Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1.[N-:14]=[N+:15]=[N-:16].[Na+].O>CS(C)=O>[N:14]([CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1)=[N+:15]=[N-:16]
Reactant: [N-]=[N+]=[N-]
Reactant: O=Cc1ccc(OCCCBr)cc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=NCCCOc1ccc(C=O)cc1
Reaction time: 16 h
Yield: 92.4 %

Procedure:
A mixture of 4-(3-bromopropyloxy)benzaldehyde (3.5 g, 14.5 mmol) and sodium azide (29 mmol, 1.9 g) in DMSO (70 ml) was stirred for 16 h, poured into water (100 ml) and extracted twice with diethyl ether. The extracts were washed with water (50 ml) and saturated aqueous sodium chloride, dried over sodium sulphate and evaporated to give a colourless oil (2.75 g). M+ 205; 360 MHz 1H n.m.r (CDCl3) 7.84 (2H, d, J 11 Hz), 7.02 (2H, d, J 11 Hz), 4.14 (2H, t, J 5.9 Hz), 3.55 (2 H, t, J 6.5 Hz), 2.09 (2 H, app. pentet, J 6.2 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[OH:8].[C:13]1(C)[CH:18]=CC(S(O)(=O)=O)=C[CH:14]=1.CC(C)=O>C1C=CC=CC=1>[CH3:14][C:13]1([CH3:18])[O:8][C:7]2[CH:6]=[CH:5][C:4]([CH2:9][CH2:10][OH:12])=[CH:3][C:2]=2[O:1]1
Reactant: O=C(O)Cc1ccc(O)c(O)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CC(C)=O
Product: CC1(C)Oc2ccc(CCO)cc2O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.7 g of 3,4-dihydroxyphenylacetic acid, a catalytic amount of p-toluenesulfonic acid, 10 ml of acetone and 10 ml of benzene were heated under reflux for 18 h. The reflux solution was dehydrated with Molecular Sieve 4A. The reaction mixture was concentrated and the obtained dark brown oil was dissolved in 20 ml of tetrahydrofuran. The solution was added to a suspension of 0.8 g of lithium aluminum hydride in 30 ml of tetrahydrofuran under cooling with ice. The mixture was stirred at room temperature for 1 h and then cooled with ice/water. 0.8 ml of water, then 0.8 ml of a 15% aqueous sodium hydroxide solution and finally 2.4 ml of water were added thereto and an insoluble substance was filtered off. The filtrate was concentrated and treated according to silica gel column chromatography (ethyl acetate/n-hexane=1:1) to obtain 1.1 g of the intended compound in the form of a colorless oil.
Reaction SMILES: FC(F)(F)S(O[CH2:7][CH:8]1[CH2:12][C:11]2[CH:13]=[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:15]=[CH:16][C:10]=2[O:9]1)(=O)=O.Br[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:27]1([CH2:26][CH2:25][CH2:7][CH:8]2[CH2:12][C:11]3[CH:13]=[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:15]=[CH:16][C:10]=3[O:9]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCCc1ccccc1
Reactant: CCOC(=O)c1ccc2c(c1)CC(COS(=O)(=O)C(F)(F)F)O2
Product: CCOC(=O)c1ccc2c(c1)CC(CCCc1ccccc1)O2
Yield: 75 %

Procedure:
Following the process described in example 3 (point B), starting from ethyl 2-trifluoromethanesulfonyloxymethyl-2,3-dihydrobenzofuran-5-carboxylate and 2-bromoethylbenzene, the title compound was prepared, which was purified by chromatography through a silica gel column, eluting with n-hexane:ethyl acetate, 95:5 (75% yield).
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[CH:18]=[C:13]3[C:12]([C:25]3[CH:26]=[N:27][NH:28][CH:29]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.[OH-].[Na+].C(Cl)Cl>CCO>[N:19]1([C:17]2[CH:18]=[C:13]3[C:12]([C:25]4[CH:29]=[N:28][NH:27][CH:26]=4)=[CH:11][NH:10][C:14]3=[N:15][CH:16]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cn[nH]c2)c2cc(N3CCOCC3)cnc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: c1n[nH]cc1-c1c[nH]c2ncc(N3CCOCC3)cc12
Temperature: 90 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
A mixture of 57 (0.031 g, 0.076 mmol) and 10% aqueous NaOH solution (1 mL) in EtOH (2 mL) was stirred at 90° C. for 1 hour. The mixture was cooled and evaporated to afford a tan syrup. The syrup was dissolved with CH2Cl2 and the solution was washed with brine. The aqueous layer was extracted twice with CH2Cl2. The combined extracts were dried (MgSO4) and concentrated to afford a syrup, which was purified by means of preparative TLC with CH2Cl2:MeOH as eluent to afford 58 (0.016 g, 78%) as a pale brown solid. 1H NMR (400 MHz, CD3OD) δ 3.13-3.17 (m, 4H), 3.85-3.89 (m, 4H), 7.51 (s, 1H), 7.74 (d, J=0.26 Hz, 1H), 7.93 (bs, 2H), 8.06 (d, J=0.26 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=1.[NH:17]1[CH2:21][CH2:20][CH2:19][C:18]1=O.P(Cl)(Cl)(Cl)=O>ClCCCl>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([C:18]3[N:17]([C:18]4[CH2:19][CH2:20][CH2:21][N:17]=4)[CH2:21][CH2:20][CH:19]=3)[C:5]=2[CH:4]=1
Reactant: O=C1CCCN1
Reactant: COc1ccc2c(c1)Nc1ccccc1S2
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(c1)N(C1=CCCN1C1=NCCC1)c1ccccc1S2

Procedure:
Reaction of 2-methoxyphenothiazine, 2-pyrrolidinone and phosphorus oxychloride in 1,2-dichloroethane according to the procedure of Example 1 affords 2-METHOXY-10-[1-(1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]PHENOTHIAZINE free base, m.p. 151°-153° C. (corr.), from isopropyl alcohol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[Br:11]Br.O>C(O)(=O)C>[Br:11][C:8]1[N:6]2[N:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: Fc1ccc2nccn2n1
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: Fc1ccc2ncc(Br)n2n1
Yield: 27.2 %

Procedure:
To an ambient temperature, stirred solution of 6-fluoro-imidazo[1,2-b]pyridazine (2.1 g, 15.3 mmol) in glacial acetic acid (20 mL) was slowly added bromine (2.5 g, 15.3 mmol). Upon completion of this addition the reaction solution was poured into water and extracted with ethyl acetate. The extract was dried (MgSO4) and flash chromatographed (silica gel, eluted with 30% (v/v) ethyl acetate/hexanes) to provide 0.9 g of 3-bromo-6-fluoro-imidazo[1,2-b]pyridazine. LRMS (ESI) m/z 215.9/217.9 [(M+H)]+, calc'd for C6H3BrFN3: 216.01.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:18]([CH2:19][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])=[N:17][C:9]2[C@H:10]3[N:14]([C:15](=[O:16])[C:8]=2[C:7]=1[C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1)[CH2:13][CH2:12][CH2:11]3)=[O:5])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:55][C@H:56]1[C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH2:58][CH2:57]1>ClCCl>[C@H:56]1([NH:55][C:29]([C:28]2[CH:27]=[CH:26][C:25]([C:7]3[C:8]4[C:15](=[O:16])[N:14]5[C@H:10]([C:9]=4[N:17]=[C:18]([CH2:19][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[C:6]=3[C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:12][CH2:13]5)=[CH:33][CH:32]=2)=[O:30])[C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH2:58][CH2:57]1
Reactant: CCOC(=O)c1c(CCCC(C)C)nc2c(c1-c1ccc(C(=O)O)cc1)C(=O)N1CCC[C@@H]21
Reactant: N[C@@H]1CCc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCOC(=O)c1c(CCCC(C)C)nc2c(c1-c1ccc(C(=O)N[C@@H]3CCc4ccccc43)cc1)C(=O)N1CCC[C@@H]21
Reaction time: 3 h
Yield: 10.4 %

Procedure:
To a stirred solution of 4-[(9aS)-3-(ethoxycarbonyl)-2-(4-methylpentyl)-5-oxo-7,8,9,9a-tetrahydro-5H-pyrido[2,3-α]pyrrolizin-4-yl]benzoic acid (0.100 g, 0.222 mmol) in 1 mL of dichloromethane, EDCI (0.051 g, 0.266 mmol), HOBT (0.036 g, 0.266 mmol) and (R)-(−)-1-aminoindane (0.065 g, 0.444 mmol) were added. The reaction mixture was allowed to stir for ˜3 h. The reaction mixture was concentrated and redissolved in 1 mL of ethyl acetate. The organics were then washed with saturated aqueous NaHCO3 and brine. Filtration and concentration provided a brown oil which was purified by radial chromatography chromatography (ethyl acetate/hexanes (4:1)) to yield 0.013 g (20%) of the desired product as a tan solid: 1H NMR (CDCl3, 400 MHz) δ 7.83–7.76 (d, 2H, J=7.9), 7.44–7.38 (d, 2H, J=7.93), 7.35–7.29 (d, 1H, J=7.76), 7.27–7.17 (m, 3H), 6.52–6.44 (m, 1H), 5.71–5.63 (q, 1H, J=7.41), 4.70–4.63 (dd, 1H, J=10.3, J=6.38), 4.09–3.94 (m, 2H), 3.68–3.56 (m, 1H), 3.35–3.24 (m, 1H), 3.07–2.95 (m, 1H), 2.95–2.76 (m, 3H), 2.74–2.58 (m, 1H), 2.51–2.40 (m, 1H), 2.35–2.19(m, 2H), 1.97–1.84 (m, 1H), 1.83–1.64 (m, 2H), 1.61–1.48 (m, 1H), 1.43–1.31 (m, 1H), 1.30–1.20 (m, 2H), 1.01–0.93 (t, 3H, J=7.09), 0.89–0.81 (d, 6H, J=6.55); low resolution MS (ES+) m/e 566 (MH); RP-HPLC (BDS Hypersil C-18 25 cm×4.6 mm; 10–100% CH3CN in H2O with 0.1% TFA buffer; 30 minutes; 1 mL/min) tr=23.8 min, 99.9% purity.
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[C:9]2[C:10]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:15][CH:14]=3)=[CH:11][S:12][C:8]=2[CH:7]=[CH:6][N:5]=1>ClCCl>[NH2:3][C:4]1[C:9]2[C:10]([C:13]3[CH:14]=[CH:15][C:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[CH:17][CH:18]=3)=[CH:11][S:12][C:8]=2[C:7]([Br:1])=[CH:6][N:5]=1
Reactant: BrBr
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2csc3ccnc(N)c23)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccc(-c2csc3c(Br)cnc(N)c23)cc1
Reaction time: 0.25 h
Yield: 95.7 %

Procedure:
A solution of bromine (0.4 mL, 4.6 mmol) in dichloromethane (5 mL) was added dropwise to a −5° C. solution of Example 76A (1.57 g, 4.6 mmol) in dichloromethane (30 mL). The mixture was stirred at −5° C. to 0° C. for 15 minutes and quenched with 1:1 saturated NaHCO3 and saturated NaHSO3 (10 mL). The organic phase was separated, washed with water and brine, dried (NaSO4), filtered, and concentrated to provide 1.85 g of the desired product. MS (ESI(+)) m/e 421 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH2:12][CH3:13])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[O:16][CH3:17].Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N:32]2[CH:36]=[CH:35][CH:34]=[N:33]2)[C:22]([Cl:37])=[CH:21][N:20]=1>>[Cl:37][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N:32]2[CH:36]=[CH:35][CH:34]=[N:33]2)=[N:24][C:19]([NH:1][C:2]2[CH:15]=[CH:14][C:5]3[N:6]([CH2:12][CH3:13])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=3[C:3]=2[O:16][CH3:17])=[N:20][CH:21]=1
Reactant: Clc1ncc(Cl)c(Nc2ccccc2-n2cccn2)n1
Reactant: CCN1C(=O)CCCc2c1ccc(N)c2OC
Product: CCN1C(=O)CCCc2c1ccc(Nc1ncc(Cl)c(Nc3ccccc3-n3cccn3)n1)c2OC
Yield: 45 %

Procedure:
Following a procedure analogous to Example 113, 7-Amino-1-ethyl-6-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (75 mgs) and (2,5-Dichloro-pyrimidin-4-yl)-(2-pyrazol-1-yl-phenyl)-amine (89 mgs) were converted to the title compound as an off-white solid (66 mgs). 1H-NMR (CDCl3): δ 10.30 (s, 1H), 8.52 (d, J=8.6 Hz, 1H), 8.26 (d, J=8.8 Hz, 1H), 8.10 (s, 1H), 7.86 (d, J=15.7 Hz, 2H), 7.44-7.41 (m, 2H), 7.28-7.25 (m, 1H), 6.94 (d, J=9.1 Hz, 1H), 6.54 (s, 1H), 3.80 (s, 3H), 2.32 (broad S, 2H), 3.15-1.5 broad absorptions, 6H), 1.15 (t, J=7.3 Hz, 3H). LC/MS, found 504.17 (M+H)+; MP: 183-185° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([CH2:14]O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.CS([Cl:29])(=O)=O>C(Cl)Cl>[Cl:29][CH2:14][C:12]1[S:13][C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:17])([F:16])[F:1])=[CH:4][CH:5]=2)=[CH:10][CH:11]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccc(-c2ccc(C(F)(F)F)cc2)s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: FC(F)(F)c1ccc(-c2ccc(CCl)s2)cc1
Temperature: 25 °C

Procedure:
To a mixture of [5-(4-Trifluoromethyl-phenyl)-thiophen-2-yl]-methanol (1.52 g, 5.89 mmole) and triethyl amine (1.64 mL, 11.78 mmole) in DCM (100 mL) at 0° C., is injected methanesulfonyl chloride (0.91 mL, 11.78 mmole) dropwise. The reaction is kept at 0° C. for an hour and warmed up to room temperature for an hour. The reaction mixture is concentrated on rota vapor, and the resulting residue is purified on a silica gel column, eluting with 0-15% ethyl acetate in hexane and concentrated to provide the titled compound as off-white solid.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=4)[N:21]=3)[CH:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:29][C:26]([F:27])([F:28])[C:24]1[CH:23]=[C:22]([C:30]2[CH:31]=[CH:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=2)[N:21]=[C:20]([C:16]2[CH:15]=[C:14]([C:11]3[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=3)[CH:19]=[CH:18][CH:17]=2)[N:25]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 50.3 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-5-{3-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide (0.44 g) in dichloromethane (7 mL) was added TFA (7 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and purified by flash chromatography (heptane/ethyl acetate) and crystallization (dichloromethane/MeOH/hexane) to yield the title compound as an off-white solid (0.2 g, 38%). MS (ISN) 528.0 [(M−H)−]; mp 204° C.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:16]([N:18]1[CH2:28][CH2:27][CH2:26][C@H:19]1[C:20]([NH:22][CH2:23][CH2:24][OH:25])=[O:21])=[O:17])[CH2:10][C:11]1[N:15]=[CH:14][NH:13][CH:12]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][C@H:9]([C:16]([N:18]1[CH2:28][CH2:27][CH2:26][C@H:19]1[C:20]([NH:22][CH2:23][CH2:24][OH:25])=[O:21])=[O:17])[CH2:10][C:11]1[N:15]=[CH:14][NH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(=O)NCCO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(=O)NCCO
Reaction time: 2.5 h

Procedure:
In 25 ml of methylene chloride was dissolved 790 mg of compound (51) and then 20 ml of trifluoroacetic acid was added dropwise to the solution at 0° C. to 5° C. After stirring the mixture for 2.5 hours in an ice-bath, the reaction mixture was concentrated to dryness under reduced pressure. Furthermore, the product was azeotropically dried several times using toluene and the residue was triturated with dry ether to provide powder of L-histidyl-N-(2-hydroxyethyl)-L-prolinamide.2-trifluoroacetate with a quantitative yield.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:14]#[N:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=1.[CH2:16]([S:24](Cl)(=[O:26])=[O:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(N(CC)CC)C>C(#N)C>[CH2:16]([S:24]([O:1][N:2]=[C:3]([C:14]#[N:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=1)(=[O:26])=[O:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: COc1ccc(C(C#N)=NO)cc1OC
Reactant: CCCCCCCCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCCCCCS(=O)(=O)ON=C(C#N)c1ccc(OC)c(OC)c1

Procedure:
As described under 1.2, 10.3 g (0.05 mol) of α-hydroxyimino-3,4-dimethoxybenzyl cyanide are reacted with 11.7 g (0.055 mol) of 1-octanesulfonyl chloride in the presence of triethylamine. After recrystallisation of the crude product from ethyl acetate/hexane, 19.1 g (87%) of α-(n-octylsulfonyloxyimino)-3,4-dimethoxybenzyl cyanide are obtained in the form of beige crystals having a melting point of 72-75° C. The 1H-NMR spectrum of the compound shows that it is a pure stereoisomer. The UV spectrum (acetonitrile) of the substance shows a broad absorption band with a maximum at 349 nm (ε=11330) that extends to 435 nm. Elemental analysis: C18H26N2O5S (382.48)
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:35])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18]([N:22]4[CH2:27][CH2:26][NH:25][CH:24]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH2:23]4)=[C:17]([F:34])[C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])C.[OH-].[K+].C(O)(=O)C>C(O)C>[F:21][C:19]1[C:18]([N:22]2[CH2:27][CH2:26][NH:25][CH:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:23]2)=[C:17]([F:34])[C:11]2=[N:12][C:13]3[N:14]([CH3:16])[CH:15]=[C:6]([C:4]([OH:5])=[O:3])[C:7](=[O:35])[C:8]=3[CH:9]=[C:10]2[CH:20]=1
Reactant: CCOC(=O)c1cn(C)c2nc3c(F)c(N4CCNC(c5ccccc5)C4)c(F)cc3cc2c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCNC(c5ccccc5)C4)c(F)c3nc21
Temperature: 75 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
A suspension of (RS)-3-ethoxycarbonyl-7,9-difluoro-1-methyl-4-oxo-8-(3-phenyl-1-piperazinyl)-1,4-dihydrobenzo[b][1,8]naphthyridine (2 g) in ethanol (25 cc) and N aqueous potassium hydroxide (15 cc) is heated with stirring to a temperature in the region of 75° C. for 2 hours. The solution obtained, at approximately 75° C., is treated with 10% strength aqueous acetic acid solution (9 g). The insoluble matter obtained is drained at a temperature in the region of 75° C. and washed with water (3×30 cc) at approximately 20° C. After 1 recrystallization in dimethylformamide (40 cc), (RS)-7,9-difluoro-1-methyl-4-oxo-8-(3-phenyl-1-piperazinyl)-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (1.5 g) is obtained in the form of an orange-colored solid, m.p. 298° C.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([CH2:13][CH3:14])=[CH:7][CH:8]=2)[N:3]=1.Cl.[NH:16]1[CH:20]=[N:19][CH:18]=[N:17]1.N1C=NC=N1.CN(C)C=O>O>[N:16]1([C:2]2[C:11]([CH3:12])=[CH:10][C:9]3[C:4](=[CH:5][C:6]([CH2:13][CH3:14])=[CH:7][CH:8]=3)[N:3]=2)[CH:20]=[N:19][CH:18]=[N:17]1
Reactant: CCc1ccc2cc(C)c(Cl)nc2c1
Reactant: c1nc[nH]n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCc1ccc2cc(C)c(-n3cncn3)nc2c1
Temperature: 100 °C
Reaction time: 6 h
Yield: 64.1 %

Procedure:
A mixture of 2.05 g of 2-chloro-3-methyl-7-ethyl-quinoline, 1.05 g of 1,2,4-triazole-hydrochloride, 0.69 g of 1,2,4-triazole and 10 ml of dimethyl formamide is stirred at 100° C. for 6 hours. The reaction mixture is poured into 100 ml of water, neutralized and the crude product is recrystallized from a mixture of ethanol and hexane. Thus 1.52 g of the desired compound are obtained, yield 64%. Mp.: 72°-73° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[CH:17]([CH3:35])[C:18]([C:24]1[CH:25]=[CH:26][C:27]2[O:31][C:30](=[O:32])[N:29]([CH3:33])[C:28]=2[CH:34]=1)([OH:23])[C:19]([F:22])([F:21])[F:20].[CH3:36][O:37][C:38]([C:40]1[CH:45]=[CH:44][C:43](Br)=[CH:42][N:41]=1)=[O:39]>>[CH3:36][O:37][C:38]([C:40]1[CH:45]=[CH:44][C:43]([C:6]2[CH:5]=[CH:4][C:3]([CH:17]([CH3:35])[C:18]([OH:23])([C:24]3[CH:25]=[CH:26][C:27]4[O:31][C:30](=[O:32])[N:29]([CH3:33])[C:28]=4[CH:34]=3)[C:19]([F:22])([F:20])[F:21])=[C:2]([Cl:1])[CH:7]=2)=[CH:42][N:41]=1)=[O:39]
Reactant: COC(=O)c1ccc(Br)cn1
Reactant: CC(c1ccc(B2OC(C)(C)C(C)(C)O2)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Product: COC(=O)c1ccc(-c2ccc(C(C)C(O)(c3ccc4oc(=O)n(C)c4c3)C(F)(F)F)c(Cl)c2)cn1

Procedure:
The title compound was prepared in analogy to Example 186, step 2 from 5-{2-[2-chloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1-hydroxy-1-trifluoromethyl-propyl}-3-methyl-3H-benzooxazol-2-one (obtained in Example 186, step 1) with methyl-5-bromopyridine-2-carboxylate [CAS Reg. No. 29682-15-3]. MS (m/e)=521.2 [M+H+].
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][N:11]2[N:10]=[C:9]1[CH:18]([NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CCN(CC)CC>C(Cl)(Cl)Cl>[CH2:22]([N:21]([CH:18]([C:9]1[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][N:11]2[N:10]=1)[CH2:19][CH3:20])[C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCC(NCc1ccccc1)c1nn2cccc2c(=O)n1Cc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCC(c1nn2cccc2c(=O)n1Cc1ccccc1)N(Cc1ccccc1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.5 %

Procedure:
3-Benzyl-2-(1-benzylamino-propyl)-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (Example 42, 23.1 mg, 0.062 mmol) in CHCl3 (5 mL) was treated with benzoylchloride (28.8 μL, 0.248 mmol) and Et3N (23.0 μL, 0.166 mmol), then stirred for 18 h at 25° C. The mixture was concentrated under vacuum and purified by preparative HPLC using a YMC S10 ODS 20×100 mm column affording the desired compound (22 mg, 83%) as a colorless film: LC/MS 87% at 3.72 min (ESI+) 477 (M++H).
Reaction SMILES: [N:1]1([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[NH:17][C:18]([N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1>P(Cl)(Cl)(Cl)=O>[F:16][C:13]1[CH:14]=[CH:15][C:10]2[N:1]3[CH2:2][CH2:3][C:4]4[C:9]3=[C:8]([CH:7]=[CH:6][CH:5]=4)[C:18]([N:20]3[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]3)=[N:17][C:11]=2[CH:12]=1
Reactant: CN1CCN(C(=O)Nc2cc(F)ccc2N2CCc3ccccc32)CC1
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCN(C2=Nc3cc(F)ccc3N3CCc4cccc2c43)CC1
Temperature: 25 °C
Yield: 20.8 %

Procedure:
A stirred mixture of 10.6 g (0.030 mole) of N-[2-(2,3-dihydro-1H-indol-1-yl)-5-fluorophenyl]-4-methyl-1-piperazine carboxamide of Example 2c in 250 ml of phosphorus oxychloride was refluxed for 6 hours under nitrogen, then cooled to room temperature. The excess phosphorus oxychloride was removed at aspirator pressure with gentle warming. The residue was chilled in an ice-bath (with exclusion of moisture) and then treated first with 250 ml of ice-cold 2N-NaOH, then with 500 ml of dichloromethane. The mixture was stirred vigorously until all the material passed into solution. The organic phase was separated, washed thrice with water, dried over Na2SO4 and concentrated in vacuo to 9.1 g of an oil. This material was adsorbed on a tall chromatography column containing 400 g of alumina made up in CH2Cl2. Elution with CH2Cl2 brought forth fractions of pure tetracycle which were combined and concentrated to afford 3.5 g (35% overall yield) of product which crystallized. This was recrystallized from a small volume of acetone to furnish 2.1 g of 9-fluoro-6-(4-methyl-1-piperazinyl)-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepine, m.p. 151°-153° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:30](=[O:31])[N:29]([CH3:32])[C:12]2[N:13]([CH3:28])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:24]=[C:23]([CH2:25][OH:26])[N:22]([CH3:27])[N:21]=1)=[CH:16][CH:15]=3.I[CH2:34][CH3:35]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:30](=[O:31])[N:29]([CH3:32])[C:12]2[N:13]([CH3:28])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:24]=[C:23]([CH2:25][O:26][CH2:34][CH3:35])[N:22]([CH3:27])[N:21]=1)=[CH:16][CH:15]=3
Reactant: Cn1nc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)cc1CO
Reactant: CCI
Product: CCOCc1cc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)nn1C

Procedure:
The process is carried out as in Example 101 above, with the compound from Example 82, 3-(2,4-dichlorophenyl)-6-(5-hydroxymethyl-1-methyl-1H-pyrazol-3-yl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and iodoethane.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2([CH2:16][OH:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[C:20](B(O)O)=[CH:21][C:22]([F:25])=[N:23][CH:24]=1>>[Cl:18][C:19]1[C:20]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([NH:8][CH2:9][C:10]3([CH2:16][OH:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[N:7]=2)=[CH:21][C:22]([F:25])=[N:23][CH:24]=1
Reactant: OB(O)c1cc(F)ncc1Cl
Reactant: OCC1(CNc2cccc(Br)n2)CCOCC1
Product: OCC1(CNc2cccc(-c3cc(F)ncc3Cl)n2)CCOCC1

Procedure:
Following the same procedure as in Example 1b using (4-((6-bromopyridin-2-ylamino)methyl)tetrahydro-2H-pyran-4-yl)methanol (from step 3) and 5-chloro-2-fluoropyridin-4-ylboronic acid, the desired product was obtained. LCMS (m/z): 352 (MH+), retention time=0.54 min.