Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][NH:7][C:8]1[C:17]2[C:12](=[C:13]([C:18]([NH2:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][N:9]=1.Cl[C:25]1[S:26][C:27]2[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:28]=2[N:29]=1>>[CH3:35][O:34][C:32]1[CH:31]=[CH:30][C:28]2[N:29]=[C:25]([NH:2][C:3]3[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=3)[CH2:6][NH:7][C:8]3[C:17]4[C:12](=[C:13]([C:18]([NH2:20])=[O:19])[CH:14]=[CH:15][CH:16]=4)[N:11]=[CH:10][N:9]=3)[S:26][C:27]=2[CH:33]=1
Reactant: COc1ccc2nc(Cl)sc2c1
Reactant: NC(=O)c1cccc2c(NCc3cccc(N)c3)ncnc12
Agent: Cl
Product: COc1ccc2nc(Nc3cccc(CNc4ncnc5c(C(N)=O)cccc45)c3)sc2c1

Procedure:
The title compound was prepared according to Example 684 starting 4-(3-Amino-benzylamino)-quinazoline-8-carboxylic acid amide hydrochloride and 2-Chloro-6-methoxy-benzothiazole:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[N:14]2[C:9]([C:10]([O:18][CH3:19])=[C:11](Cl)[CH:12]=[CH:13]2)=[C:8]([CH:20]2[CH2:22][CH2:21]2)[CH:7]=1)=[O:5])C.C([NH:30][CH2:31][CH2:32][CH:33]1[CH2:37][CH2:36][NH:35][CH2:34]1)(OC(C)(C)C)=O>>[NH2:30][CH2:31][CH2:32][CH:33]1[CH2:37][CH2:36][N:35]([C:11]2[CH:12]=[CH:13][N:14]3[C:9]([C:10]=2[O:18][CH3:19])=[C:8]([CH:20]2[CH2:21][CH2:22]2)[CH:7]=[C:6]([C:4]([OH:3])=[O:5])[C:15]3=[O:16])[CH2:34]1
Reactant: CC(C)(C)OC(=O)NCCC1CCNC1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(OC)c(Cl)ccn2c1=O
Product: COc1c(N2CCC(CCN)C2)ccn2c(=O)c(C(=O)O)cc(C3CC3)c12

Procedure:
A series of procedures similar to Example 1 above is carried out, using Ethyl-8-chloro-1-cyclopropyl-9-methoxy-4-oxo-4H-quinolizine-3-carboxylate (Precursor B) and 3-(N-boc-aminoethyl)pyrrolidine (Precursor D) as the starting materials.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([C:6]([NH:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])=[C:4]([CH3:16])[CH:3]=1.C([Li])CCC.CN(C)[CH:24]=[O:25].Cl>O1CCCC1.O>[CH:24]([C:2]1[CH:15]=[CH:14][C:5]([C:6]([NH:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])=[C:4]([CH3:16])[CH:3]=1)=[O:25]
Reactant: CN(C)C=O
Reactant: Cc1cc(Br)ccc1C(=O)NCC(F)(F)F
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C=O)ccc1C(=O)NCC(F)(F)F

Procedure:
In a solution of 1.00 g of 4-bromo-2-methyl-N-(2,2,2-trifluoroethyl) benzoic acid amide in 15 ml of tetrahydrofuran under nitrogen atmosphere, 4.7 ml of n-butyl lithium (1.58M hexane solution) was added dropwise at −70° C. with stirring, and then 0.4 ml of N,N-dimethylformamide were added dropwise. After stirring at the same temperature for 30 minutes, 10 ml of 1N hydrochloric acid and then 30 ml of water were added, and extracted with ethyl acetate (30 ml×2). The organic phase was dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 0.80 g of the aimed product as pale yellow crystal.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH2:6]([N:8]1[C:16](OC)=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]2)=[C:9]1[CH:19]=[CH:20][C:21]1[O:22][C:23]2[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=2[N+:25]=1[CH2:26][CH3:27])[CH3:7].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:43]([N+:45]1[C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=2[S:47][C:46]=1[CH3:54])[CH3:44].C(N(CC)CC)C>C(#N)C>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH2:6]([N:8]1[C:16]([CH:54]=[C:46]2[N:45]([CH2:43][CH3:44])[C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=3[S:47]2)=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]2)=[C:9]1[CH:19]=[CH:20][C:21]1[O:22][C:23]2[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=2[N+:25]=1[CH2:26][CH3:27])[CH3:7]
Reactant: CCn1c(C=Cc2oc3ccccc3[n+]2CC)c2ccccc2c1OC
Reactant: CC[n+]1c(C)sc2ccccc21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCN1C(=Cc2c3ccccc3c(C=Cc3oc4ccccc4[n+]3CC)n2CC)Sc2ccccc21

Procedure:
2-[2-(2-Ethyl-3-methoxyisoindol-1-yl)vinyl]-3-ethyl-benzoxazolium perchlorate (1.0 g) and 3-ethyl-2-methylbenzothiazolium p-toluenesulfonate (0.9 g) were dissolved in acetonitrile. Triethylamine was added and the reaction mixture stirred until the absorption at 520 nm disappeared. The reaction mixture was evaporated to dryness and chromatographed on silica gel. After recrystallization of the product from methanol, the melting point was 180° C. CH3CN λ max 625 nm.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH:12]=O)=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[BH4-].[Na+].P(Br)(Br)[Br:17]>CCO>[Br:17][CH2:12][C:9]1[O:10][C:11]2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=2[CH:8]=1
Reactant: BrP(Br)Br
Reactant: COc1cccc2cc(C=O)oc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc2cc(CBr)oc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Compound 29 (450 mg, 2.56 mmol) was dissolved in EtOH (10 mL). NaBH4 (104 mg, 2.81 mmol) was added portionwise at 0° C., with vigorous stirring. The suspension was stirred at 0° C. for 15 min and then at room temperature for 1.5 h. Solvent was evaporated off in-vacuo. The resulting crude alcohol residue was dissolved in toluene (5 mL) and the solution was cooled to 0° C. PBr3 (240 μL, 2.56 mmol) was added dropwise over 10 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:12]Br)[C:5]([C:8]([O:10]C)=O)=[N:6][CH:7]=1.[NH2:14][C@@H:15]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=1)[CH2:16][N:17]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:27].C(N(CC)C(C)C)(C)C>C(O)CCC>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][N:14]([C@@H:15]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=3)[CH2:16][N:17]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]3=[O:27])[C:8](=[O:10])[C:5]2=[N:6][CH:7]=1
Reactant: COC(=O)c1ncc(Br)cc1CBr
Reactant: N[C@@H](Cc1cccc(F)c1)CN1C(=O)c2ccccc2C1=O
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2ccccc2C(=O)N1C[C@H](Cc1cccc(F)c1)N1Cc2cc(Br)cnc2C1=O
Temperature: 120 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
A mixture of methyl 5-bromo-3-(bromomethyl)pyridine-2-carboxylate (500.0 mg, 1.618 mmol), 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (482.8 mg, 1.618 mmol) and N,N-diisopropylethylamine (0.564 mL, 3.24 mmol) in 1-butanol (10.0 mL) was stirred at 120° C. for 2 h under microwave. Purification by combi-flash chromatography gave 0.48 g (61% yield) of the desired product. LC-MS found: 494.1 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[S:14][C:15]=2[Br:16])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[C:28]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>C(Cl)Cl>[C:31]([O:30][C:28]([N:35]1[CH2:40][CH2:39][N:38]([S:17]([C:13]2[S:14][C:15]([Br:16])=[C:11]([C:7]3[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=3[CH3:10])[CH:12]=2)(=[O:19])=[O:18])[CH2:37][CH2:36]1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Cl)sc2Br)s1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)N3CCN(C(=O)OC(C)(C)C)CC3)sc2Br)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
4-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]-5-bromothiophene-2-sulfonyl chloride, prepared as in Step III of Example 23 (400 mg; 0.96 mmol; 1 eq), is dissolved in anhydrous DCM (20 ml). The solution is cooled down to 0° C. and put under nitrogen. Triethylamine (0.54 ml; 1.92 mmol; 4 eq) and 1-Boc-piperazine (358.4 mg; 1.92 mmol; 2 eq) are added successively and the reaction mixture is stirred at 0° C. for 1 hour. The reaction mixture is washed with water, NaHCO3 and dried over MgSO4, affording the title compound (440 mg; 76%).
Reaction SMILES: [OH-].[Ca+2].[OH-].[CH2:4]([O:6][C:7]([CH:9]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:10][S:11]([C:14]([CH3:25])([CH3:24])[CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:13])=[O:12])=[O:8])[CH3:5].O>C(O)C>[C:19]([O:18][C:17]([NH:16][CH2:15][C:14]([S:11]([CH2:10][C@H:9]([CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:7]([O:6][CH2:4][CH3:5])=[O:8])(=[O:12])=[O:13])([CH3:25])[CH3:24])=[O:23])([CH3:20])([CH3:21])[CH3:22]
Reactant: CCOC(=O)C(Cc1ccccc1)CS(=O)(=O)C(C)(C)CNC(=O)OC(C)(C)C
Agent: [Ca+2]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)[C@@H](Cc1ccccc1)CS(=O)(=O)C(C)(C)CNC(=O)OC(C)(C)C
Yield: 49.1 %

Procedure:
A 0.039N calcium hydroxide solution is added while stirring to a mixture of 1.75 g (4.1 mmol) of tert-butyl [2-[[(RS)-2-(ethoxycarbonyl)-3-phenylpropyl]sulphonyl]-2-methylpropyl]carbamate and 70 mg of α-chymotrypsin in 5 ml of ethanol and 250 ml of water in such a manner that the pH value is maintained at 7.5. When calcium hydroxide is no longer consumed, the working-up of the reaction mixture is effected by extracting the aqueous solution twice with 50 ml of ethyl acetate each time. The combined organic phases are washed with 25 ml of saturated sodium bicarbonate solution, dried over sodium sulphate and evaporated under reduced pressure. There is obtained 0.86 g of ethyl (R)-α-[[[2-(1-tert-butoxyformamido)-1,1-dimethylethyl]sulphonyl]methyl]hydrocinnamate as a yellowish oil; MS: 445 (M+NH4)+.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)([OH:11])[C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1.[C@@:21]12(O)[N:28](C)[C@@H:25]([CH2:26][CH2:27]1)[CH2:24][CH:23]=[CH:22]2>>[F:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)([OH:11])[C:7]([O:9][C@@:10]23[N:28]([CH3:21])[C@@H:25]([CH2:26][CH2:27]2)[CH2:24][CH:23]=[CH:22]3)=[O:8])=[CH:4][CH:3]=1
Reactant: COC(=O)C(O)(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CN1[C@@H]2CC=C[C@@]1(O)CC2
Product: CN1[C@@H]2CC=C[C@@]1(OC(=O)C(O)(c1ccc(F)cc1)c1ccc(F)cc1)CC2

Procedure:
4.5 is prepared analogously to the method according to II.1. Yield: 8.71 g (69% of theory) starting from 8.35 g (0.03 mol) of 3c and 4.18 g (0.03 mol) of tropenol; TLC: Rf value: 0.34 (eluant as in step II.1); melting point: 167° C.-169° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([Cl:29])[N:24]=3)[CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:30][S:31](Cl)(=[O:33])=[O:32]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([Cl:29])[N:24]=3)[CH:18]=2)[S:31]([CH3:30])(=[O:33])=[O:32])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(CNCc2cccc(-c3ccnc(Cl)n3)c2)CC1
Reactant: CS(=O)(=O)Cl
Product: CC(C)(C)OC(=O)N1CCC(CN(Cc2cccc(-c3ccnc(Cl)n3)c2)S(C)(=O)=O)CC1

Procedure:
Intermediate 55 was coupled with methanesulfonyl chloride following procedure D. LC-MS showed the product had the expected M+H+ of 495.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[NH:10]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][C:20]3[C:21]4[S:28][C:27]([C:29]5[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=5)=[CH:26][C:22]=4[N:23]=[CH:24][N:25]=3)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1>>[NH:10]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][C:20]3[C:21]4[S:28][C:27]([C:29]5[CH:36]=[CH:35][C:32]([CH2:33][NH:1][CH2:2][CH2:3][N:4]6[CH2:9][CH2:8][O:7][CH2:6][CH2:5]6)=[CH:31][CH:30]=5)=[CH:26][C:22]=4[N:23]=[CH:24][N:25]=3)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1
Reactant: O=Cc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Reactant: NCCN1CCOCC1
Product: c1nc(Nc2ccc3[nH]ccc3c2)c2sc(-c3ccc(CNCCN4CCOCC4)cc3)cc2n1

Procedure:
The title compound was prepared from N-(2-aminoethyl)morpholine and 4-[4-(1H-indol-5-ylamino)-thieno[3,2-d]pyrimidin-6-yl]-benzaldehyde by a procedure analogous to example 17. M.P. 100-111° C.; LC-MS: 485 (MH+); HPLC RT: 4.23 minutes.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[C:19]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH:18]=[C:17]([F:28])[CH:16]=2)=[O:13])[N:8]([CH3:10])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:36][C:37]([Cl:42])([Cl:41])[C:38](Cl)=[O:39]>ClCCl>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[C:19]([O:21][CH:22]3[CH2:23][CH2:24][N:25]([C:38](=[O:39])[C:37]([Cl:42])([Cl:41])[Cl:36])[CH2:26][CH2:27]3)[CH:18]=[C:17]([F:28])[CH:16]=2)=[O:13])[N:8]([CH3:10])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1nc(C(C)(C)C)cc1NC(=O)Nc1cc(F)cc(OC2CCNCC2)c1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1nc(C(C)(C)C)cc1NC(=O)Nc1cc(F)cc(OC2CCN(C(=O)C(Cl)(Cl)Cl)CC2)c1
Temperature: 22 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To an ice-water cooled solution of 1-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-3-{3-fluoro-5-(piperidin-4-yloxy)-phenyl}-urea (390.6 mg, 1.0 mmol) and triethylamine (280 μL, mmol) in dichloromethane (5 mL) is added trichloroacetyl chloride (115 μL, 1.0 mmol). The reaction mixture is allowed to warm up to 22° C. and stirred for 1 hour. After removal of solvent, the residue is purified on a silica gel chromatography with hexanes and ethyl acetate to provide a white solid (520.0 mg, 97% yield, ES+(m/z) 535.9 [M+H]).
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[C:8]([C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])[CH:15]=O)([CH3:11])([CH3:10])[CH3:9].N1CCCCC1>C(O)C>[C:21]([C:18]1[CH:17]=[C:14]([CH:15]=[C:5]2[S:1][C:2](=[O:7])[NH:3][C:4]2=[O:6])[CH:13]=[C:12]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:19]=1[OH:20])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: O=C1CSC(=O)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(C)(C)c1cc(C=C2SC(=O)NC2=O)cc(C(C)(C)C)c1O
Yield: 42.7 %

Procedure:
To a solution of 12.5 g (107 mmol) of 2,4-thiazolidinedione and 25.0 g (107 mmol) of 3,5-di-tert-butyl-4-hydroxybenzaldehyde in 300 ml of ethanol, 1.05 ml (10.7 mmol) of piperidine was added, and the mixture was heated under reflux for 5 hours. After cooling, the precipitated crystals were filtered and washed with cooled ethanol to give 15.23 g of the desired compound (42.8% yield, pale yellow crystals).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:3]=1[CH2:4][O:5][C@@H:6]1[O:11][C@@H:10]([CH2:12]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:9][CH2:8][CH2:7]1.[Na].[NH:30]1[CH:34]=[CH:33][N:32]=[CH:31]1>CN(C)C=O>[Cl:1][C:2]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:3]=1[CH2:4][O:5][C@@H:6]1[O:11][C@@H:10]([CH2:12][N:30]2[CH:34]=[CH:33][N:32]=[CH:31]2)[CH2:9][CH2:8][CH2:7]1
Reactant: c1c[nH]cn1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCC[C@H](OCc3ccc(Cl)cc3Cl)O2)cc1
Agent: [Na]
Solvent: CN(C)C=O
Product: Clc1ccc(CO[C@H]2CCC[C@H](Cn3ccnc3)O2)c(Cl)c1

Procedure:
As in Example 1(b), 5 ml of a dimethylformamide solution containing 1.70 g of trans-6-(2,4-dichlorobenzyloxy)-2-tosyloxymethyltetrahydropyran were added to 15 ml of a dimethylformamide solution containing 5.73 mmoles of the sodium salt of imidazole and the mixture was allowed to react for 2 hours at 85° C., after which it was treated and purified as in Example 1(b), to give 1.2 g of the title compound as a colourless oil.
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH2:10][C:11]#[C:12][CH:13]([OH:18])[CH:14]([Cl:17])[CH2:15][CH3:16])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].N1C2C(=CC=CC=2)C=CC=1>C(OCC)(=O)C.[Pd]>[O:1]=[C:2]([CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH:13]([OH:18])[CH:14]([Cl:17])[CH2:15][CH3:16])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CC(=O)CCC#CC(O)C(Cl)CC
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: c1ccc2ncccc2c1
Product: CCOC(=O)CC(=O)CC/C=C\C(O)C(Cl)CC
Yield: 99.3 %

Procedure:
A solution of 4.6 g of the product of Step A in 66 ml of ethyl acetate containing 0.5 g of 5% palladium on barium sulfate and 0.625 ml of quinoline was hydrogenated and then was filtered to remove the catalyst. The filtrate was washed with dilute hydrochloric acid and then with water, was dried and evaporated to dryness to obtain 4.6 g of ethyl 3-oxo-8-hydroxy-9-chloro-cis-6-undecenoate with a refractive index of nD20 = 1.4800.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4]1.C(N(CC)CC)C.[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([O:1][CH2:2][C@H:3]2[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:15])[CH2:4]2)(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](CO)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)C2)cc1
Temperature: 0 °C
Yield: 70.5 %

Procedure:
To a stirred solution of tert-butyl (1R,3S)-3-(hydroxymethyl)cyclopentylcarbamate (Step 2, about 4.5 g, 21.12 mmol) in DCM (50 ml), triethyl amine (about 9.5 ml, 68.1 mmol) was added at room temperature and cooled to about 0° C. After ten minutes, 4-methylbenzene-1-sulfonyl chloride (about 6.0 g) was added and stirred the reaction at room temperature for about 6 hours. Completion of the reaction was monitored by TLC. The reaction mixture was neutralized with saturated NaHCO3 and extracted with DCM, the organic layer was dried over Na2SO4 and concentrated under reduced pressure to furnish the title compound (5.5 g) as light yellow liquid. 1H NMR (300 MHz, CDCl3): 1.45 (s, 9H); 246-2.55 (m, 4H); 2.90-2.91 (m, 1H); 3.95-3.98 (m, 2H); 4.59-4.70 (m, 2H); 5.66-5.77 (m, 2H); 7.34-7.37 (d, J=9 Hz, 2H); 7.77-7.80 (d, J=9 Hz, 2H); ES Mass: 369 [M+1] 370 (100%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:2]1.Cl[C:34]([CH2:36][O:37]C(=O)C)=[O:35]>>[OH:37][CH2:36][C:34]([N:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:2]1)=[O:35]
Reactant: CC(=O)OCC(=O)Cl
Reactant: O=C(NCC1CCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Product: O=C(NCC1CCN(C(=O)CO)C1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12

Procedure:
Starting from 4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (pyrrolidin-3-ylmethyl)-amide (example A146) and acetic acid chlorocarbonyl-methyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[O:5][C:6]1[N:7]=[C:8]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[C:9]([C:14]([NH2:16])=[O:15])=[N:10][C:11]=1[CH2:12][CH3:13].C(N(C(C)C)CC)(C)C.[C:43](Cl)(=[O:46])[CH:44]=[CH2:45]>C(Cl)(Cl)Cl>[C:43]([NH:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[O:5][C:6]1[N:7]=[C:8]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]3)=[CH:22][CH:23]=2)[C:9]([C:14]([NH2:16])=[O:15])=[N:10][C:11]=1[CH2:12][CH3:13])(=[O:46])[CH:44]=[CH2:45]
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1Oc1cccc(N)c1
Reactant: C=CC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cccc(Oc2nc(Nc3ccc(N4CCN(C)CC4)cc3)c(C(N)=O)nc2CC)c1
Reaction time: 1 h

Procedure:
To a mixture of 5-(3-aminophenoxy)-6-ethyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (2 g), diisopropylethylamine (1.53 mL), and chloroform (100 mL) was added acryloyl chloride (508 μL) under ice-cooling, followed by stirring for 1 hour. Acryloyl chloride (363 μL) was added thereto, followed by stirring for 1 hour. The mixture was subject to liquid separation by the addition of chloroform and a saturated aqueous sodium hydrogen carbonate solution, and the organic phase was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was concentrated and the obtained residue was purified by silica gel column chromatography (chloroform:methanol:28% aqueous ammonia=1:0:0-200:10:1). Ethyl acetate was added thereto, the solid was collected by filtration and then dried under reduced pressure to obtain 5-[3-(acryloylamino)phenoxy]-6-ethyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (1.6 g) as a pale yellow solid.
Reaction SMILES: [C:1]([Si:5]([CH3:23])([CH3:22])[O:6][C:7]1[CH:8]=[C:9]([CH:13]2[C:18](=[O:19])[NH:17][C:16](=[O:20])[NH:15][C:14]2=[O:21])[CH:10]=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[Br:24]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([Si:5]([CH3:23])([CH3:22])[O:6][C:7]1[CH:8]=[C:9]([C:13]2([Br:24])[C:14](=[O:21])[NH:15][C:16](=[O:20])[NH:17][C:18]2=[O:19])[CH:10]=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C2C(=O)NC(=O)NC2=O)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C2(Br)C(=O)NC(=O)NC2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.4 %

Procedure:
A mixture of 5-[3-(tertbutyldimethylsilyloxy)phenyl]barbituric Acid (680 mg), N-bromosuccinimide (432 mg) and dibenzoyl peroxide (catalytic amount) in 10 ml of carbon tetrachloride are stirred at room temperature for 1 hour. The solvent is evaporated off and the residue is purified by silica gel chromatography (eluent:ethyl acetate/hexane 7:3) to give 550 mg of the product, m.p. 170-172° C.
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C@@H:10]([CH3:14])[C:11](O)=[O:12])=[CH:3][CH:2]=1.[CH3:29][S:30]([NH2:33])(=[O:32])=[O:31].CCN=C=NCCCN(C)C.Cl.ON1C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:19]([O:18][C:16](=[O:17])[NH:15][C@H:8]([CH2:7][C:4]1[CH:5]=[CH:6][C:1]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:2][CH:3]=1)[CH2:9][C@@H:10]([CH3:14])[C:11]([NH:33][S:30]([CH3:29])(=[O:32])=[O:31])=[O:12])([CH3:22])([CH3:21])[CH3:20]
Reactant: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)NS(C)(=O)=O
Temperature: 25 °C
Yield: 55.4 %

Procedure:
To a solution of (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methyl-pentanoic acid (500 mg, 1.304 mmol) in DMF (10 ml) at room temperature is added methyl sulfonamide (223 mg, 2.347 mmol), EDC.HCl (450 mg, 2.347 mmol), 1-hydroxy-7-azabenzotriazole (284 mg, 2.086 mmol) and DIPEA (0.501 ml, 2.87 mmol). The reaction mixture is stirred at room temperature over night. The reaction is quenched by brine and is extracted with EtOAc. The combined organic layer is washed with brine and is dried over anhydrous sodium sulfate, filtered and concentrated. Reverse phase HPLC [15 to 60% ACN—H2O (0.1% NH4OH) over 10 min by X-bridge phenyl column] provides ((1S,3R)-1-Biphenyl-4-ylmethyl-4-methanesulfonylamino-3-methyl-4-oxo-butyl)-carbamic acid tert-butyl ester (333 mg, 55%). HPLC retention time=1.03 minutes (condition D), MS (m−1)=495.5, MS (m−55)=405.3, MS (m−99)=361.3.
Reaction SMILES: [C:1]([O-:4])([O-])=O.[K+].[K+].C1(C)C=CC=CC=1.[CH3:14][CH:15]1[CH2:23][C:22]2[C:17](=[CH:18][C:19]([CH3:24])=[CH:20][CH:21]=2)[C:16]1=O>O>[CH3:14][C:15]1([CH2:1][OH:4])[CH2:16][C:17]2[C:22](=[CH:21][CH:20]=[C:19]([CH3:24])[CH:18]=2)[CH2:23]1
Reactant: Cc1ccc2c(c1)C(=O)C(C)C2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc2c(c1)CC(C)(CO)C2
Reaction time: 2 h
Yield: 215.1 %

Procedure:
147.53 g of K2CO3, 875 g of toluene and 350 g of 2,6-dimethyl indanone were introduced, under nitrogen, into a Schmizo-type 1.5 l vessel provided with a condenser and a mechanical stirrer. The mixture was heated to 51°. 122.45 g of Formcel® 55% (origin: Hoechst) were then added over a period of 1 h. The mixture was stirred continuously at 51° for 2 h. The reaction medium was then cooled to 24° and 350 g of water were added. After being stirred for 10 mins, the mixture was decanted, then washed 3 times with water. Concentration in vacuo produced 404.71 g of raw product pure to 97.6% (GC).