Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH2:10][CH:11]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=1[CH3:32])[C:12]1[C:20]2[C:15](=[C:16]([CH2:21][S:22][CH2:23][CH3:24])[CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)(=O)=O.O.C(OCC)(=O)C>CN(C=O)C>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH:11]([C:12]2[C:20]3[C:15](=[C:16]([CH2:21][S:22][CH2:23][CH3:24])[CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:9][C:1]#[N:2])=[C:26]([CH3:32])[CH:27]=1
Reactant: CCSCc1cccc2c(C(CCOS(C)(=O)=O)c3ccc(Cl)cc3C)c[nH]c12
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCSCc1cccc2c(C(CCC#N)c3ccc(Cl)cc3C)c[nH]c12
Temperature: 80 °C
Reaction time: 2 h

Procedure:
86.4 mg (1.33 mmol) of potassium cyanide were added to 300 mg (0.66 mmol) of the compound from Example 60A in 4 ml of DMF. Stirring at 80° C. for 2 h was followed by addition of water, extraction with ethyl acetate, washing of the combined organic phases with saturated aqueous sodium bicarbonate solution, drying over magnesium sulfate, filtration and concentration. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 207 mg (81% of theory) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[N:16]=[C:15]([C:25](O)=[O:26])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.ClC1C=C(C2N(C3C=NC=CC=3)N=C(C(N3CCNC(=O)C3)=O)C=2)C=C(F)C=1.[S:56]1[CH2:60][CH2:59][NH:58][CH2:57]1>>[Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[N:16]=[C:15]([C:25]([N:58]3[CH2:59][CH2:60][S:56][CH2:57]3)=[O:26])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:10])([F:12])[F:11])[CH:7]=1
Reactant: C1CSCN1
Reactant: O=C(O)c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2ccc(Cl)nc2)n1
Agent: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3cccnc3)n2)CCN1
Product: O=C(c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2ccc(Cl)nc2)n1)N1CCSC1

Procedure:
170 mg (0.28 mmol, 76% purity) of the compound of Example 40A is reacted analogously to the synthesis of the compound of Example 4 with 27 mg (0.30 mmol) of thiazolidine. 96 mg (62% of theory) of the title compound is obtained.
Reaction SMILES: Cl[C:2]1[C:7]([S:8]([N:11]2[CH2:32][CH2:31][C:14]3([C:18](=[O:19])[N:17]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=4)[CH2:16][CH2:15]3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:33][NH:34][CH3:35]>>[CH3:33][N:34]([CH3:35])[C:2]1[C:7]([S:8]([N:11]2[CH2:12][CH2:13][C:14]3([C:18](=[O:19])[N:17]([C:20]4[CH:21]=[CH:22][C:23]([O:26][C:27]([F:30])([F:28])[F:29])=[CH:24][CH:25]=4)[CH2:16][CH2:15]3)[CH2:31][CH2:32]2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1cccnc1Cl)CC2
Reactant: CNC
Product: CN(C)c1ncccc1S(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1

Procedure:
The title compound was prepared in analogy to example 189 from 8-(2-chloro-pyridine-3-sulfonyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 188) and dimethyl amine (7.9M in H2O). Off-white solid. MS (ESI): 499.3 (MH+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]3[CH:14]=[N:13][NH:12][C:10]3=2)[N:5]=[C:4]([CH3:15])[CH:3]=1.[CH:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH:16]1([NH:22][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]4[CH:14]=[N:13][NH:12][C:10]4=3)[N:5]=[C:4]([CH3:15])[CH:3]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Cc1cc(Cl)c2c(ccc3cn[nH]c32)n1
Reactant: NC1CCCCC1
Product: Cc1cc(NC2CCCCC2)c2c(ccc3cn[nH]c32)n1
Yield: 67.8 %

Procedure:
9-Chloro-7-methyl-1H-pyrazolo[3,4-f]quinoline (0.44 g, 2.0 mmol) and cyclohexylamine (0.79 g, 8.0 mmol) were placed in a sealable reaction vessel which was flushed with nitrogen and then sealed. The reaction was placed in a ° C. bath and heated overnight. The excess cyclohexylamine was removed by rotary evaporation and the residue dissolved in methanol and treated with decolorizing carbon. After filtration through diatomaceous earth (Celite™), the methanol was removed by rotary evaporation and the residue partitioned between ethyl acetate and aqueous potassium hydroxide (KOH). The organic layer was washed with water and dried over sodium sulfate (Na2SO4), and the solvent was removed by rotary evaporation to give a white solid. The solid was washed with ether giving 9-(cyclohexylamino)-7-methyl-1H-pyrazolo[3,4-f]quinoline as white needles (0.38 g, 68%). The free base was converted to the corresponding hydrochloride salt by treatment with anhydrous hydrogen chloride (HCl)/ether.
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3SC=C[N:18]=3)[S:13][C:6]=12.ClC1C=CN=C2C=C(C#N)SC=12>>[F:1][C:2]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]#[N:18])[S:13][C:6]=12
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4nccs4)sc23)c(F)c1
Agent: N#Cc1cc2nccc(Cl)c2s1
Product: N#Cc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1

Procedure:
Following the procedure described above for the synthesis of compound 11 (example 12, step 3, scheme 2) but substituting compound 10 for compound 126, title compound 127 was obtained as a yellow solid (114 mg, 60% yield). MS (m/z) 316.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9](I)=[CH:8][C:6]=2[N:7]=1.[CH2:18]([O:20][C:21]([C:23]1[CH:24]=[N:25][CH:26]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:28]=1)=[O:22])[CH3:19]>C([O-])([O-])=O.[Na+].[Na+].C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([C:27]3[CH:28]=[C:23]([C:21]([O:20][CH2:18][CH3:19])=[O:22])[CH:24]=[N:25][CH:26]=3)=[CH:8][C:6]=2[N:7]=1
Reactant: CCOC(=O)c1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Clc1nc(N2CCOCC2)c2sc(I)cc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1cncc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Yield: 75 %

Procedure:
2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19, 200 mg of 3-ethoxycarbonylpyridine-5-boronic acid pinacol ester (250 mg) and 23 mg of bis(triphenylphosphine)palladium(II) dichloride in 1.5 mL of 1M Na2CO3 aqueous solution and 1.5 mL of acetonitrile was heated to 100° C. in a sealed microwave reactor for 10 min. The reaction mixture was evaporated. The crude product was purified by flash chromatography eluting with 10˜100% EtOAc/hexane to yield ethyl 5-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)pyridine-3-carboxylate (240 mg, 75%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:5]=[N:4][C:3]=1[C:23]#[N:24].[NH2:25][C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:23]([C:3]1[N:4]=[CH:5][C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[N:7][C:2]=1[NH:25][C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=1)#[N:24]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cnc(C#N)c(Cl)n1
Reactant: N#Cc1ccc(N)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cnc(C#N)c(Nc2ccc(C#N)cc2)n1
Reaction time: 20 h
Yield: 149.6 %

Procedure:
A mixture of tert-butyl (1S,2R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)cyclohexylcarbamate (90 mg, 0.256 mmol), 4-aminobenzonitrile (42 mg, 0.355 mmol), K2CO3 (100 mg, 0.724 mmol), BINAP (30 mg, 0.048 mmol) and Pd(OAc)2 (15 mg, 0.066 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 110 C for 20 h. Water and EtOAc were added. Organic phase was separated, dried over Na2SO4, concentrated in vacuo to give a crude tert-butyl (1S,2R)-2-(5-cyano-6-(4-cyanophenylamino)pyrazin-2-ylamino)cyclohexylcarbamate (166 mg).
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][NH2:24])=[CH:19][CH:18]=1.C(N(CC)CC)C>ClCCl>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][NH:24][S:2]([C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=2)(=[O:4])=[O:3])=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(CN)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(S(=O)(=O)NCc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a solution of methyl 4-(chlorosulfonyl)benzoate (Example 5-10c) (4 g, 17.09 mmol) in dichloromethane (40 mL) at 0° C. in an ice bath, was added (4-methoxyphenyl)methanamine (2.56 mL, 19.65 mmol) and triethylamine (2.38 mL, 17.1 mmol). The ice bath was then removed and the mixture was allowed to warm to ambient temperature with stirring for an additional 2 hours. Upon completion (monitored by TLC 40% ethyl acetate/hexanes), the solvent was removed in vacuo. The residue was re-dissolved in ethyl acetate (200 mL), washed with 1N HCl (aq, 20 mL), water (20 mL) and brine (20 mL) then dried over magnesium sulfate. The solution was concentrated and the product purified by re-crystallization with hot ethyl acetate/hexanes to afford pure methyl 4-(N-(4-methoxybenzyl)sulfamoyl)benzoate (4.3 g, 74.8%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ, ppm: 3.67 (s, 3H), 3.78 (s, 3H), 3.93 (s, 2H), 6.78 (m, 2H), 7.09 (m, 2H), 7.87 (m, 2H), 8.08 (m, 2H), 8.25 (br, s, 1H).
Reaction SMILES: [C:1]([C:3]1([C:16]2[CH:20]=[C:19]([CH3:21])[O:18][N:17]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2]>ClCCl>[NH2:2][CH2:1][C:3]1([C:16]2[CH:20]=[C:19]([CH3:21])[O:18][N:17]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: Cc1cc(C2(C#N)CCN(C(=O)OC(C)(C)C)CC2)no1
Solvent: ClCCl
Product: Cc1cc(C2(CN)CCN(C(=O)OC(C)(C)C)CC2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 107 %

Procedure:
470 mg tert-butyl 4-cyano-4-(5-methylisoxazol-3-yl)piperidine-1-carboxylate and 1.24 g Bu4NBH4 were dissolved in 10 ml dichloromethane in a sealed tube and heated in a microwave reactor to 80 C for 1 hour. The reaction mixture was cooled to room temperature, the vial opened and the excess borohydride was quenched by slow addition of 5 ml MeOH. After stirring for 1 hour the vial was re-sealed and heated to 100 C. for 20 minutes (to hydrolyse the boron complex of the product). The reaction mixture was poured into sat. aq. NaHCO3 solution and extracted with dichloromethane. The organic layer was washed with brine, dryed over MgSO4, filtered and concentrated. The crude title amine (0.51 g, quant. yield) was used “as is”.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH2:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:45][C:46]1[CH:51]=[CH:50][C:49]([C:52]2[O:53][C:54]3[CH:64]=[CH:63][C:62]([C:65]4[CH:66]=[C:67]([CH:71]=[CH:72][CH:73]=4)[C:68](O)=[O:69])=[CH:61][C:55]=3[C:56]=2[C:57](=[O:60])[NH:58][CH3:59])=[CH:48][CH:47]=1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:11][C:68]([C:67]2[CH:66]=[C:65]([C:62]3[CH:63]=[CH:64][C:54]4[O:53][C:52]([C:49]5[CH:50]=[CH:51][C:46]([F:45])=[CH:47][CH:48]=5)=[C:56]([C:57]([NH:58][CH3:59])=[O:60])[C:55]=4[CH:61]=3)[CH:73]=[CH:72][CH:71]=2)=[O:69])([CH3:9])[CH3:10])=[CH:6][CH:7]=1
Reactant: CC(C)(N)c1ccc(Cl)cc1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)O)c3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)NC(C)(C)c4ccc(Cl)cc4)c3)cc12
Reaction time: 1 h
Yield: 57.4 %

Procedure:
2-(4-chlorophenyl)propan-2-amine (21 mg, 0.123 mmol) was added to a stirring solution of HATU (59 mg, 0.154 mmol), DIEA (54 μL, 0.308 mmol), and 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid (40 mg, 0.103 mmol) in DMF (1 mL) at rt. It was allowed to stir for 1 hour. The mixture was diluted with EtOAc and washed with sat NaHCO3, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated and was purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (32 mg, 57%). 1H NMR (500 MHz, DMSO-d6) d ppm 8.64 (1 H, s), 8.47-8.55 (1 H, m), 8.14 (1 H, s), 7.99-8.04 (2 H, m), 7.92 (1 H, s), 7.74-7.89 (4 H, m), 7.57 (1 H, t, J=7.78 Hz), 7.37-7.45 (4 H, m), 7.34 (2 H, d, J=8.85 Hz), 2.87 (3 H, d, J=4.58 Hz), 1.69 (6 H, s). LC-MS retention time: 1.95 min; m/z (MH+): 541. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10 u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 mm, Rt=15.18 min, purity=99%; Column: Waters Xbridge Phenyl column 4 6×150 mm, 3.5 mm, Rt=13.66 min, purity=99%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([CH:12]([F:14])[F:13])=[CH:10][C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)=[N:8][C:7]=12)#[CH:2].[CH3:25][N:26]([CH3:39])[CH2:27][CH2:28][NH:29][S:30]([C:33]1[S:34][C:35](Br)=[CH:36][CH:37]=1)(=[O:32])=[O:31]>>[CH3:25][N:26]([CH3:39])[CH2:27][CH2:28][NH:29][S:30]([C:33]1[S:34][C:35]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([CH:12]([F:14])[F:13])=[CH:10][C:9]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=4)=[N:8][C:7]=23)=[CH:36][CH:37]=1)(=[O:32])=[O:31]
Reactant: CN(C)CCNS(=O)(=O)c1ccc(Br)s1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Product: CN(C)CCNS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)F)cc(-c4cccc(C(F)(F)F)c4)nc23)s1

Procedure:
The title compound was prepared from 3-ethynyl-7-difluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.15) (169 mg, 0.5 mmol) and 5-bromo-thiophene-2-sulfonic acid (2-dimethylamino-ethyl)-amide (example B.49) (157 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (180 mg, 63%). MS (ISN) 568.2 [(M−H)−]; mp 170° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])(=O)=O.[CH2:21]([NH2:23])[CH3:22]>C1COCC1>[CH2:21]([NH:23][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:12])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:22]
Reactant: CS(=O)(=O)OCCCCNC(=O)OCc1ccccc1
Reactant: CCN
Solvent: C1CCOC1
Product: CCNCCCCNC(=O)OCc1ccccc1

Procedure:
Following the general procedure of Example 4, Step 2, and making non-critical variations but using 4-(benzyloxycarbonylamino)butyl methanesulfonate and ethyl amine in THF, the compound of Step 1 was obtained.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:8](OC)=[O:9])[C:6]=1[NH2:7].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[NH2:7][C:6]1[C:5]([CH2:8][OH:9])=[CH:4][S:3][C:2]=1[CH3:1]
Reactant: COC(=O)c1csc(C)c1N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: Cc1scc(CO)c1N

Procedure:
m.p. 70°-71° C. by the reduction of methyl 2-methyl-3-aminothiophene-4-carboxylate with lithium aluminum hydride in diethyl ether.
Reaction SMILES: [CH:1]1([N:4]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:23][CH2:24][C:25](OC)=[O:26])[CH:16]=[C:17]3[C:22]=2[N:21]=[CH:20][CH:19]=[CH:18]3)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH2:3][CH2:2]1.[BH4-].[Li+]>C1COCC1.CCOCC>[CH:1]1([N:4]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:23][CH2:24][CH2:25][OH:26])[CH:16]=[C:17]3[C:22]=2[N:21]=[CH:20][CH:19]=[CH:18]3)[C:5](=[O:6])[O:7][C:8]([CH3:10])([CH3:11])[CH3:9])[CH2:2][CH2:3]1
Reactant: COC(=O)CCc1cc(CN(C(=O)OC(C)(C)C)C2CC2)c2ncccc2c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N(Cc1cc(CCCO)cc2cccnc12)C1CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of methyl 3-{8-[(cyclopropyl{[(1,1-dimethylethyl)oxy]carbonyl}amino)methyl]-6-quinolinyl}propanoate (1 eq.) from the previous step in THF (0.08 M) was added lithium borohydride (5 eq.). The resulting mixture was stirred at RT for 14 h before it was diluted with ether and quenched with 1 N aq. NaOH. The aqueous layer was separated and back-extracted with ether. The combined organic extracts were washed further with water and brine, dried over Na2SO4, and filtered. Concentration of the filtrate in vacuo afforded the crude title compound as a colorless oil.
Reaction SMILES: Br[CH:2]1[CH2:15][CH2:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=[CH:5][C:4]=2[C:3]1=O.Cl.[NH:18]1[CH:22]=[C:21]([CH2:23][C:24]([NH2:26])=[S:25])[N:20]=[CH:19]1>>[NH:18]1[CH:22]=[C:21]([CH2:23][C:24]2[S:25][C:2]3[CH2:15][CH2:14][C:13]4[C:12]5[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=5[CH:6]=[CH:5][C:4]=4[C:3]=3[N:26]=2)[N:20]=[CH:19]1
Reactant: NC(=S)Cc1c[nH]cn1
Reactant: O=C1c2ccc3ccccc3c2CCC1Br
Agent: Cl
Product: c1ccc2c3c(ccc2c1)-c1nc(Cc2c[nH]cn2)sc1CC3

Procedure:
Starting compounds: 2-bromo-1,2,3,4-tetrahydrophenanthren-1-one, 4-imidazolylthioacetamide hydrochloride
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].N[C@H:8]([C:13]([OH:15])=[O:14])CC(C)C.N[C@H](C(O)=O)CC1C=CC=CC=1>>[NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH2:3][CH2:8][C:13](=[O:14])[OH:15]
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: C[C@H](N)C(=O)O
Agent: N[C@@H](Cc1ccccc1)C(=O)O
Product: N[C@@H](CCC(=O)O)C(=O)O

Procedure:
Ala 0.98 (1); Leu 0.76 (1); Phe 0.81 (1) LSIMS (Liquid Secondary Ion Mass Spectrometry) (M+H+)=647, (theoretical value)=647
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[C:4]([NH:6]C1C=CC(C(Cl)=O)=CC=1)=[O:5].[N:21]1[C:31]2[C:30]3[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=3[NH:28][CH2:27][CH2:26][C:25]=2[CH:24]=[N:23][CH:22]=1>N1C=CC=CC=1>[N:21]1[C:31]2[C:30]3[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=3[N:28]([C:4]([C:3]3[CH:16]=[CH:17][C:18]([C:19]4[C:2]([Cl:1])=[C:3]([CH:16]=[C:17]([Cl:20])[CH:18]=4)[C:4]([NH2:6])=[O:5])=[CH:19][CH:2]=3)=[O:5])[CH2:27][CH2:26][C:25]=2[CH:24]=[N:23][CH:22]=1
Reactant: O=C(Cl)c1ccc(NC(=O)c2cc(Cl)ccc2Cl)cc1
Reactant: c1ccc2c(c1)NCCc1cncnc1-2
Solvent: c1ccncc1
Product: NC(=O)c1cc(Cl)cc(-c2ccc(C(=O)N3CCc4cncnc4-c4ccccc43)cc2)c1Cl

Procedure:
As described for Example 1, 5 mmol of 4-[(2,5-dichlorobenzoyl)amino]benzoyl chloride is reacted with 5 mmol of 5,6-dihydro-7H-pyrimido-[5,4-d][1]benzazepine in pyridine to give the product as a solid.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:9]=[N+:10]=[N-:11].[Na+]>CN(C)C=O.C(OCC)(=O)C>[N:9]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[N+:10]=[N-:11]
Reactant: BrCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1ccccc1
Reaction time: 24 h
Yield: 79.5 %

Procedure:
To a solution of benzylbromide (350 μL, 2.92 mmol) in anhydrous dimethylformamide (7 mL), under argon, was added sodium azide (288 mg, 6.43 mmol). After 24 h at room temperature, the reaction mixture was diluted with ethyl acetate and then washed three times with brine. The combined organic layers were dried over sodium sulfate, filtered and evaporated. The residue was diluted with water and extracted with pentane, dried over sodium sulfate, filtered and evaporated to afford the title compound (309 mg, 80%) as a colorless oil.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[N-:5]=[N+:6]=[N-:7].[Na+].[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N:16]=[C:17]=[O:18])[C:11]=1[CH3:19].N([O-])=O.[Na+].Cl>O.CN(C)C=O>[CH3:19][C:11]1[C:10]([Br:9])=[CH:15][CH:14]=[CH:13][C:12]=1[N:16]1[C:17](=[O:18])[NH:7][N:6]=[N:5]1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1c(Br)cccc1N=C=O
Agent: Cl
Agent: O=N[O-]
Agent: [Al+3]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(Br)cccc1-n1nn[nH]c1=O
Temperature: 0 °C
Yield: 86.1 %

Procedure:
Under ice-cooling, to N,N-dimethylformamide 220 mL was added anhydrous aluminum chloride 19.7 g and the resulting mixtures were stirred for fifteen minutes. Thereto was added sodium azide 9.6 g and the resulting mixtures were stirred for fifteen minutes and thereto was then added 1-bromo-3-isocyanato-2-methylbenzene 30.3 g and the resulting mixtures were heated at 80° C. for five hours. After cooling the mixtures, to a mixture of sodium nitrite 33 g, water 2 L and ice 500 g was added the reaction solutions with stirring. The mixtures were acidified with 10% hydrochloric acid and were extracted with ethyl acetate. The organic layers were washed with water and saturated saline, and were dried over anhydrous magnesium sulfate and were then concentrated under reduced pressure to give 1-(2-methyl-3-bromophenyl)-1,4-dihydrotetrazole-5-one 31.4 g.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([Cl:23])[CH:17]=1)[CH2:10][C:9]2([CH3:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:5])C.[OH-].[Na+].Cl>CO.O1CCCC1.O>[Cl:23][C:18]1[CH:17]=[C:16]([CH:11]2[CH2:10][C:9]([CH3:30])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:8]3[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=3)[NH:12]2)[CH:21]=[CH:20][C:19]=1[F:22]
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(c1ccccc1)CC(c1ccc(F)c(Cl)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC1(c2ccccc2)CC(c2ccc(F)c(Cl)c2)Nc2ccc(C(=O)O)cc21
Temperature: 60 °C
Reaction time: 6 h
Yield: 96 %

Procedure:
To a stirred mixture solution of 2-(3-chloro-4-fluoro-phenyl)-4-methyl-4-phenyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (423 mg, 1 mmol) in methanol (10 mL) and tetrahydrofuran (20 mL) was added 30% sodium hydroxide in water (10 mL). The reaction mixture was stirred at 60° C. for 6 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(3-chloro-4-fluoro-phenyl)-4-methyl-4-phenyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (380 mg, 95%) as a light white solid which was used for next step without further purification: MS (ESI) M+1=396.1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:20]=[C:19]([N:21]4[CH2:26][CH2:25][N:24]([CH2:27][C:28]5[CH2:33][CH:32]([OH:34])[CH2:31][CH2:30][C:29]=5[C:35]5[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=5)[CH2:23][CH2:22]4)[CH:18]=[CH:17][C:12]=3[C:13]([O:15]C)=[O:14])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.O[Li].O.Cl.C(OCC)(=O)C>O1CCCC1.CO.O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:20]=[C:19]([N:21]4[CH2:26][CH2:25][N:24]([CH2:27][C:28]5[CH2:33][CH:32]([OH:34])[CH2:31][CH2:30][C:29]=5[C:35]5[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=5)[CH2:23][CH2:22]4)[CH:18]=[CH:17][C:12]=3[C:13]([OH:15])=[O:14])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: COC(=O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CCC(O)C3)CC2)cc1Oc1ccc2[nH]ccc2c1
Agent: Cl
Agent: [Li]O
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CCC(O)C3)CC2)cc1Oc1ccc2[nH]ccc2c1
Reaction time: 8 h

Procedure:
To a mixture of EXAMPLE 224C (1.78 g) in tetrahydrofuran (30 mL), methanol (10 mL) and water (10 mL) was added LiOH.H2O (0.262 g). The mixture was stirred overnight. The mixture was then neutralized with 5% aqueous HCl and exacted with ethyl acetate (3×) and the combined organic layers were washed with brine and dried over Na2SO4. Evaporation of solvent gave the title compound.