturated sodium carbonate solution, each of the aqueous phases being re-extracted with a small amount of methylene chloride. The combined aqueous phases are acidified to pH 1 with concentrated hydrochloric acid. The precipitated product is extracted with two 150 ml portions of methylene chloride. The combined organic phases are dried over sodium sulfate. The solvent is distilled off, whereby the product crystallizes out. For purification, the product is recrystallized from ca 30 ml of methanol. There is obtained 3-hydroxy-2-methyl-4-(4-chlorophenylcarbamoyl)-2H-thieno[3,4-e]-1,2-thiazine 1,1-dioxide of melting point 154°-156° C.