Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.[OH:25][CH2:26][C:27]([NH:31][S:32]([C:35]1[CH:36]=[N:37][CH:38]=[C:39](Br)[CH:40]=1)(=[O:34])=[O:33])([CH2:29][OH:30])[CH3:28]>>[OH:25][CH2:26][C:27]([NH:31][S:32]([C:35]1[CH:36]=[N:37][CH:38]=[C:39]([C:13]#[C:12][C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:1])[F:24])=[CH:4][C:5]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=4)=[N:6][C:7]=23)[CH:40]=1)(=[O:34])=[O:33])([CH2:29][OH:30])[CH3:28]
Reactant: CC(CO)(CO)NS(=O)(=O)c1cncc(Br)c1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CC(CO)(CO)NS(=O)(=O)c1cncc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-Difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2)(340 mg, 1.0 mmol) and 5-Bromo-pyridine-3-sulfonic acid (2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-amide (example B.4) (295 mg, 1.0 mmol) according to general procedure II. Obtained as a light-brown solid (240 mg, 40%). MS (ISP) 582.2 [(M+H)+]; mp 204–206° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[S:10][C:9]([C:11]#[C:12][CH2:13][OH:14])=[CH:8][C:6]=2[N:7]=1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[S:10][C:9]([C:11]#[C:12][CH2:13][O:14][S:29]([CH3:28])(=[O:31])=[O:30])=[CH:8][C:6]=2[N:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCC#Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)OCC#Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 3-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-prop-2-yn-1-ol (142 mg) in chloroform (10 ml) was added triethylamine (77 μL) and methanesulfonyl chloride (49 μL). Stir at room temperature for 2 hours then partition between chloroform and brine, the combined organics were dried (MgSO4). The solvents were removed in vacuo to yield methanesulfonic acid 3-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-prop-2-ynyl ester (150 mg).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[C:13]([CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])[CH:14]=[CH:15][C:16]=3[O:17][CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22]C[CH2:20]3)[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl.FC1C=C(CCC(O)=O)C=CC=1[O:40]C>C(O)C>[CH:19]1([CH2:18][O:17][C:16]2[CH:15]=[CH:14][C:13]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:12][C:11]=2[C:9]2[CH:8]=[CH:7][C:5]3[NH:6][C:2](=[O:40])[S:3][C:4]=3[CH:10]=2)[CH2:24][CH2:23][CH2:22][CH2:20]1
Reactant: CCOC(=O)CCc1ccc(OCC2CCCCC2)c(-c2ccc3nc(Br)sc3c2)c1
Reactant: COc1ccc(CCC(=O)O)cc1F
Agent: Cl
Solvent: CCO
Product: O=C(O)CCc1ccc(OCC2CCCC2)c(-c2ccc3[nH]c(=O)sc3c2)c1
Temperature: 80 °C
Reaction time: 18.5 h

Procedure:
A solution of Intermediate 76 (202 mg) in ethanol (8 ml) was added with 5 N aqueous hydrochloric acid (1.5 ml), and stirred at 80° C. for 18.5 hours. The reaction mixture was concentrated under reduced pressure, and added with water (20 ml) and ethyl acetate (80 ml) for extraction. The organic layer was washed with saturated brine and dried, and then the solvent was evaporated under reduced pressure. The residue was added with 2 N aqueous sodium hydroxide (1.0 ml), reacted and treated according to the procedure described in the synthesis method of Intermediate 9 provided that the reaction was carried out for 2 hours to obtain the title compound (Compound No. V-89, 250 mg).
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10][C@@H:11]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27]Cl>CN(C)C=O>[C:1]1([CH:7]([CH2:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=2)[C:8]([O:10][C@@H:11]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCc1ccccn1
Reactant: O=C(Cc1ccccc1)O[C@H]1CN2CCC1CC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O[C@H]1CN2CCC1CC2)C(Cc1ccccn1)c1ccccc1
Yield: 35.9 %

Procedure:
A mixture of (R)-3-quinuclidinyl 2-phenylacetate (see Preparation 9) 1.23 g) and sodium hydride (165 mg of an 80% dispersion in oil) in dimethylformamide (10 ml) was stirred for 1/4 hour, treated with 2-picolyl chloride (0.64 g), stirred for 24 hours then partitioned between ethyl acetate and 10% aqueous potassium carbonate. The organic layer was dried over magnesium sulphate and the residue, after evaporation, was purified by chromatography on silica gel by gradient elution using chloroform plus methanol (0→10%) and aqueous ammonia (0→1%). Appropriate fractions were combined and evaporated to give the title compound as an oil (605 mg, 36%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:27])=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCCCN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CCCCN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(F)cc4)nc23)CC1
Yield: 355.6 %

Procedure:
Beginning with 0.15 gm (0.55 mMol) 5-amino-3-(1-butyl-piperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.079 mL (0.067 mMol) 4-fluorobenzoyl chloride, 0.094 gm (43%) of the title compound were prepared as an ivory foam essentially by the procedure described in Example 4. An analytical sample was crystallized from aqueous ethanol.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]1[N:11]=[C:10]([CH:12]2[CH2:17][CH2:16][NH2+:15][CH2:14][CH2:13]2)[O:9][N:8]=1.C(N(CC)CC)C.[Cl:25][CH2:26][C:27](Cl)=[O:28]>ClCCl>[Cl:25][CH2:26][C:27]([N:15]1[CH2:16][CH2:17][CH:12]([C:10]2[O:9][N:8]=[C:7]([C:3]3[S:2][CH:6]=[CH:5][CH:4]=3)[N:11]=2)[CH2:13][CH2:14]1)=[O:28]
Reactant: O=C(Cl)CCl
Reactant: c1csc(-c2noc(C3CC[NH2+]CC3)n2)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)N1CCC(c2nc(-c3cccs3)no2)CC1
Temperature: -15 °C
Yield: 95 %

Procedure:
168 mg (1 eq.) of 4-(3-thiophen-2-yl[1,2,4]oxadiazol-5-yl)-piperidinium hydrochloride obtained in step 1) above and 220 μl (3.1 eq.) of triethylamine were dissolved in 1 ml of dichloromethane and stirred at a temperature of −15° C. A solution of chloroacetyl chloride (40 μl, 1 eq.) in 1 ml of dichloromethane (CH2Cl2) was added dropwise to the resulting suspension. The resulting mixture was stirred at room temperature for 2 hours. 20 ml of dichloromethane were then added, and the resulting organic phase was washed with three times 50 ml of 5% hydrochloric acid and then dried over MgSO4, filtered and evaporated. 2-Chloro-1-[4-(3-thiophen-2-yl[1,2,4]oxa-diazol-5-yl)piperid-1-yl]ethanone was obtained in the form of a white solid, in a yield of 95%.
Reaction SMILES: [H][H].[N:3]([CH:6]([F:25])[C:7]([NH:9][C:10]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:11]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O)=[O:8])=[N+]=[N-]>[Pd].C(OCC)(=O)C>[F:25][CH:6]1[N:3]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]2[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:10]=2[NH:9][C:7]1=[O:8]
Reactant: [N-]=[N+]=NC(F)C(=O)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C1Nc2ccc(Cl)cc2C(c2ccccc2)=NC1F

Procedure:
Hydrogen is passed into a solution of 3.33 g. of 2-(α-azido-α-fluoro-acetamido)-5-chlorobenzophenone in 100 ml. of ethyl acetate in the presence of 0.3 g. of 5% palladium-on-charcoal for 4 hours. After filtering off the catalyst, evaporation and working up in the customary manner, there is obtained 3-fluoro-5-phenyl-7-chloro-2,3-dihydro-1H-1,4-benzodiazepin-2-one, m.p. 235° (decomposition).
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([NH:14]S(C(C)(C)C)=O)[CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11].Cl.O1CCOCC1>CO>[C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([NH2:14])[CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)CCC(NS(=O)C(C)(C)C)c1ccccc1-c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)CCC(N)c1ccccc1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A cooled (0° C.) slightly yellow solution of methyl 4-([1,1′-biphenyl]-2-yl)-4-(1,1-dimethylethylsulfinamido)butanoate (330 mg; 0.88 mmol) in MeOH (4 ml) was treated dropwise with a solution of 4 M HCl in 1,4-dioxane (0.44 ml; 1.77 mmol). The resulting yellow mixture was further stirred at 0° C., under nitrogen, for 10 min., and then at rt for 1 h. The reaction mixture was then concentrated to dryness under reduced pressure and the oily residue was further dried under HV to give the chlorhydrate salt of methyl 4-([1,1′-biphenyl]-2-yl)-4-aminobutanoate. LC-MS (conditions A): tR=0.56 min.; [M+H]+: 270.06 g/mol.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12](O)[CH3:13]>C(Cl)(Cl)Cl>[Cl:3][CH:12]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[F:5])[CH3:13]
Reactant: CC(O)c1ccccc1F
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC(Cl)c1ccccc1F
Temperature: 20 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
767 mg of thionyl chloride are added to a solution of 1 g of commercial 1-(2-fluorophenyl)ethanol in 20 ml of chloroform. After stirring overnight at a temperature in the region of 20° C., the reaction mixture is washed with a saturated aqueous solution of sodium bicarbonate and then dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure. 780 mg of 1-(1-chloroethyl)-2-fluorobenzene are thus obtained, said product being used as it is in the next stage.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:19])[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1.O.Cl>C1COCC1.O>[CH3:18][N:15]1[CH2:14][CH2:13][N:12]([C:9]2[CH:10]=[CH:11][C:6]([C:5]([OH:19])=[O:4])=[CH:7][CH:8]=2)[CH2:17][CH2:16]1
Reactant: COC(=O)c1ccc(N2CCN(C)CC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(c2ccc(C(=O)O)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
LiOH (67 mg, 1.6 mmol) was added to a stirred solution 4-(4-methyl-piperazin-1-yl)-benzoic acid methyl ester (124 mg, 0.73 mmol) in THF:H2O (1:1, 4 mL), and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to get the residue. Cold water was then added and acidified it with 10% aqueous HCl and concentrated under reduced pressure to afford 116 mg (85.13% yield) of 4-(4-methyl-piperazin-1-yl)-benzoic acid. 1H NMR (DMSO-D2O): δ 7.8 (d, 2H), 7.0 (d, 2H), 3.4 (s, 4H), 2.8 (s, 4H), 2.4 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[O:7])=[CH:4][CH:3]=1.[NH:17]1[CH2:26][CH2:25][CH2:24][C@H:18]1[C:19]([O:21]CC)=[O:20].[OH-].[K+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([N:17]2[CH2:26][CH2:25][CH2:24][C@H:18]2[C:19]([OH:21])=[O:20])=[O:14])=[O:7])=[CH:15][CH:16]=1
Reactant: O=C(O)CCCNC(=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)[C@@H]1CCCN1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(NCCCC(=O)N1CCC[C@H]1C(=O)O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl)-4-aminobutyric acid and ethyl L-prolinate and suitable processing, dissolving the evaporation residue in ethanol, adding an ethanolic solution of potassium hydroxide, stirring for 12 hours at room temperature and further processing yields N-[N-(p-chlorobenzoyl)-4-aminobutyryl]-L-proline.
Reaction SMILES: [CH3:1][CH:2]1[N:15]2[C:6]([CH2:7][O:8][C:9]3[C:14]2=[CH:13][C:12]([NH:16][C:17]2([CH3:21])[CH2:20][NH:19][CH2:18]2)=[C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:10]=3)=[N:5][NH:4][C:3]1=[O:28].C=O.[BH3-][C:32]#N.[Na+]>CO.CC(O)=O>[CH3:32][N:19]1[CH2:20][C:17]([NH:16][C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][C:11]=2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[O:8][CH2:7][C:6]2[N:15]3[CH:2]([CH3:1])[C:3](=[O:28])[NH:4][N:5]=2)([CH3:21])[CH2:18]1
Reactant: CC1C(=O)NN=C2COc3cc(-c4ccccc4)c(NC4(C)CNC4)cc3N21
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC1C(=O)NN=C2COc3cc(-c4ccccc4)c(NC4(C)CN(C)C4)cc3N21
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 102.2 %

Procedure:
A solution of 4-methyl-6-(3-methyl-azetidin-3-ylamino)-7-phenyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.095 g, 57% purity, 0.15 mmol) and paraformaldehyde (0.015 g, 0.45 mmol) in MeOH (10 mL) and AcOH (1 mL) was heated at 80° C. for 2 h. NaBH3CN (0.019 g, 0.30 mmol) was added and the reaction mixture was stirred at 80° C. for 0.5 h. The reaction mixture was cooled to ambient temperature. The solvent was removed in vacuo and the residue was washed with aqueous saturated Na2CO3 solution (2 mL). The aqueous phase was extracted with EtOAc (4×20 mL). The combined organic layer was dried, filtered and concentrated in vacuo to give crude 6-(1,3-dimethyl-azetidin-3-ylamino)-4-methyl-7-phenyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.060 g, 78% over two steps), which was used in the next step directly. LC/MS (Table 1, Method 2) Rt=0.924 min; MS m/z: 392 [M+H]+. A solution of 6-(1,3-dimethyl-azetidin-3-ylamino)-4-methyl-7-phenyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.060 g, 0.15 mmol) in ammonium hydroxide (25%, 5 mL) and dioxane (5 mL) was stirred at ambient temperature for 2 h. The solvent was removed in vacuo and the residue was purified by preparative HPLC (Table 3, Method 16) to give 6-(1,3-dimethyl-azetidin-3-ylamino)-4-methyl-7-phenyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid (0.022 g, 27%). LC/MS (Table 1, Method 4) Rt=1.722 min; MS m/z: 392 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[N:8]=[C:7]([O:9]C)[CH:6]=[C:5]([CH3:11])[N:4]=1.I[CH3:13]>>[CH3:13][N:4]1[C:5]([CH3:11])=[CH:6][C:7](=[O:9])[NH:8][C:3]1=[O:2]
Reactant: COc1cc(C)nc(OC)n1
Reactant: CI
Product: Cc1cc(=O)[nH]c(=O)n1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
14.2 g (92 mmol) 2,4-dimethoxy-6-methylpyrimidine was dissolved in 210 mL iodomethane and the reaction allowed to continue for 2 days at room temperature. After 2 days, the excess of iodomethane was evaporated off under reduced pressure, the residue treated with 675 mL 1 N HCl and the resulting mixture refluxed for one and a half hours. After cooling to room temperature and neutralization with a concentrated sodium hydroxide solution, the water was removed under reduced pressure and the residue extracted with chloroform using a Soxhlet extractor. The chloroform was evaporated under reduced pressure and the crude compound recrystallized first from ethanol and then from water yielding 4.03 g (31%) of 1,6-dimethyluracil (m.p. 221–223° C.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH:13]([CH3:16])[CH:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([N:33]2[CH:37]=[N:36][N:35]=[N:34]2)=[C:22]([CH:32]=1)[CH2:23][NH:24][C:25](=[O:31])[C@@H:26]1[CH2:30][CH2:29][CH2:28][NH:27]1>C(Cl)CCl>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH:13]([CH3:16])[C@H:9]1[C:10]([N:27]1[CH2:28][CH2:29][CH2:30][C@H:26]1[C:25]([NH:24][CH2:23][C:22]1[CH:32]=[C:18]([Cl:17])[CH:19]=[CH:20][C:21]=1[N:33]1[CH:37]=[N:36][N:35]=[N:34]1)=[O:31])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(NCc1cc(Cl)ccc1-n1cnnn1)[C@@H]1CCCN1
Reactant: CC1CCN(C(=O)OC(C)(C)C)C1C(=O)O
Solvent: ClCCCl
Product: CC1CCN(C(=O)OC(C)(C)C)[C@@H]1C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1-n1cnnn1

Procedure:
The title compound was prepared as a mixture of diastereomers from 1-(tert-butoxycarbonyl-3-methyl-dl-proline (16 mg, 0.07 mmol) and N-[5-chloro-2-(1H-tetraazol-1-yl)benzyl]-L-prolinamide (Example 26, Step B, 21 mg, 0.07 mmol), essentially according to the EDC coupling procedure described in Example 39, Step D. The diastereomeric products were separated by reverse phase HPLC and were carried on directly to deprotection.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:33][N:34]1[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36][CH2:35]1.C(N(C(C)C)CC)(C)C>C(#N)C>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:40][CH:37]5[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CN1CCC(N)CC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 8 h

Procedure:
Combine 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid (3.108 kg, 6.17 mol) and acetonitrile (14.56 kg) and adjust the temperature to about 0° C. Add N-methyl-4-aminopiperidine (0.775 k, 1.1 eq.). Diisopropylethylamine (1.595 kg) was added aver about 29 minutes at temperature of about 6 to 12° C., the temperature was adjusted to about 20 to 25° C. and the reaction mixture was stirred overnight. The solid was collected by filtration, rinsed with acetonitrile (4.47 kg) and dried under at stream of nitrogen for 1 hour, then in a vacuum oven at 40° C. for 2 days to give the title compound.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][OH:9])[CH:5]=[CH:4][N:3]=[N:2]1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl>[CH3:17][S:18]([O:9][CH2:8][CH2:7][CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[N:2]1)(=[O:20])=[O:19]
Reactant: OCCCn1ccnn1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCn1ccnn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 74.6 %

Procedure:
3-(1,2,3-triazol-1-yl)propanol (2.5 g, 19.66 mmol) was dissolved in dichloromethane (50 mL), and the solution was cooled to 0° C. Then, triethylamine (5.53 mL, 39.32 mmol) and methane sulfonyl chloride (2.3 mL, 29.5 mmol) were added thereto. The reaction mixture was warmed to room temperature, stirred for 2 hours, extracted with dichloromethane and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford the title compound (3.01 g, 75%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH2:8][CH2:9][O:10][C:6]=2[C:5]([C:11]([NH:13][C@H:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]#[N:22])[CH2:16][C@H:15]2[O:23][CH3:24])=[O:12])=[CH:4][C:3]=1[Cl:25].O1CCCC1.[H][H]>[Ni].CO>[NH2:1][C:2]1[C:7]2[CH2:8][CH2:9][O:10][C:6]=2[C:5]([C:11]([NH:13][C@H:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][NH2:22])[CH2:16][C@H:15]2[O:23][CH3:24])=[O:12])=[CH:4][C:3]=1[Cl:25]
Reactant: [H][H]
Reactant: CO[C@@H]1CN(CC#N)CC[C@@H]1NC(=O)c1cc(Cl)c(N)c2c1OCC2
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: CO[C@@H]1CN(CCN)CC[C@@H]1NC(=O)c1cc(Cl)c(N)c2c1OCC2
Yield: 53.6 %

Procedure:
A solution of 15.7 parts of cis-4-amino-5-chloro-N-[1-(cyanomethyl)-3-methoxy-4-piperidinyl]-2,3-dihydro-7-benzofurancarboxamide in 178 parts of tetrahydrofuran and 158 parts of methanol was hydrogenated at normal pressure and at room temperature with 6 parts of Raney nickel. After the calculated amount of hydrogen was taken up, Me catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2 /CH3OH(NH3) 93:7). The eluent of the desired fraction was evaporated and the residue was crystallized from acetonitrile (to which a few drops of water were added). The product was filtered off at 0° C. and dried in vacuo at 40° C., yielding 8.5 parts (53.6%)of cis-4-amino-N-[1-(2-aminoethyl)-3-methoxy-4-piperidinyl]-5-chloro-2,3-dihydro-7-benzofurancarboxamide (comp. 35).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(N(CC)CC)C.[OH:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([C:37]2[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=2)[C:29]2[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=2[CH2:31]Br)=[CH:24][CH:23]=1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:31][C:30]2[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=2[CH:28]([C:25]2[CH:24]=[CH:23][C:22]([OH:21])=[CH:27][CH:26]=2)[C:37]2[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=2)[CH2:10][CH2:9]1
Reactant: Clc1ccccc1N1CCNCC1
Reactant: Oc1ccc(C(c2ccc(O)cc2)c2ccccc2CBr)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Oc1ccc(C(c2ccc(O)cc2)c2ccccc2CN2CCN(c3ccccc3Cl)CC2)cc1
Yield: 14.6 %

Procedure:
In 50 ml of tetrahydrofuran were dissolved 1.5 g of 1-(2-chlorophenyl)piperazine and 5 ml of triethylamine, and 3.4 g of 2-[bis(4-hydroxyphenyl)methyl]benzylbromide was added thereto. The mixture was heated under reflux for 3.5 hours, and then insoluble substances were filtered off. The filtrate was concentrated, and the residue was subjected to extraction with the addition of water and ethyl acetate. The organic layer was separated, and the aqueous layer was then extracted with ethyl acetate. The organic layers were combined and then dried over anhydrous magnesium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel chromatography to afford 0.54 g of the desired compound (Compound 89).
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:7][CH:8]=2)[N:3]1[CH2:17][C:18]([O:20]C)=[O:19].[OH-].[Na+]>C1COCC1.C(OCC)(=O)C>[O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:12][C:13]([F:15])([F:14])[F:16])=[CH:7][CH:8]=2)[N:3]1[CH2:17][C:18]([OH:20])=[O:19]
Reactant: COC(=O)Cn1c(=O)ccc2ccc(OC(F)(F)F)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)Cn1c(=O)ccc2ccc(OC(F)(F)F)cc21
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Methyl 2-(2-oxo-7-(trifluoromethoxy)quinolin-1(2H)-yl)acetate (0.49 g, 1.62 mmol) was dissolved in THF (4 mL). Sodium hydroxide (1.08 mL of a 3 N aqueous solution, 3.25 mmol) was added and the reaction mixture was stirred 60° C. for 2 h. The resulting solution was diluted with ethyl acetate and washed with water. The aqueous phase was separated, adjusted to pH 2 with aqueous HCl and extracted with ethyl acetate. The organic phase was separated, dried (Na2SO4), filtered and concentrated under vacuum to give 2-(2-oxo-7-(trifluoromethoxy)quinolin-1(2H)-yl)acetic acid. Retention time (min)=1.75, method [1], MS (ESI) 288.1 (M+H).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:34]=[CH:35][CH:36]=1)[CH2:12][O:13][CH:14]1[CH:19]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:37]>CO>[ClH:37].[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH:19]2[CH2:18][CH2:17][NH:16][CH2:15][CH:14]2[O:13][CH2:12][C:11]2[CH:10]=[C:9]([C:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:8])[CH:36]=[CH:35][CH:34]=2)=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(F)cc2)C(OCc2cccc(C(=O)c3ccccc3)c2)C1
Agent: Cl
Solvent: CO
Product: O=C(c1ccccc1)c1cccc(COC2CNCCC2c2ccc(F)cc2)c1

Procedure:
In an analogous manner to that described in Example 22 (l), from tert-butyl (3RS,4RS)-3-(3-benzoyl-benzyloxy)-4-(4-fluoro-phenyl)-piperidine-1-carboxylate by cleavage of the BOC group with hydrogen chloride in methanol there was obtained [3-[(3RS,4RS)-4-(4-fluoro-phenyl)-piperidin-3-yloxymethyl]-phenyl]-phenyl-methanone hydrochloride (1:1) in the form of colourless crystals; MS: 390 (M+H)+.