Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([NH:27][C@@H:28]2[C:34](=[O:35])[NH:33][C:32]3[CH:36]=[CH:37][CH:38]=[CH:39][C:31]=3[S:30][CH2:29]2)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>O.CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][C@@H:21]([NH:27][C@@H:28]2[C:34](=[O:35])[N:33]([CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:32]3[CH:36]=[CH:37][CH:38]=[CH:39][C:31]=3[S:30][CH2:29]2)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CCl
Reactant: CCOC(=O)C(CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@H]1CSc2ccccc2NC1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 37.6 %

Procedure:
A mixture of 3(R)-[5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl]amino-2,3-dihydro-1,5(5H)-benzothiazepin-4-one (1.0 g), tert-butyl chloroacetate (0.27 g), potassium iodide (0.3 g), potassium carbonate (0.24 g) and N,N-dimethylformamide (10 ml) is stirred for 15 hours at room temperature. The mixture is poured into water (50 ml) and extracted with ethyl acetate (40 ml). The extract is washed with diluted hydrochloric acid, sodium bicarbonate solution and water successively, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give firstly tert-butyl 3(R)-[5-(1-benzyloxycarbonyl-4-piperidyl)-1(R)-ethoxycarbonylpentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate (0.45 g) as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8])([O-])=O>[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8]
Reactant: N#Cc1cccc([N+](=O)[O-])c1
Agent: [Ni]
Product: NCc1cccc(N)c1
Yield: 49 %

Procedure:
A process wherein M-nitrobenzonitrile is subjected to high pressure catalytic reduction with Raney nickel catalyst to obtain m-aminobenzylamine (yield: 49%) (J.R. Griffith et al., NRL Report 6439)).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][C:11]=2[C:10]([C:18]2[CH:23]=[CH:22][C:21](Cl)=[CH:20][CH:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25]C1C=CC(C(Cl)=O)=CC=1>>[CH2:1]([N:8]1[C:17]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][C:11]=2[C:10]([C:18]2[CH:23]=[CH:22][C:21]([CH3:25])=[CH:20][CH:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2nn(Cc3ccccc3)c3c2CCNCC3)cc1
Reactant: Cc1ccc(C(=O)Cl)cc1
Product: Cc1ccc(-c2nn(Cc3ccccc3)c3c2CCNCC3)cc1
Yield: 6.3 %

Procedure:
The title compound (0.2 g) was prepared from 4-oxo-azepane-1-carboxylic acid tert-butyl ester (Example 59, Step B; 10 mmol) as in Example 59, Steps C through E, using 4-methyl-benzoyl chloride (11 mmol) in place of 4-chloro-benzoyl chloride. MS (ESI): exact mass calculated for C21H23N3, 317.19; found, m/z 318.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.34-7.33 (m, 2H), 7.29-7.26 (m, 2H), 7.24-7.21 (m, 3H), 7.10-7.09 (m, 2H), 5.40 (s, 2H), 3.33-3.27 (m, 4H), 3.11-3.09 (m, 2H), 3.00-2.98 (m, 2H), 2.30 (s, 3H).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([Br:14])=[CH:11][CH:12]=2)[C@H:7]([NH2:15])[CH2:6][C@@H:5]1[CH3:16])(=[O:3])[CH3:2].CCN(C(C)C)C(C)C.Cl[C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28].C1(C)C=CC=CC=1>ClCCl>[CH3:31][CH:30]([O:29][C:27](=[O:28])[NH:15][C@H:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([Br:14])[CH:9]=2)[N:4]([C:1](=[O:3])[CH3:2])[C@@H:5]([CH3:16])[CH2:6]1)[CH3:32]
Reactant: CC(C)OC(=O)Cl
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](N)C[C@@H]1C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reaction time: 2 h

Procedure:
(cis)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinamine (for a preparation see Intermediate 4) (3.165 g, 9.90 mmol) and DIPEA (5.19 ml, 29.7 mmol) were stirred in dichloromethane (DCM) (66.0 ml) under nitrogen. 1M isopropyl chloroformate in toluene (14.85 ml, 14.85 mmol) was added, the mixture stirred for 2 hours, evaporated to dryness, partitioned between ethyl acetate (200 ml) water (70 ml) and the aqueous layer run off. The organic layer was washed (water (50 ml), brine (20 ml)), dried (sodium sulfate), evaporated to dryness, loaded on to a 40+M Biotage silica column and eluted with cyclohexane:ethyl acetate (9:1 to 1:1). The product containing fractions were evaporated to a white solid (3.23 g). LCMS (Method B): Rt=1.03, MH+=371
Reaction SMILES: [CH3:1][CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Si:12]([CH2:17][CH3:18])([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][CH:7]=1)[CH2:3]Cl.[CH3:19][C@H:20]1[O:25][C@@H:24]([CH3:26])[CH2:23][NH:22][CH2:21]1.C([O-])([O-])=O.[Na+].[Na+]>>[CH2:13]([Si:12]([CH2:17][CH3:18])([CH2:15][CH3:16])[C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH:2]([CH3:1])[CH2:3][N:22]2[CH2:21][C@H:20]([CH3:19])[O:25][C@H:24]([CH3:26])[CH2:23]2)=[CH:7][CH:8]=1)[CH3:14]
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: CC[Si](CC)(CC)c1ccc(CC(C)CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC[Si](CC)(CC)c1ccc(CC(C)CN2C[C@@H](C)O[C@@H](C)C2)cc1
Temperature: 150 °C
Reaction time: 6 h

Procedure:
13.5 parts of 2-methyl-3-(4-triethylsilylphenyl)-propyl chloride and 16.5 parts of cis-2,6-dimethylmorpholine were mixed and the mixture was stirred at 150° C. for 6 hours, cooled and brought to about pH 9 with saturated Na2CO3 solution. After extraction with methylene chloride, the organic phase was dried and concentrated and the residue was distilled to give, at a boiling point of 110°-114° C./0.01 mm Hg, 12.6 parts of 4-[3-(4-triethylsilylphenyl)-2-methylpropyl]-cis-2,6-dimethylmorpholine of nD23 1.5025 (Compound No. 15).
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10]([C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][CH:16]=[N:15]2)=[O:11].C([O-])([O-])=O.[K+].[K+].Br[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CC#N>[CH2:29]([O:8][C:7]1[C:2]([F:1])=[C:3]([C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[CH:17][CH:16]=[N:15]3)=[O:11])[C:4]([F:9])=[CH:5][CH:6]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: BrCc1ccccc1
Reactant: O=C(c1ccc2nccnc2c1)c1c(F)ccc(O)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(c1ccc2nccnc2c1)c1c(F)ccc(OCc2ccccc2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
To a solution of (2,6-difluoro-3-hydroxyphenyl)(quinoxalin-6-yl)methanone (57 mg, 0.2 mmol, 1.0 eq.) in CH3CN (10 mL) were added K2CO3 (56 mg, 0.4 mmol, 2 eq.) and (bromomethyl)benzene (38 mg, 0.22 mmol, 1.1 eq). The resulting mixture was stirred at rt overnight, then concentrated. The residue was purified via flash column chromatography (PE/EA=10/1, v/v) to afford (3-(benzyloxy)-2,6-difluorophenyl)(quinoxalin-6-yl)methanone as brown solid (38.4 mg, 51.2%). LRMS (M+H+) m/z calculated 377.1, found 377.1. 1H NMR (CDCl3, 400 MHz) δ 8.93-8.95 (d, 2 H), 8.48 (s, 1 H), 8.39-8.41 (d, 1 H), 8.23-8.26 (d, 1 H), 7.33-7.45 (m, 5 H), 7.10-7.16 (m, 1 H), 6.91-6.95 (t, 1 H), 5.17 (s, 2 H).
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][C:8]=1[N:9]([C:16](=O)[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=1[F:26])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:3])[NH2:2].[H-].[Na+].Cl>CN(C=O)C.CCOCC>[F:26][C:20]1[C:21]([F:25])=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][CH2:17][C:16]1[N:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:8]2[CH:7]=[CH:6][S:5][C:4]=2[C:1](=[O:3])[N:2]=1
Reactant: CCOC(=O)CN(C(=O)CCc1cccc(F)c1F)c1ccsc1C(N)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)Cn1c(CCc2cccc(F)c2F)nc(=O)c2sccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
Ethyl 2-((2-carbamoylthiophen-3-yl)-(3-(2,3-difluorophenyl)propanoyl)amino)acetate (Int. B56) (500 mg) in dry DMF (3 ml) was cooled in an ice bath and treated portion wise with sodium hydride (50 mg, 60% dispersion in oil). The reaction mixture was stirred at room temperature for 30 min to give an orange homogeneous solution. Excess 1 M hydrogen chloride in ether was added giving a pale yellow solution and a precipitate. The mixture was heated in an oil bath at 120° C. for 30 min. The solution was concentrated and re-dissolved in ethyl acetate. The solution was washed with saturated sodium bicarbonate, brine, dried and concentrated in vacuo to give a solid. Trituration with ether afforded the title compound as a white solid (375 mgs, 78%); 1H-NMR (CDCl3) δ 1.29 (3H, t), 3.01 (2H, t), 3.30 (2H, t), 4.29 (2H, q), 4.84 (2H, s), 6.96 (1H, d), 7.03, (3H, m) and 7.77 (1H, d). (APCI+) Found (M+1)=379, C18H16F2N2O3S requires 378.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]3[CH:24]=[CH:25][CH:26]=[C:20]3[CH:19]=2)=[CH:8]1)(C)(C)C.Br[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1>>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][CH2:28][O:17][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]4[CH:24]=[CH:25][CH:26]=[C:20]4[CH:19]=2)=[CH:8][C:7]3=[N:6][OH:5])=[CH:31][CH:32]=1
Reactant: Clc1ccc(CCBr)cc1
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(O)cc12
Product: ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCc3ccc(Cl)cc3)cc12

Procedure:
6-[2-(4-Chloro-phenyl)-ethoxy]-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime was prepared in 28% overall yield using the method described in example 85, starting from 6-hydroxy-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl oxime (example 81A) and 1-(2-Bromo-ethyl)-4-chloro-benzene.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10](=[CH2:13])[CH2:11][OH:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(Cl)Cl.[O-2].[O-2].[Mn+4].O=[Mn]=O>[Si:1]([O:8][CH2:9][C:10](=[CH2:13])[CH:11]=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: C=C(CO)CO[Si](C)(C)C(C)(C)C
Agent: O=[Mn]=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: C=C(C=O)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 59.6 %

Procedure:
To a solution of 2-(((tert-butyldimethylsilyl)oxy)methyl)prop-2-en-1-ol (Intermediate 157, 11.35 g, 56.09 mmol) in DCM (150 mL) was added manganese dioxide (activated, 5 g) (28.7 g, 280.43 mmol). The reaction mixture was stirred at room temperature for three days. More MnO2 was added and continued stirring until TLC shows minimum starting material. The reaction mixture was filtered through a pad of silica, evaporated at ˜15° C. and purified on silica gel column (5-20%, EA/Hex) to afford the title compound (6.70 g, 59.6%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[N:14]([CH2:17][C:18]([F:21])([F:20])[F:19])[N:15]=[CH:16][C:11]3=[C:10]([N:22]3[CH:27]4[CH2:28][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:30][CH:23]3[CH2:24][O:25][CH2:26]4)[N:9]=2)=[CH:4][CH:3]=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.CN.[N:52]([C:55]1C=CC(C2N=C3N(CC(F)(F)F)N=CC3=C(N3C4CN(C(OC(C)(C)C)=O)CC3COC4)N=2)=CC=1)=[C:53]=[O:54]>ClCCl.O1CCCC1.C(N(CC)CC)C>[CH3:55][NH:52][C:53](=[O:54])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]3[N:14]([CH2:17][C:18]([F:19])([F:21])[F:20])[N:15]=[CH:16][C:11]3=[C:10]([N:22]3[CH:27]4[CH2:28][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:30][CH:23]3[CH2:24][O:25][CH2:26]4)[N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC2COCC(C1)N2c1nc(-c2ccc(N=C=O)cc2)nc2c1cnn2CC(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC2COCC(C1)N2c1nc(-c2ccc(N)cc2)nc2c1cnn2CC(F)(F)F
Agent: CN
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNC(=O)Nc1ccc(-c2nc(N3C4COCC3CN(C(=O)OC(C)(C)C)C4)c3cnn(CC(F)(F)F)c3n2)cc1

Procedure:
A solution of tert-butyl 9-(6-(4-aminophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate (230 mg, 0.45 mmol) in dichloromethane (6 mL) was treated triethylamine (520 μL), followed by triphosgene (90 mg, 0.30 mmol) as a solution in dichloromethane (2 mL). After the passage of 5 minutes, the appropriate nucleophile—in the case, 2.0 M methylamine solution in tetrahydrofuran (4 mL)—was added to tert-butyl 9-(6-(4-isocyanatophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate (“isocyanate”) mixture. The reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography using a Phenomenex Prodigy 21 mm×250 mm column, running a gradient elution of 10% acetonitrile/90% of 0.1% aqueous trifluoroacetic acid to 100% acetonitrile to provide tert-butyl 9-(6-(4-(3-methylureido)phenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate. MS (ES+): 577.2 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]3[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=3)[CH:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.Cl[CH2:32][CH2:33][S:34](Cl)(=[O:36])=[O:35]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]3[CH:18]=[C:19]([NH:23][S:34]([CH:33]=[CH2:32])(=[O:36])=[O:35])[CH:20]=[CH:21][CH:22]=3)[CH:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Nc1cccc(Nc2cc(Nc3ccc(F)c(Cl)c3)ncn2)c1
Reactant: O=S(=O)(Cl)CCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CS(=O)(=O)Nc1cccc(Nc2cc(Nc3ccc(F)c(Cl)c3)ncn2)c1
Reaction time: 1 h
Yield: 9.3 %

Procedure:
A solution of 3-[6-(3-chloro-4-fluorophenylamino)-pyrimidin-4-ylamino]phenylamine (IR-4) (300 mg, 0.9 mmol) and triethylamine (500 mg, 5 mmol) in 10 mL of THF was stirred at RT. 2-Chloroethanesulfonyl chloride (360 mg, 2.25 mmol) was added into the reaction mixture and stirring was continued at RT for 1 hr. The crude product was purified by flash chromatography on silica gel with EtOAc/heptane solvent system to afford 35 mg (9%) of the title compound, a brown colored solid. MS (m/z): MH+=420, 422. 1H NMR (DMSO): 9.92 (s, 1H), 9.29 (s, 1H), 9.21 (s, 1H), 8.26 (s, 1H), 7.92 (m, 1H), 7.40-7.22 (m, 4H), 7.14 (m, 1H), 6.20 (m, 2H), 6.05 (m, 3H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:25]([CH:26]=1)[C:8]1[N:9]([C:18]3[CH:19]=[N:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[C:10](=[O:17])[C:11]3[C:16]([C:7]=1[N:6]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3.[CH2:27]([N:29]=[C:30]=[O:31])[CH3:28]>C(Cl)(Cl)Cl>[CH2:27]([NH:29][C:30]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:25]([CH:26]=1)[C:8]1[N:9]([C:18]3[CH:19]=[N:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[C:10](=[O:17])[C:11]3[C:16]([C:7]=1[N:6]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:31])[CH3:28]
Reactant: CCN=C=O
Reactant: Nc1ccc2nc3c4ccccc4c(=O)n(-c4ccc(Cl)nc4)c3n2c1
Solvent: ClC(Cl)Cl
Product: CCNC(=O)Nc1ccc2nc3c4ccccc4c(=O)n(-c4ccc(Cl)nc4)c3n2c1
Temperature: 25 °C
Reaction time: 216 h
Yield: 38.5 %

Procedure:
A mixture of compound 53 (1.0 equiv., 0.276 mmol, 0.100 g) and ethyl isocyanate (5.0 equiv., 1.382 mmol, 0.098 g) in chloroform (3 ml) was stirred at room temperature for 9 days. The resulting precipitate was filtered off and successively washed with methanol, isopropanol and isopropyl ether to give 1-ethyl-3-[6-(6-chloro-pyridin-3-yl)-5,6-dihydro-5-oxo-pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-9-yl]-urea (60) (0.046 g, yield=38%, purity (LC)=90%).
Reaction SMILES: [Br:1][CH2:2][C@@H:3]([OH:13])[CH2:4][C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>>[Br:1][CH2:2][C@H:3]1[CH2:4][C:5]2[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=2[O:13]1
Reactant: Oc1ccc(F)cc1C[C@H](O)CBr
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Fc1ccc2c(c1)C[C@H](CBr)O2
Yield: 75.7 %

Procedure:
Treatment of (S)-2-(3-bromo-2-hydroxy-propyl)4-fluoro-phenol (1.97 g, 8 mmol), triphenylphosphine (5.2 g, 20 mmol), and diethylazodicarboxylate (3.11 ml, 20 mmol) generally according to the procedure described for Intermediate 18 afforded 1.40 g (76%) of (R)-2-bromomethyl-5-fluoro-2,3-dihydro-benzofuran as a colorless oil. HRMS ESI m/e 228.9661 [M−H]−. [α]D25=−33.0 (c 1% in methanol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2[CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:10])[CH:5]=[CH:6][C:7]=1[OH:8].Cl[CH2:23][C:24]1[CH:34]=[CH:33][C:27]([C:28]([N:30]([CH3:32])[CH3:31])=[O:29])=[CH:26][CH:25]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2[CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:10])[CH:5]=[CH:6][C:7]=1[O:8][CH2:23][C:24]1[CH:34]=[CH:33][C:27]([C:28]([N:30]([CH3:31])[CH3:32])=[O:29])=[CH:26][CH:25]=1
Reactant: O=C(c1ccc(O)c(F)c1)N1CCC[C@H]1CN1CCCC1
Reactant: CN(C)C(=O)c1ccc(CCl)cc1
Product: CN(C)C(=O)c1ccc(COc2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2F)cc1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure C from (3-Fluoro-4-hydroxy-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)methanone and 4-chloromethyl-N,N-dimethyl-benzamide [CAS 121083-51-0]. MS (ES+) 454.2
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([CH:6]=[C:7]2[S:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])=[CH:4][CH:3]=1>C(O)(=O)C>[NH2:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH:7]2[S:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])=[CH:4][CH:3]=1
Reactant: Nc1ccc(C=C2SC(=O)NC2=O)cc1
Solvent: CC(=O)O
Product: Nc1ccc(CC2SC(=O)NC2=O)cc1

Procedure:
Prepared by catalytic hydrogenation of 5-(4-amino-benzylidene)-thiazolidin-2,4-dione in glacial acetic acid on palladium/charcoal (10%) (50° C., 3.5 bar, 6 hours).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[NH2:12])[NH:8][C:7](=[O:13])[CH2:6][C:5]2([CH3:15])[CH3:14].[C:16](OC(=O)C)(=O)[CH3:17].Cl>C(O)C>[CH3:16][C:17]1[NH:1][C:2]2=[CH:3][C:4]3[C:5]([CH3:15])([CH3:14])[CH2:6][C:7](=[O:13])[NH:8][C:9]=3[CH:10]=[C:11]2[N:12]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)CC(=O)Nc2cc(N)c(N)cc21
Agent: Cl
Solvent: CCO
Product: Cc1nc2cc3c(cc2[nH]1)C(C)(C)CC(=O)N3

Procedure:
3.1 g. 6,7-diamino-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-2-one and 2.8 ml. acetic anhydride were stirred in 50 ml. ethanol for 30 minutes at ambient temperature. 20 ml. concentrated hydrochloric acid were then added thereto and the reaction mixture refluxed for 18 hours. The solvent was removed in a vacuum and the residue was dissolved in water, rendered alkaline with ammonia, filtered off with suction and washed with water. After recrystallization from ethyl acetate, there were obtained 2.4 g. of the title compound; m.p. 290°-294° C.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[N:16][C:15]([C:18]([O:20]C)=[O:19])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1.O.[OH-].[Li+].Cl>C1COCC1.O>[F:26][C:2]([F:1])([F:27])[C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[N:16][C:15]([C:18]([OH:20])=[O:19])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1
Reactant: COC(=O)c1ccc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)nn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 6-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}pyridazine-3-carboxylate (800 mg, 2.1 mmol) and lithium hydroxide monohydrate (352 mg, 8.4 mmol) in THF (10 mL) and water (5 mL) was stirred at r.t. overnight, then acidified with 1M aqueous HCl (9 mL). Volatile materials were removed in vacuo. The residue was diluted with water and extracted with EtOAc. The organic extract was washed with diluted brine, dried (Na2SO4), concentrated and swished with Et2O to give the title compound as a white powder. 1H NMR (400 MHz, acetone-d6): δ 1.97 (m, 2H), 2.15-2.21 (m, 2H), 4.00-4.10 (m, 4H), 5.04-5.08 (m, 1H), 7.13 (t, 1H), 7.39 (m, 2H), 7.63-7.69 (m, 2H), 7.94 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:23]([N+:24]([O-])=O)=[CH:22][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][C@H:10]2[O:20][CH3:21])=[O:7])=[C:4]([O:27][CH3:28])[CH:3]=1.S1C=CC=C1.[H][H]>CO.[Pt]>[NH2:24][C:23]1[C:2]([Cl:1])=[CH:3][C:4]([O:27][CH3:28])=[C:5]([CH:22]=1)[C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][C@H:10]1[O:20][CH3:21])=[O:7]
Reactant: [H][H]
Reactant: CCOC(=O)N1CC[C@H](NC(=O)c2cc([N+](=O)[O-])c(Cl)cc2OC)[C@H](OC)C1
Agent: [Pt]
Solvent: c1ccsc1
Solvent: CO
Product: CCOC(=O)N1CC[C@H](NC(=O)c2cc(N)c(Cl)cc2OC)[C@H](OC)C1
Yield: 94 %

Procedure:
A mixture of 90.5 parts of ethyl cis-4-[(4-chloro-2-methoxy-5-nitrobenzoyl)amino]-3-methoxy-1-piperidinecarboxylate, 3 parts of a solution of thiophene in methanol 4% and 400 parts of methanol was hydrogenated at normal pressure and at 50° C. with 5 parts of platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 80 parts (94%) of ethyl cis-4-[(5-amino-4-chloro-2-methoxybenzoyl)amino]-3-methoxy-1-piperidinecarboxylate: mp. 142.5° C. (interm. 14).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([O:14][CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)[N:6]=1.CN1CCOCC1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>CN(C)C=O.ClCCl>[S:36]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([O:14][CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:9]2)[N:6]=1)([CH3:35])(=[O:38])=[O:37]
Reactant: Nc1nc(CN2CCC(OC(c3ccccc3)c3ccccc3)CC2)cs1
Reactant: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CS(=O)(=O)Nc1nc(CN2CCC(OC(c3ccccc3)c3ccccc3)CC2)cs1
Reaction time: 1 h
Yield: 34 %

Procedure:
To a stirred mixture of 2-amino-4-[4-(diphenylmethoxy)piperidinomethyl]thiazole (0.78 g), N-methylmorpholine (1.15 ml) in N,N-dimethylformamide (8 ml) was added dropwise a solution of methanesulfonyl chloride (0.5 g) in dichloromethane (0.5 ml) under ice-bath cooling. After 1 hour, the reaction mixture was filtered. The filtrate was made basic with 1N sodium hydroxide solution (12 ml). After being stirred for 30 minutes, the mixture was neutralized with 1N hydrochloric acid and extracted with dichloromethane (40 ml×2). The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off and the residue was subjected to column chromatography on silica gel, and eluted with a mixture of chloroform and methanol (10:1 V/V). The fractions containing the object compound were combined and concentrated under reduced pressure to give white crystals. The crystals were recrystallized from ethanol to give 2-mesylamino-4-[4-(diphenylmethoxy)piperidinomethyl]thiazole (0.32 g).
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[CH2:3][CH2:4][C:5](=NOCC(O)=O)[C:6]1[CH:10]=[CH:9][S:8][CH:7]=1.[OH-].[Na+].S(OOS([O-])(=O)=O)([O-])(=O)=[O:21].[K+].[K+]>O>[CH3:17][C:2]1([CH3:1])[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[C:5](=[O:21])[CH2:4][CH2:3]1
Reactant: CC(C)CCC(=NOCC(=O)O)c1ccsc1
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(C)CCC(=O)c2ccsc21
Reaction time: 2 h
Yield: 12.8 %

Procedure:
(4-Methyl-1-thiophen-3-yl-pentylideneaminooxy)-acetic acid (2.17 g, 8.5 mmol) was added to a 0.1 M sodium hydroxide solution (93.5 ml) and heated to reflux. A solution of potassium persulfate (3.45 g, 12.75 mmol) in water (10 ml) was added dropwise and heating continued. After 2 hours, the reaction mixture was extracted with dry diethyl ether (100 ml). The organic layer was then washed with saturate sodium bicarbonate, water and brine, dried (Na2SO4) and concentrated in vacuo. The resulting oil was purified by silica gel chromatography to afford the title compound as a colourless oil (196 mg, 13%). MS (ES+) 18. δH (d6DMSO): 1.42 (6H, s), 2.03 (2H, t), 2.60 (2H, t), 7.22 (1H, d), 7.42 (1H, d).