Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[CH:14]=[N:15][N:16]4[C:21]([NH2:22])=[C:20]5[CH2:23][NH:24][CH2:25][C:19]5=[N:18][C:17]=34)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26](O)(=[O:30])[C@@H:27]([CH3:29])[OH:28].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:22][C:21]1[N:16]2[N:15]=[CH:14][C:13]([C:10]3[CH:11]=[N:12][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:8][CH:9]=3)=[C:17]2[N:18]=[C:19]2[CH2:25][N:24]([C:26](=[O:30])[C@H:27]([OH:28])[CH3:29])[CH2:23][C:20]=12
Reactant: Nc1c2c(nc3c(-c4ccc(-c5ccccc5)nc4)cnn13)CNC2
Reactant: C[C@@H](O)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: C[C@@H](O)C(=O)N1Cc2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N)c2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of crude 3-(6-phenylpyridin-3-yl)-6,7-dihydro-5H-pyrazolo[1,5-a]pyrrolo[3,4-d]pyrimidin-8-amine (0.28 mmol), D-(−)-lactic acid (33.6 mg, 0.37 mmol), EDC (109.7 mg, 0.57 mmol), HOBt (77.6 mg, 0.57 mmol) and DIEA (299.7 uL, 1.72 mmol) in DMF (4 mL) was stirred at room temperature overnight. Purification with prep-LC provided (R)-1-(8-amino-3-(6-phenylpyridin-3-yl)-5H-pyrazolo[1,5-a]pyrrolo[3,4-d]pyrimidin-6(7H)-yl)-2-hydroxypropan-1-one: LCMS tR=2.65 Min (10 min run, UV254nm), Mass calculated for, M+400.1, observed LC/MS m/z 401.1 (M+H).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:12]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-])=O)[CH:22]=4)[CH2:17][CH2:16]3)=[N:11][N:10]([CH3:30])[C:9]2=[O:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CO.CC#N.[Pd]>[NH2:27][C:23]1[CH:22]=[C:21]([N:18]2[CH2:17][CH2:16][N:15]([CH2:14][CH2:13][C:12]3[N:8]([CH2:7][CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[C:9](=[O:31])[N:10]([CH3:30])[N:11]=3)[CH2:20][CH2:19]2)[CH:26]=[CH:25][CH:24]=1
Reactant: Cn1nc(CCN2CCN(c3cccc([N+](=O)[O-])c3)CC2)n(CC2CCCCC2)c1=O
Agent: [Pd]
Solvent: CC#N
Solvent: CO
Product: Cn1nc(CCN2CCN(c3cccc(N)c3)CC2)n(CC2CCCCC2)c1=O
Yield: 98.8 %

Procedure:
A slurry of 4-(cyclohexylmethyl)-2-methyl-5-{2-[4-(3-nitrophenyl)piperazino]ethyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (D15; 490 mg, 1.143 mmol) and 10% Pd/C (250 mg) in MeOH (30 mL) was hydrogenated in an autoclave at 30 bar and room temperature for 4 hrs. The reaction mixture was filtered over a pad of Celite and the solvent was removed in vacuo to afford a light-brown film. This was re-dissolved in MeCN (20 mL) and filtered again through a Celite plug. The solvent was evaporated in vacuo to afford 450 mg (99%) of the title compound as a brown solid.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[CH2:10][C:9]([CH3:11])=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:7]2[N:19]=[CH:20][C:21]([C:22]#[N:23])=[C:6]12)=[O:4].C(=O)([O-])[O-].[Na+].[Na+].[CH2:30]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:55].Cl>C1(C)C=CC=CC=1>[ClH:1].[ClH:55].[Cl:18][C:14]1[CH:13]=[C:12]([C:8]2[N:7]3[N:19]=[CH:20][C:21]([C:22]#[N:23])=[C:6]3[N:5]([C:3](=[O:4])[CH2:2][N:40]3[CH2:41][CH2:42][N:37]([CH2:30][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:38][CH2:39]3)[CH2:10][C:9]=2[CH3:11])[CH:17]=[CH:16][CH:15]=1
Reactant: CC1=C(c2cccc(Cl)c2)n2ncc(C#N)c2N(C(=O)CCl)C1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC1=C(c2cccc(Cl)c2)n2ncc(C#N)c2N(C(=O)CN2CCN(Cc3ccccc3)CC2)C1

Procedure:
A mixture of 3.1 g of 4-(chloroacetyl)-7-(3-chlorophenyl)-4,5-dihydro-6-methylpyrazolo[1,5-a]pyrimidine-3-carbonitrile, 1.1 g of sodium carbonate, 1.7 g of N-benzylpiperazine and 115 ml of toluene was reacted as described in Example 16, giving the base form of the product which was converted to the dihydrochloride salt by the procedure of Example 97, giving 1.3 g, mp 201°-203° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-])=O>C(O)C.[Ni]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[NH2:10]
Reactant: COc1ccc(Br)c([N+](=O)[O-])c1
Agent: [Ni]
Solvent: CCO
Product: COc1ccc(Br)c(N)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.3 %

Procedure:
A mixture of 1-bromo-4-methoxy-2-nitro-benzene (10 g, 43 mmol) and Raney Ni (5 g) in ethanol (100 mL) was stirred under H2 (1 atm) for 4 h at room temperature. Raney Ni was filtered off and the filtrate was concentrated under reduced pressure. The resulting solid was purified by column chromatography to give 2-bromo-5-methoxy-phenylamine (7.5 g, 86%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH:9]([Cl:11])[Cl:10])[CH:5]=[C:4]([C:12]([Cl:15])([Cl:14])[Cl:13])[N:3]=1.[Cl:16]C1N=C(Cl)C=C(C(Cl)(Cl)Cl)N=1>>[Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]([Cl:16])([Cl:10])[Cl:11])[CH:5]=[C:4]([C:12]([Cl:15])([Cl:13])[Cl:14])[N:3]=1
Reactant: Clc1cc(C(Cl)(Cl)Cl)nc(Cl)n1
Reactant: Clc1nc(OC(Cl)Cl)cc(C(Cl)(Cl)Cl)n1
Product: Clc1nc(OC(Cl)(Cl)Cl)cc(C(Cl)(Cl)Cl)n1
Yield: 83 %

Procedure:
The filtrate (113.8 g) consisted, according to the gas chromatograph, of 83% of the title compound, 4% of 2-chloro-4-dichoromethoxy-6-trichloromethylpyrimidine and 9% of 2,4-dichloro-6-trichloromethylpyrimidine. The total yield of the title compound was 87.6% of theory.
Reaction SMILES: [C:1]([NH:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]([O:36]CC2C=CC=CC=2)=[C:16]([CH2:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[O:29])=[C:24]([CH3:35])[CH:23]=2)=[O:20])[CH:17]=1)=[NH:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[H][H].[Pd]>[C:1]([NH:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]([OH:36])=[C:16]([CH2:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([N:30]3[CH2:31][CH2:32][CH2:33][CH2:34]3)=[O:29])=[C:24]([CH3:35])[CH:23]=2)=[O:20])[CH:17]=1)=[NH:11])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(NC(=O)Cc2cc(C(=N)NC(=O)c3ccccc3)ccc2OCc2ccccc2)ccc1C(=O)N1CCCC1
Reactant: [H][H]
Agent: [Pd]
Product: Cc1cc(NC(=O)Cc2cc(C(=N)NC(=O)c3ccccc3)ccc2O)ccc1C(=O)N1CCCC1

Procedure:
Prepared analogously to Example 5h from 2-[5-(N-benzoyl-carbamimidoyl)-2-benzyloxy-phenyl]-N-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-phenyl]-acetamide and hydrogen/palladium on activated charcoal.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[NH:13][C:14]1[N:18]([CH2:19][CH2:20][CH2:21][C:22](OCC)=[O:23])[C:17]2[C:27]([CH:32]([CH2:35][CH3:36])[CH2:33][CH3:34])=[CH:28][CH:29]=[C:30]([Cl:31])[C:16]=2[N:15]=1.[BH4-].[Li+]>O1CCCC1>[Br:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:11])([F:10])[F:12])[CH:5]=[CH:4][C:3]=1[NH:13][C:14]1[N:18]([CH2:19][CH2:20][CH2:21][CH2:22][OH:23])[C:17]2[C:27]([CH:32]([CH2:35][CH3:36])[CH2:33][CH3:34])=[CH:28][CH:29]=[C:30]([Cl:31])[C:16]=2[N:15]=1
Reactant: CCOC(=O)CCCn1c(Nc2ccc(OC(F)(F)F)cc2Br)nc2c(Cl)ccc(C(CC)CC)c21
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(CC)c1ccc(Cl)c2nc(Nc3ccc(OC(F)(F)F)cc3Br)n(CCCCO)c12
Temperature: 25 °C
Reaction time: 12 h
Yield: 44 %

Procedure:
To a solution of ethyl 4-[2-{[2-bromo-4-(trifluoromethoxy)phenyl]amino}-4-chloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (1.37 g, 2.32 mmol) in tetrahydrofuran (15.0 mL) was added lithium borohydride (151.5 mg, 6.96 mmol) at 0° C. The reaction mixture was stirred at room temperature for 12 hr. The reaction mixture was warmed to 60° C. and stirred for 24 hr. After cooling, the reaction mixture was quenched with water at 0° C. and extracted with ethyl acetate (×3). The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-20% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless powder (558.0 mg, 1.02 mmol, 44%).
Reaction SMILES: C(NC(C)C)(C)C.C([Mg]Cl)CCC.[CH2:14]([O:21][C:22]([NH:24][C@@H:25]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:26]([O:28]C)=O)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Br:37][CH2:38][Br:39].Cl>C(OCC)(=O)C.O.C1COCC1>[CH2:30]([C@H:25]([NH:24][C:22](=[O:23])[O:21][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:26](=[O:28])[CH:38]([Br:39])[Br:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reactant: BrCBr
Agent: CCCC[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: O
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)C(Br)Br)OCc1ccccc1
Reaction time: 2 h
Yield: 41.2 %

Procedure:
Under nitrogen gas, diisopropylamine (38.8 g, 383.4 mmol) was added to n-butylmagnesiumchloride (1.8 mol/kg, 178 g, 319.5 mmol) over 30 minutes at 40° C. and the mixture was further stirred for 2 hours at the same temperature to prepare a white slurry (liquor A). Separately, under nitrogen gas was in another vessel, a solution was prepared from methyl (S)-2-benzyloxycarbonylamino-3-phenylpropanoate (20.0 g, 63.9 mmol), dibromomethane (22.22 g, 127.8 mmol) and THF (40 mL) (liquor B). To this liquor B was added said liquor A over 2 hours at an internal temperature of about 5° C., and the reaction was further conducted at 5° C. for 2 hours. This reaction mixture was poured in a mixture of concentrated hydrochloric acid (73.3 g), water (100 g) and ethyl acetate (50 mL) over 1 hour for hydrolysis. After phase separation, the organic layer was washed with 2 portions of water (100 mL each). The organic layer was concentrated under reduced pressure to recover 34.38 g of black oil. This oil was purified by silica gel column chromatography to recover 22.34 g of yellow crude crystals. This crystal crop was recrystallized from ethyl acetate/hexane to provide white crystals of benzyl (S)-(1-benzyl-3,3-dibromo-2-oxopropyl)carbamate (11.99 g, 88.0 area %, yield 57%).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[C@@H:13]([OH:21])[C@H:12]2[OH:22])=[C:4]([NH:23][CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[N:3]=1.C(OC(=O)N([C@H:40]1[CH2:44][C@@H:43]([N:45]2[CH:53]=[N:52][C:51]3[C:46]2=NC(Cl)=NC=3Cl)C=[CH:41]1)C(=O)CC)(C)(C)C.NCCN1CCCCC1>>[CH2:25]([CH:24]([NH:23][C:4]1[N:3]=[C:2]([NH:52][CH2:51][CH2:46][N:45]2[CH2:53][CH2:41][CH2:40][CH2:44][CH2:43]2)[N:10]=[C:9]2[C:5]=1[N:6]=[CH:7][N:8]2[C@@H:11]1[CH2:15][C@H:14]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[C@@H:13]([OH:21])[C@H:12]1[OH:22])[CH2:27][CH3:28])[CH3:26]
Reactant: CCC(=O)N(C(=O)OC(C)(C)C)[C@@H]1C=C[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NC(CC)CC)nc(Cl)nc32)[C@H](O)[C@@H]1O
Agent: NCCN1CCCCC1
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NC(CC)CC)nc(NCCN4CCCCC4)nc32)[C@H](O)[C@@H]1O

Procedure:
N-{(1S,2R,3S,4R)-4-[2-Chloro-6-(1-ethyl-propylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide (the compound of Example 14) is reacted with 1-(2-aminoethyl)-piperidine to give the title compound using a procedure analogous to that of Example 9. MS (ES+) m/e 503 (MH+).
Reaction SMILES: C[Al](C)C.[CH2:5]([NH2:8])[CH2:6][NH2:7].C(O[C:12](=O)[CH2:13][N:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=1)[CH3:15])C>C1(C)C=CC=CC=1>[Cl:22][C:18]1[CH:17]=[C:16]([N:14]([CH2:13][C:12]2[NH:7][CH2:6][CH2:5][N:8]=2)[CH3:15])[CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)CN(C)c1cccc(Cl)c1
Reactant: NCCN
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CN(CC1=NCCN1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1.67 h
Yield: 29.4 %

Procedure:
To dry toluene (4 ml) under an inert atmosphere at 0° C. was added a toluene solution of trimethylaluminium (2.13 ml, 4.26 mmol, 2 M solution). A solution of ethylenediamine (0.29 ml, 4.26 mmol) in toluene (1.5 ml) was then added dropwise and the reaction mixture was then allowed to warm to room temperature and stirred for 100 min at this temperature before being re-cooled to 0° C. To this mixture was added dropwise a solution of [(3-chloro-phenyl)-methyl-amino]-acetic acid ethyl ester (0.49 g, 2.13 mmol) in toluene (3 ml). The reaction mixture was then heated at reflux for 2.5 h and then cooled first to room temperature and finally to 0° C. The mixture was quenched by dropwise addition of methanol (1 ml) and when all gas evolution had ceased the mixture was diluted with water and extracted twice with ethyl acetate. The combined organic extracts were dried over sodium sulphate, filtered and concentrated in vacuo. The residue was triturated in ether to yield a white solid (0.14 g, 29%) which was collected by filtration; MS (ISP): 226.2, 224.1 ([M+H]+.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([F:15])=[CH:13][N:12]=[C:11]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:18]=2)[N:10]=1.[F:28][C:29]1[CH:30]=[C:31]([CH2:35][OH:36])[CH:32]=[CH:33][CH:34]=1>>[F:15][C:14]1[C:9]([C:3]2[CH:4]=[CH:5][C:6]([O:36][CH2:35][C:31]3[CH:32]=[CH:33][CH:34]=[C:29]([F:28])[CH:30]=3)=[CH:7][C:2]=2[F:1])=[N:10][C:11]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][S:24]([CH3:27])(=[O:25])=[O:26])[CH:18]=2)=[N:12][CH:13]=1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncc(F)c(-c3ccc(F)cc3F)n2)c1
Reactant: OCc1cccc(F)c1
Product: CS(=O)(=O)Cc1cccc(Nc2ncc(F)c(-c3ccc(OCc4cccc(F)c4)cc3F)n2)c1

Procedure:
Example 18 was prepared under similar conditions as described in the preparation of Example 16 using 4-(2,4-difluorophenyl)-5-fluoro-N-{3-[(methylsulfonyl)methyl]phenyl}pyrimidin-2-amine (Intermediate 16.2) and (3-fluorophenyl)methanol (ABCR GmbH & CO. KG). The batch was purified by preparative HPLC.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:28]=[CH:27][C:16]([CH2:17][N:18]([CH3:26])[CH2:19][C:20]([O:22]CC=C)=[O:21])=[CH:15][CH:14]=1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>C1COCC1.O>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[CH:15][C:16]([CH2:17][N:18]([CH3:26])[CH2:19][C:20]([OH:22])=[O:21])=[CH:27][CH:28]=1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCOC(=O)CN(C)Cc1ccc(N(C(=O)OC(C)(C)C)S(C)(=O)=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(CC(=O)O)Cc1ccc(N(C(=O)OC(C)(C)C)S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 89 %

Procedure:
To a solution of allyl 2-((4-(N-(tert-butoxycarbonyl)methylsulfonamido)-benzyl)(methyl)amino)acetate (0.390 g, 0.945 mmol) in THF (22 ml), LiOH 1N (0.945 ml, 0.945 mmol) was added, and the mixture was stirred at RT for 3 days. The mixture was diluted with water and washed twice with EtOAc. The aqueous phase was acidified with 0.189 ml of HCl 1N and frozen dry. The residue was dissolved in DCM/MeOH and transferred in a small container. 2-((4-(N-(tert-butoxycarbonyl)methylsulfonamido)-benzyl)(methyl)amino)acetic acid was obtained (0.313 g, 0.840 mmol, 89% yield, MS/ESI+ 373.2 [MH]+) and used without any further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][C:12]([N+:14]([O-])=O)=[CH:13][C:8]=3[S:7](=O)[C:6]=2[CH:18]=1.C(O)(=O)C.O.O.Cl[Sn]Cl>Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][C:12]([NH2:14])=[CH:13][C:8]=3[S:7][C:6]=2[CH:18]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)S(=O)c1cc(Br)ccc1-2
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc2c(c1)sc1cc(Br)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A flask equipped with a stirrer and a thermometer was charged with 26.98 g of the intermediate 3-bromo-7-nitrodibenzothiophene-5-oxide prepared in Example 1-2 and 269.8 g of glacial acetic acid in a nitrogen atmosphere. 112.7 g of SnCl2.2H2O dissolved in 158 g of concentrated hydrochloric acid was added dropwise at 14 to 18° C. over 1 hour, and stirred overnight at room temperature. The resulting reactant was filtered, washed with 1:1 glacial acetic acid/concentrated hydrochloric acid, and neutralized with 1100 g of a 7 wt % aqueous solution of sodium hydroxide. The reactant was extracted with ethyl acetate, washed with water, concentrated, and purified by silica gel chromatography using 1:1 hexane/chloroform mixed with 0.1 wt % triethylamine as an eluting solvent, to thereby obtain 17.31 g of objective 7-bromodibenzothiophene-3-yl-amine. The product was subjected to elemental analysis, the results of which are as follows:
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](=[O:13])[CH2:11][CH2:10][C@H:5]1[C:6]([O:8]C)=[O:7])[CH3:3].CO.[OH-].[Na+]>O>[CH3:3][CH:2]([N:4]1[C:12](=[O:13])[CH2:11][CH2:10][C@H:5]1[C:6]([OH:8])=[O:7])[CH3:1]
Reactant: COC(=O)[C@@H]1CCC(=O)N1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)N1C(=O)CC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 42.7 %

Procedure:
Methyl 1-(1-methylethyl)-5-oxo-prolinate (0.152 g, 0.82 mmol) was dissolved in water (3 ml) and methanol (0.5 ml) and treated with 2M aqueous sodium hydroxide (0.682 ml, 1.36 mmol). The mixture was stirred for ˜4 hrs at room temperature and then washed with dichloromethane. The aqueous layer was evaporated and the residue treated with an excess of 1M hydrogen chloride in ether (˜5 ml). The mixture was evaporated once more and the residue was triturated with dichloromethane. The solid material was discarded and the combined dichloromethane fractions were evaporated to give 1-(1-methylethyl)-5-oxo-proline (0.060 g) as a yellow oil which crystallized on standing.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+](C1C=CC=CC=1)([O-])=O.C(=O)([O-])[O-].[K+].[K+].[CH3:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1>[Cu].O>[CH3:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:2]2[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:30][CH:29]=1
Reactant: Cc1ccc(I)c(C(=O)O)c1
Reactant: Cc1ccc(O)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Product: Cc1ccc(Oc2ccc(C)cc2C(=O)O)cc1

Procedure:
393 G. of 2-iodo-5-methyl-benzoic acid in 150 ml. of nitrobenzene are heated to 145° C. 138 G. of potassium carbonate are added thereto in small portions with stirring. Subsequently, 156 ml. of 4-methyl-phenol and 276 g. of potassium carbonate are added. To the resulting mixture, 3 g. of copper powder are carefully added, and the mixture is subsequently stirred at 165° C. for 20 minutes. After cooling, 1.25 liters of water are added to the mixture which is then extracted twice with ether. The aqueous phase is acidified with hydrochloric acid and extracted twice with ether. The ethereal solutions are washed with water, dried over sodium sulfate and concentrated in vacuo. The residue (brown crystals) is recrystallized from 1100 ml. of methanol and 700 ml. of water, and there is obtained 2-(4-methylphenoxy)-5-methyl-benzoic acid, which after repeated recrystallization from methanol/water, melts at 113°-115° C.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].Cl.[CH2:8]1[C:14]2[CH:15]=[CH:16][C:17]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:18][C:13]=2[CH2:12][CH2:11][NH:10][CH2:9]1.C(N(CC)CC)C>CO>[CH3:1][N:2]([CH3:6])[C:3]([N:10]1[CH2:9][CH2:8][C:14]2[CH:15]=[CH:16][C:17]([S:19]([NH2:22])(=[O:20])=[O:21])=[CH:18][C:13]=2[CH2:12][CH2:11]1)=[O:4]
Reactant: CN(C)C(=O)Cl
Reactant: NS(=O)(=O)c1ccc2c(c1)CCNCC2
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CN(C)C(=O)N1CCc2ccc(S(N)(=O)=O)cc2CC1
Temperature: 25 °C

Procedure:
8.05 Ml. of dimethylcarbamoyl chloride are added dropwise while cooling at about 25° C. in the course of 3 minutes to a solution of 21.5 g. of 2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide hydrochloride and 24.5 ml. of triethylamine in 400 ml. of methanol and the mixture is subsequently stirred for a further 15 hours, during which a crystalline precipitate results. By evaporation of the solvent in vacuo and digestion and washing of the crystalline evaporation residue with water, there is obtained 3-dimethylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide, m.p. 192°-193° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[N:12]([CH2:15][CH2:16][CH2:17][F:18])[N:11]=[N:10]1.Cl[CH2:20][C:21]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:22]=1[O:23][CH:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:18][CH2:17][CH2:16][CH2:15][N:12]1[C:13](=[O:14])[N:9]([C:3]2[CH:4]=[CH:5][C:6]([O:8][CH2:20][C:21]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:22]=3[O:23][CH:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26])=[CH:7][C:2]=2[F:1])[N:10]=[N:11]1
Reactant: COC(=O)C(C)Oc1cc(C)ccc1CCl
Reactant: O=c1n(CCCF)nnn1-c1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1cc(C)ccc1COc1ccc(-n2nnn(CCCF)c2=O)c(F)c1
Yield: 27.5 %

Procedure:
By the method Example 1, Step I, 0.85 g (0.0033 mole) of 1-(2-fluoro-4-hydroxyphenyl)-1,4-dihydro-4-(3-fluoropropyl)-5H-tetrazol-5-one and 1.21 g (0.0050 mole) of methyl 2-(2-chloromethyl-5-methylphenoxy)propionate (Example 1, Step H) were reacted in the presence of 0.70 g (0.0050 mole) of anhydrous potassium carbonate in 60 mL of N,N-dimethylformamide, yielding 0.42 g of methyl 2-[2-[4-[1,4-dihydro-4-(3-fluoropropyl)-5H-tetrazol-5-on-1-yl]-3-fluorophenoxymethyl]-5-methylphenoxy]propionate as an oil. The NMR spectrum was consistent with the proposed structure. NMR: 1.64 (d, 3H, JHH=8 Hz); 2.2-2.4 (m, 2H); 2,32 (s, 3H); 3.72 (s, 3H); 4.18 (t, 2H, JHH =8 Hz); 4.50-4.64 (dt, 2H, JHH=8 Hz, JHF=45 Hz); 4.84 (q, 1H, JHH=8 Hz), 5.20 (q, 2H, JHH=8 Hz); 6.58-7.40 (m, 6H).
Reaction SMILES: [OH-].[OH:2][CH2:3][CH2:4][N+:5]([CH3:8])([CH3:7])[CH3:6].[CH2:9]([CH:11]([CH2:15][CH2:16][CH2:17][CH3:18])[C:12]([OH:14])=[O:13])[CH3:10].OCC[N+](C)(C)C.C(OC(=O)CCCCC)C>>[CH3:18][CH2:17][CH2:16][CH2:15][CH:11]([C:12]([O-:14])=[O:13])[CH2:9][CH3:10].[CH3:6][N+:5]([CH2:4][CH2:3][OH:2])([CH3:8])[CH3:7]
Reactant: CCCCC(CC)C(=O)O
Agent: C[N+](C)(C)CCO
Agent: [OH-]
Solvent: CCCCCC(=O)OCC
Product: CCCCC(CC)C(=O)[O-]

Procedure:
272.13 g of a 40% solution of choline hydroxide and 145.73 g of 2-ethylhexanoic acid were stirred vigorously for 30 min at RT in a glass flask with reflux condenser, heatable oil bath, mechanical stirrer and internal thermometer. Water and methanol were distilled off in a rotary evaporator at 30-45° C. under a vacuum increased gradually to 20 mbar. The product was then taken up in n-hexane and re-evaporated in the rotary evaporator and dried at 0.1 mbar and 40° C. for 2 h, giving a slightly colored, viscous liquid whose 1H-NMR spectrum showed equi-molar ratios of choline and ethylhexanoate, but only a weak signal in the region of aliphatic carboxylic acids.
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.[C:31]1(=[O:36])[CH2:35][CH2:34][CH2:33][CH2:32]1.[Cl-].[NH4+]>O1CCCC1>[OH:36][C:31]1([C:2]2[C:12]3[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Reactant: O=C1CCCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2C2(O)CCCC2)C1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 14.9 %

Procedure:
To a solution of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.605 mmol) in tetrahydrofuran (4 ml) was added dropwise 1.6 M solution of n-butyllithium in hexane (0.396 ml, 0.634 mmol) at −78° C., and the mixture was stirred at −78° C. for 10 min. A solution of cyclopentanone (0.0696 ml, 0.787 mmol) in tetrahydrofuran (2 ml) was added dropwise, and the mixture was stirred at 78° C. for 2 hr. The reaction mixture was poured into saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product (30.0 mg, 14.9%) as an oil.