Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10](O)[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.P(Br)(Br)([Br:15])=O>C1(C)C=CC=CC=1>[Br:15][C:10]1[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=[C:2]([NH2:1])[N:11]=1
Reactant: O=P(Br)(Br)Br
Reactant: Nc1nc(O)c2c(n1)CCCC2
Solvent: Cc1ccccc1
Product: Nc1nc(Br)c2c(n1)CCCC2
Temperature: 95 °C
Yield: 74.5 %

Procedure:
To a suspension of 2-amino-5,6,7,8-tetrahydroquinazoline-4-ol (1.65 g, 10 mmol) in toluene (16.5 ml) was added phosphorous oxybromide (3 g) and the mixture was kept to warm in a bath (bath temperature 90-100° C.) for 2 hours. After confirming disappearance of the starting materials, the reaction mixture was poured into ice-water, and was extracted with chloroform and a saturated aqueous NaHCO3 solution. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (CHCl3) to give the object compound (1.7 g, 75%).
Reaction SMILES: [CH2:1]1[CH2:20][O:19][C:3]2([CH2:8][CH2:7][C:6](O)([C:9]3[CH:14]=[C:13]([F:15])[C:12]([F:16])=[C:11]([F:17])[CH:10]=3)[CH2:5][CH2:4]2)[O:2]1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:20]1[CH2:1][O:2][C:3]2([CH2:8][CH2:7][C:6]([C:9]3[CH:14]=[C:13]([F:15])[C:12]([F:16])=[C:11]([F:17])[CH:10]=3)=[CH:5][CH2:4]2)[O:19]1
Reactant: OC1(c2cc(F)c(F)c(F)c2)CCC2(CC1)OCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1cc(C2=CCC3(CC2)OCCO3)cc(F)c1F
Yield: 65.8 %

Procedure:
1,1-Ethylenedioxy-4-hydroxy-4-(3',4',5'-trifluoro-phenyl)cyclohexane (166.2 g) was dissolved in toluene (500 ml), followed by adding p-toluenesulfonic acidmonohydrate (20 g) into the solution, stirring the mixture under reflux for one hour, washing the reaction solution with water (500 ml), drying the organic layer over anhydrous magnesium sulfate, and distilling off the solvent under reduced pressure, to obtain 1,1-ethylenedioxy-4-(3',4',5'-trifluorophenyl)-3-cyclohexene (102.6 g).
Reaction SMILES: Cl[CH2:2][C:3]1[NH:8][C:7](=[O:9])[NH:6][C:5](=[O:10])[CH:4]=1.Br.BrCC1C=CC=CN=1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]2([C:32]3=[CH:33][C:34]4[O:38][CH2:37][O:36][C:35]=4[CH:39]=[C:31]3[O:30][CH2:29]2)[C:21]1=[O:40].FC1C2OCCOC=2C=C2OCC3(C4C(=CC=CC=4)NC3=O)C=12>>[O:40]=[C:21]1[C:22]2([C:32]3=[CH:33][C:34]4[O:38][CH2:37][O:36][C:35]=4[CH:39]=[C:31]3[O:30][CH2:29]2)[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:20]1[CH2:2][C:3]1[NH:8][C:7](=[O:9])[NH:6][C:5](=[O:10])[CH:4]=1
Reactant: O=c1cc(CCl)[nH]c(=O)[nH]1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: Br
Agent: BrCc1ccccn1
Agent: O=C1Nc2ccccc2C12COc1cc3c(c(F)c12)OCCO3
Product: O=C1N(Cc2cc(=O)[nH]c(=O)[nH]2)c2ccccc2C12COc1cc3c(cc12)OCO3

Procedure:
Following the procedure as described in EXAMPLE 5.25 and making non-critical variations using 6-(chloromethyl)uracil to replace 2-(bromomethyl)pyridine hydrobromide, and spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 9-fluoro-2,3-dihydro-spiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, 6-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]pyrdimidine-2,4(1H,3H)-dione was obtained (5%) as an off-white solid: mp>300° C.; 1H NMR (300 MHz, DMSO-d6) δ11.11 (s, 1H), 11.05 (s, 1H), 7.29 (dd, J=7.7, 7.7 Hz, 1H), 7.18 (d, J=6.8 Hz, 1H), 7.05 (dd, J=7.5, 7.5 Hz, 1H), 7.03 (dd, J=7.7, 7.7 Hz, 1H), 6.66 (s, 1H), 6.26 (s, 1H), 5.90 (s, 2H), 5.14 (s, 1H), 4.75 (ABq, 2H), 4.60 (ABq, 2H); 13C NMR (75 MHz, DMSO-d6) δ177.4, 164.2, 155.9, 151.8, 151.5, 148.8, 142.3, 142.2, 132.1, 129.4, 124.2, 123.9, 120.1, 109.8, 103.6, 101.9, 96.9, 93.8, 80.4, 57.9, 40.5; MS (ES+) m/z 406.3 (M+1).
Reaction SMILES: C([O:4][C:5]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:8]([CH:15]([NH:17][OH:18])[CH3:16])=[CH:7][C:6]=1[C:19]([CH3:22])([CH3:21])[CH3:20])(=O)C.[CH3:23][N:24]=[C:25]=[S:26]>>[CH3:21][C:19]([C:6]1[CH:7]=[C:8]([CH:15]([N:17]([OH:18])[C:25]([NH:24][CH3:23])=[S:26])[CH3:16])[CH:9]=[C:10]([C:11]([CH3:13])([CH3:12])[CH3:14])[C:5]=1[OH:4])([CH3:22])[CH3:20]
Reactant: CC(=O)Oc1c(C(C)(C)C)cc(C(C)NO)cc1C(C)(C)C
Reactant: CN=C=S
Product: CNC(=S)N(O)C(C)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 0.500 g (0.0016 mole) of 2,6-bis (1,1-dimethylethyl) -4- [1- (hydroxyamino) ethyl ]phenol acetate is added 0.128 g (0.00175) of methyl isothiocyanate. The reaction mixture is stirred at room temperature for 18 hours and evaporated to near dryness. The residue is washed with Et2O and there is obtained 0. 300 g (55% ) white solid, m.p. 175°-175.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](I)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.[CH3:25][O:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N:30]3[CH2:31][CH2:32][CH:27]([O:26][CH3:25])[CH2:28][CH2:29]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(I)cc2C1
Reactant: COC1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: COC1CCN(c2ccc3c(c2)CN(C(=O)OC(C)(C)C)C3)CC1

Procedure:
Prepared in analogy to Example A3(d) from 5-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A38(b)) and 4-methoxy-piperidine trifluoroacetate. Yellow oil. MS (m/e): 333.3 ([M+H]+, 100%).
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[C:12]2[O:13][CH2:14][CH2:15][O:16][C:11]=2[C:10]([C:17]([O:19][CH3:20])=[O:18])=[CH:9][CH:8]=1.[N+:21]([O-])([O-:23])=[O:22].[K+].C(=O)([O-])[O-].[K+].[K+]>O.C(O)(=O)C>[NH2:6][C:7]1[C:12]2[O:13][CH2:14][CH2:15][O:16][C:11]=2[C:10]([C:17]([O:19][CH3:20])=[O:18])=[CH:9][C:8]=1[N+:21]([O-:23])=[O:22]
Reactant: COC(=O)c1ccc(N)c2c1OCCO2
Reactant: O=[N+]([O-])[O-]
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc([N+](=O)[O-])c(N)c2c1OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.4 %

Procedure:
Concentrated sulphuric acid (6.5 ml) was treated cautiously with stirring at 5°-10° C. with glacial acetic acid (12 ml) and to the resulting solution was added methyl 8-amino-1,4-benzodioxan-5-carboxylate (1.5 g, 0.0072 mole). The mixture was stirred at room temperature for 1 h, then treated portionwise over 45 minutes with potassium nitrate (0.85 g, 0.0084 mole). The mixture was stirred for a further 4 h then poured into water (100 ml) and basified with potassium carbonate. A precipitate was produced and this was filtered off, washed with water and dried to afford methyl 8-amino-7-nitro-1,4-benzodioxan-5-carboxylate as a yellow solid (0.30 g). The filtrate was extracted with ethyl acetate and the extract dried (Na2SO4) and concentrated in vacuo to afford a further 1.1 g of the product as an orange solid. 1H NMR (CDCl3) δ:8.50(s,1 H), 6.0-7.0(v br,2 H), 4.30-4.55(m,4 H), 3.87(s,3 H).
Reaction SMILES: [CH2:1](C1C=C2C(COC2=O)=CC=1)[CH3:2].[C:13]1([S:19]([CH2:22][C:23]2[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:27]([O:34][CH3:35])[C:26](Br)=[CH:25][CH:24]=2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(B(CC)CC)C>>[C:13]1([S:19]([CH2:22][C:23]2[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:27]([O:34][CH3:35])[C:26]([CH2:1][CH3:2])=[CH:25][CH:24]=2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1OC
Reactant: CCc1ccc2c(c1)C(=O)OC2
Agent: CCB(CC)CC
Product: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(CC)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 18, starting from ethyl 6-(benzenesulphonylmethyl)-3-bromo-2-methoxybenzoate (Intermediate 61) and triethylborane.
Reaction SMILES: [Cl-].[NH4+].C(O)C.[CH3:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[N:14]1[CH2:19][CH2:18][N:17]([C:20]([C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=2)=[O:21])[CH2:16][CH2:15]1>[Fe].O>[NH2:28][C:25]1[CH:24]=[CH:23][C:22]([C:20]([N:17]2[CH2:18][CH2:19][N:14]([C:8]3[CH:9]=[CH:10][C:11]([CH3:13])=[CH:12][C:7]=3[CH3:6])[CH2:15][CH2:16]2)=[O:21])=[CH:27][CH:26]=1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc([N+](=O)[O-])cc3)CC2)c(C)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N)cc3)CC2)c(C)c1
Yield: 109.7 %

Procedure:
4-Nitrobenzoic acid (2 g), 1-(2,4-dimethylphenyl)piperazine (2.28 g), and 1-hydroxybenzotriazole 1 hydrate (1.62 g) were dissolved in N,N-dimethylformamide (30 mL), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (2.31 g) was added, and the mixture was stirred at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. To the obtained residue was added ethyl acetate/diisopropyl ether and the insoluble material was collected by filtration to give [4-(2,4-dimethylphenyl)piperazin-1-yl](4-nitrophenyl)methanone (4.17 g). Then, ammonium chloride (3.71 g) and iron (2.68 g) were added to a solution of ethanol (61 mL) and water (17 mL), and the obtained [4-(2,4-dimethylphenyl)piperazin-1-yl](4-nitrophenyl)methanone (4.17 g) was added with stirring at 60° C.-70° C. After completion of the reaction, the insoluble material was filtered off, and the filtrate was concentrated. To the residue was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate, and the solvent was evaporated to give crude (4-aminophenyl) [4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (4.17 g). To the obtained crude (4-aminophenyl) [4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (1 g) were added itaconic acid (0.42 g), water (5 mL), 1,2-dimethoxyethane (2 mL) and acetic acid (5 mL), and the mixture was stirred with heating under reflux for 13 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. To the obtained residue was added ethyl acetate, and the precipitate was collected by filtration to give the title compound (508 mg).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[C:5](F)[CH:4]=1.[Cl:14]C1C=C(C=CC=1F)C=O>>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[C:5]([Cl:14])[CH:4]=1
Reactant: CS(=O)(=O)c1ccc(CBr)cc1F
Reactant: O=Cc1ccc(F)c(Cl)c1
Product: CS(=O)(=O)c1ccc(CBr)cc1Cl

Procedure:
The titled compound is prepared analogously to 4-bromomethyl-2-fluoro-1-methanesulfonyl-benzene by replacing 3,4-difluorobenzaldehyde with 3-chloro-4-fluoro-benzaldehyde.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([OH:11])[CH2:6]1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CCCCCC.CN(C)C=O>[CH2:12]([O:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([OH:11])[CH2:6]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCC1CCCC(O)C1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: OC1CCCC(COCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 5 h
Yield: 56.4 %

Procedure:
50% Sodium hydride (5.77 g; 120 mmol) is washed with n-hexane, and dimethylformamide (50 ml) is added thereto. To the resultant mixture, 3-hydroxymethylcyclohexanol (9) (10.0 g; 76.8 mmol) is dropwise added under ice-cooling, and then benzyl bromide (13.15 g; 76.8 mmol) is dropwise added thereto under ice-cooling. The resulting mixture is stirred at a temperature of 0° to 10° C. for 5 hours. The reaction mixture is poured into ice-water, extracted with toluene. The organic layer is washed with water, dried and concentrated under reduced pressure. The residue is chromatographed on a silica gel column to give 3-benzyloxymethylcyclohexanol (10) (9.55 g).
Reaction SMILES: C([O:8][C:9](=[O:39])[CH2:10][C@@H:11]([N:22]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:29][CH:28]=2)=[CH:23]1)[C:12]([NH:14][C@@H:15]([CH2:20][OH:21])[C:16]([OH:19])([CH3:18])[CH3:17])=[O:13])C1C=CC=CC=1>CCO.CCOC(C)=O>[C:30]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:29]=[CH:28][C:27]([C:24]2[CH:25]=[CH:26][N:22]([C@@H:11]([C:12]([NH:14][C@@H:15]([CH2:20][OH:21])[C:16]([OH:19])([CH3:17])[CH3:18])=[O:13])[CH2:10][C:9]([OH:39])=[O:8])[CH:23]=2)=[CH:32][CH:31]=1
Reactant: CC(C)(O)[C@H](CO)NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccccc3)cc2)c1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(O)[C@H](CO)NC(=O)[C@@H](CC(=O)O)n1ccc(-c2ccc(-c3ccccc3)cc2)c1
Reaction time: 1.83 h
Yield: 74.9 %

Procedure:
According to the procedure described in Example 1(a), a mixture of 3(R)-[3-(biphenyl-4-yl)-1H-pyrrol-1-yl]-N-[2-hydroxy-1(S)-(hydroxymethyl)-2-methylpropyl]succinamic acid benzyl ester (137 mg, 0.26 mmol) in EtOH (2.5 mL) and EtOAc (2.5 mL) was hydrogenolyzed after 110 minutes to give a white solid, which was triturated with CH2Cl2/hex to provide 85 mg(75%) of 3(R)-[3-(biphenyl-4-yl)-1H-pyrrol-1-yl]-N-[2-hydroxy-1(S)-(hydroxymethyl)-2-methylpropyl]succinamic acid as a white solid, mp 150-2° C. 1H NMR (acetone-d6): δ 7.67-7.61 (m, 6H), 7.46-7.39 (m, 3H), 7.33 (t, 1H, J=7.4 Hz), 7.09 (bd, 1H, J=8.5 Hz), 6.97 (t, 1H, J=2.4 Hz), 6.53 (t, 1H, J=2.2 Hz), 5.28 (t, 1H, J=7.2 Hz), 3.81-3.67 (m, 3H), 3.35 (dd, 1H, J=7.4, 16.9 Hz), 3.02 (dd, 1H, J=7.4, 16.9 Hz), 1.24 (s, 3H), 1.12 (s, 3H). Anal. Calculated for C25H28N2O5: C, 68.79; H, 6.47; N, 6.42. Found: C, 68.54; H, 6.50; N, 6.39.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([CH2:8][CH2:9][C:10]([N:12]2[CH2:19][CH2:18][CH2:17][C@H:13]2[C:14]([OH:16])=[O:15])=[O:11])=[O:7])=[CH:4][CH:3]=1.[Br:22]Br>Br.C(O)(=O)C>[Br:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([CH:8]([Br:22])[CH2:9][C:10]([N:12]2[CH2:19][CH2:18][CH2:17][C@H:13]2[C:14]([OH:16])=[O:15])=[O:11])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(CCC(=O)N1CCC[C@H]1C(=O)O)c1ccc(Br)cc1
Reactant: BrBr
Agent: Br
Solvent: CC(=O)O
Product: O=C(c1ccc(Br)cc1)C(Br)CC(=O)N1CCC[C@H]1C(=O)O
Reaction time: 18 h

Procedure:
To a solution of 17.7 g. of 1-[3-(4-bromobenzoyl)propionyl]-L-proline (Example 36) in 150 ml. of acetic acid is added dropwise, a solution of 9.0 g. of bromine in 20 ml. of acetic acid followed by 5 drops of hydrobromic acid in acetic acid. The mixture is stirred for 18 hours, evaporated to 1/2 its volume, poured into 300 ml. of ice water and extracted with methylene chloride. The organic extract is washed twice with water, once with saturated sodium chloride solution, dried over magnesium sulfate, clarified with charcoal and evaporated to dryness in vacuo. The desired product is recovered as 20.5 g. of a white amorphous solid.
Reaction SMILES: OCCCN1C=C(C2C=CC(N[C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=C3C=2CN(C)C3=O)C=N1.C(OP1(=O)CC2C=CC(=CC=2)NC2=NC(=C(C(F)(F)F)C=N2)NC2C=CC(=NC=2C(NC)=O)C2=CN(N=C2)CCCCO1)C.[NH2:94][C:95]1[C:96]([C:112]([NH:114][CH3:115])=[O:113])=[N:97][C:98]([C:101]2[CH:102]=[N:103][N:104]([CH2:106][C:107]([F:111])([F:110])[CH2:108][OH:109])[CH:105]=2)=[CH:99][CH:100]=1>>[F:110][C:107]([F:111])([CH2:108][OH:109])[CH2:106][N:104]1[CH:105]=[C:101]([C:98]2[N:97]=[C:96]([C:112](=[O:113])[NH:114][CH3:115])[C:95]([NH:94][C:26]3[C:27]([C:28]([F:29])([F:30])[F:31])=[CH:22][N:23]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:25]=3)=[CH:100][CH:99]=2)[CH:102]=[N:103]1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Reactant: CNC(=O)c1nc(-c2cnn(CC(F)(F)CO)c2)ccc1N
Agent: CCOP1(=O)Cc2ccc(cc2)Nc2ncc(C(F)(F)F)c(n2)Nc2ccc(nc2C(=O)NC)-c2cnn(c2)CCCCO1
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CC(F)(F)CO)c4)nc3C(=O)NC)n2)c(OC)c1)OCC
Yield: 84 %

Procedure:
Prepared analogously to Compound 1B using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 1 E, 275 mg, 0.606 mmol) and 3-amino-6-[1-(2,2-difluoro-3-hydroxypropyl)-1H-pyrazol-4-yl]-N-methylpyridine-2-carboxamide (Compound 59C, 198 mg, 0.636 mmol) to afford 388 mg of the title compound (84%). MS (ESI): m/z=729.68 [M+H]+. UPLC: tR=1.33 min (UPLC-TOF: polar—2 min).
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].Br[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[OH:4][CH2:3][CH2:2][N:1]([CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:5][CH2:6][OH:7]
Reactant: OCCNCCO
Reactant: BrCCCc1ccccc1
Product: OCCN(CCO)CCCc1ccccc1

Procedure:
2-[(2-Hydroxy-ethyl)-(3-phenyl-propyl)-amino]-ethanol was prepared according to the general method as outlined in example 83. Starting from diethanolamine (15.8 g, 151 mmol). and 1-bromo-3-phenylpropane (20 g, 101 mmol). Yield 21.31 g, (95%); yellow oil; MS: 223.9 (M+H)+.
Reaction SMILES: [N:1]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:6][CH2:5][C:4]2([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C@@H:12]3[C@@H:8]([CH2:9][CH2:10][NH:11]3)[CH2:7]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34]>ClCCl>[C:33]([N:11]1[C@H:12]2[C@H:8]([CH2:7][C:4]3([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=42)[CH2:5][CH2:6][N:1]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:2][CH2:3]3)[CH2:9][CH2:10]1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C[C@@H]1CCN[C@@H]1c1ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CC[C@H]2CC3(CCN(C(=O)OC(C)(C)C)CC3)c3ccccc3[C@H]21

Procedure:
The product of Step 2 (52 mg) was dissolved in dichloromethane (10 ml), treated with triethylamine (0.07 ml) and acetyl chloride (0.014 ml) for 1 h. The reaction mixture was diluted with dichloromethane, washed with water. The organic phase was concentrated to give (3aR,9bS)-tert-butyl 1-acetyl-1,2,3,3a,4,9b-hexahydrospiro[benzo[g]indole-5,4′-piperidine]-1′-carboxylate 14 (47 mg). LC-MS: m/e=329.6 (M+-tBu, 100%). Rt=3.21 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Br:15])[CH2:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[F:16][C:17]1[CH:18]=[C:19]([N:23]=[C:24]=[O:25])[CH:20]=[CH:21][CH:22]=1>C(Cl)Cl>[F:16][C:17]1[CH:18]=[C:19]([NH:23][C:24]([N:9]2[CH2:10][CH2:11][N:6]([CH2:5][C:4]3[CH:12]=[CH:13][C:14]([Br:15])=[C:2]([Br:1])[CH:3]=3)[CH2:7][CH2:8]2)=[O:25])[CH:20]=[CH:21][CH:22]=1
Reactant: Brc1ccc(CN2CCNCC2)cc1Br
Reactant: O=C=Nc1cccc(F)c1
Solvent: ClCCl
Product: O=C(Nc1cccc(F)c1)N1CCN(Cc2ccc(Br)c(Br)c2)CC1
Reaction time: 16 h

Procedure:
A solution of 1-(3,4-dibromo-benzyl)-piperazine (167 mg) in DCM (2 mL) was treated with 3-fluorophenyl isocyanate (0.07 mL). After 16 h, the resulting mixture was chromatographed, giving the title compound as a white foam (188 mg). 1H NMR (400 MHz, CDCl3): 7.61 (d, J=2.0 Hz, 1H), 7.56 (d, J=8.1 Hz, 1H), 7.31-7.12 (m, 3H), 7.01-6.97 (m, 1H), 6.75-6.99 (m, 1H), 6.47 (br m, 1H), 3.51-3.47 (m, 4H), 3.45 (s, 2H), 2.48-2.43 (m, 4H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:21])[C:7]([C:16]([O:18]CC)=[O:17])=[CH:8][N:9]2[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:4][C:3]=1[F:22].[CH:23]1([NH:26][CH2:27][C@@H:28]2[C@H:32]([F:33])[CH2:31][NH:30][CH2:29]2)[CH2:25][CH2:24]1.N12CCCN=C1CCCCC2>C(#N)C>[CH:23]1([NH:26][CH2:27][C@@H:28]2[C@H:32]([F:33])[CH2:31][N:30]([C:2]3[N:11]=[C:10]4[C:5]([C:6](=[O:21])[C:7]([C:16]([OH:18])=[O:17])=[CH:8][N:9]4[C:12]([CH3:13])([CH3:14])[CH3:15])=[CH:4][C:3]=3[F:22])[CH2:29]2)[CH2:25][CH2:24]1
Reactant: F[C@@H]1CNC[C@@H]1CNC1CC1
Reactant: CCOC(=O)c1cn(C(C)(C)C)c2nc(Cl)c(F)cc2c1=O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)n1cc(C(=O)O)c(=O)c2cc(F)c(N3C[C@H](CNC4CC4)[C@H](F)C3)nc21
Temperature: 80 °C
Reaction time: 1 h
Yield: 33.5 %

Procedure:
Ethyl 7-chloro-6-fluoro-1,4-dihydro-1-(1,1-dimethylethyl)-4-oxo-1,8-naphthyridine-3-carboxylate (327 mg), (3R,4S)-3-cyclopropylaminomethyl-4-fluoropyrrolidine (174 mg), 1,8-diazabicyclo[5.4.0]undec-7-ene (160 mg) and acetonitrile (5 mL) were mixed together. The reaction mixture was stirred at 80° C. for 1 hour and was concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane (30 mL), washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: dichloromethane: acetone=2:1->1:1->dichloromethane: methanol=10:1). The eluted pale yellow solid was dissolved in ethanol (4 mL), followed by addition of a 10% aqueous solution of sodium hydroxide (4 mL), stirring at 60° C. for 70 min, and concentration under reduced pressure. The resulting residue was diluted with water (10 mL), neutralized with 1 mol/L hydrochloric acid (pH 7.5), and extracted with dichloromethane (2×30 mL). The dichloromethane extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: dichloromethane: methanol=10:1) to give 7-[(3S,4S)-3-cyclopropylaminomethyl-4-fluoro-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-1-(1,1-dimethylethyl)-4-oxo-1,8-naphthyridine-3-carboxylic acid as white crystals (141 mg).
Reaction SMILES: O[N:2]1C(=O)C2=CC=CC=C2C1=O.[C@H:13]1([CH2:21][OH:22])[CH2:18][CH2:17][C@H:16]([CH2:19][OH:20])[CH2:15][CH2:14]1>>[NH2:2][O:20][CH2:19][C@H:16]1[CH2:17][CH2:18][C@H:13]([CH2:21][OH:22])[CH2:14][CH2:15]1
Reactant: OC[C@H]1CC[C@H](CO)CC1
Reactant: O=C1c2ccccc2C(=O)N1O
Product: NOC[C@H]1CC[C@H](CO)CC1

Procedure:
Prepared by a similar procedure as described for preparation 31. Starting materials: N-hydroxyphthalimide and trans-1,4-cyclohexanedimethanol (Acros). 13C-NMR (CDCl3) δ 81.6, 68.2, 40.3, 36.8, 29.0, 28.7.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][S:13]([N:16]1[CH2:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[S:19][CH2:18][CH2:17]1)(=[O:15])=[O:14]>ClCCl>[CH3:12][S:13]([N:16]1[CH2:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[S:19](=[O:9])[CH2:18][CH2:17]1)(=[O:14])=[O:15]
Reactant: CS(=O)(=O)N1CCSc2ccccc2C1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)(=O)N1CCS(=O)c2ccccc2C1
Reaction time: 0.25 h

Procedure:
A solution of 3-chloroperbenzoic acid (1.4 g) in dichloromethane (200 ml) was added dropwise with cooling from 0° C. to -2° C. to a stirred solution of 4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine (2 g, prepared as Example 17 above) in dichloromethane (50 ml). The reaction mixture was stirred for 15 minutes, washed with water, dried and the solvent was removed by evaporation at reduced pressure. Purification of the residue by flash chromatography using dichloromethane/ethanol (95:5) as eluent gave 4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide, which was recrystallised from ethanol. Yield 1.65 g (m.p. 195°-197° C.).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[N:19]=[C:18]([N:20]4[CH2:25][CH2:24][CH2:23][CH:22]([NH2:26])[CH2:21]4)[CH:17]=[CH:16][CH:15]=3)[CH:5]=[CH:4][C:3]1=2.Cl[CH2:29][CH2:30][CH2:31][OH:32].Cl>>[CH3:1][C:2]1([CH3:27])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[N:19]=[C:18]([N:20]4[CH2:25][CH2:24][CH2:23][CH:22]([NH:26][CH2:29][CH2:30][CH2:31][OH:32])[CH2:21]4)[CH:17]=[CH:16][CH:15]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCCC(N)C4)n3)ccc21
Reactant: OCCCCl
Agent: Cl
Product: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCCC(NCCCO)C4)n3)ccc21

Procedure:
The preparation is carried out analogously to FS301 starting from 73 mg (0.20 mmol) of 6′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-3,4,5,6-tetrahydro-2H-1,2′-bipyridinyl-3-ylamine and 33 μl of 3-chloro-1-propanol. The product is the hydrochloride.