Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[Cl:19][C:20]1[N:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[N:25]=[CH:24][C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)=[CH:22][CH:21]=1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Reactant: OB(O)c1ccc(Cl)nc1
Product: Cc1c2n(c3c(-c4ccc(Cl)nc4)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, light yellow solid (66 mg, 78%), MS (ISP) m/z=335.5 [(M+H)+], mp 318° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 6-chloro-pyridin-3-ylboronic acid (51.1 mg, 0.325 mmol).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][C@@H:5]([CH:8]([CH3:10])[CH3:9])[C@H:4]([O:11][CH2:12][CH2:13][N:14]([CH2:16][CH2:17]O)[CH3:15])[CH2:3]1.S(Cl)([Cl:21])=O.C1(C)C=CC=CC=1>ClCCl.CN(C)C=O>[ClH:21].[CH3:1][C@@H:2]1[CH2:7][CH2:6][C@@H:5]([CH:8]([CH3:10])[CH3:9])[C@H:4]([O:11][CH2:12][CH2:13][N:14]([CH2:16][CH2:17][Cl:21])[CH3:15])[CH2:3]1
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OCCN(C)CCO
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OCCN(C)CCCl
Product: Cl
Yield: 97.6 %

Procedure:
19 g of N-[2-((1R,3R,4S)-1-methyl-4-isopropylcyclohex-3-yloxy)ethyl]-N-(2-hydro xyethyl)-N-methylamine were dissolved in 200 ml of dichloromethane. 17.6 g of thionyl chloride were then added dropwise to the solution with ice-cooling. Two drops of dimethylformamide were then added as a catalyst, and the solution was heated under reflux for 3 hours. The reaction mixture was worked up by adding toluene and then evaporating the solution, after which fresh toluene was added to the residue and evaporated two more times. The remaining residue was then dissolved in dichloromethane, and ether was added dropwise to the solution to precipitate the reaction product. The resulting precipitate was filtered out and dried. 22.5 g of N-[2-((1R,3R,4S)-1-methyl-4-isopropylcyclohex-3-yloxy)ethyl]-N-(2-chloroethyl)-N-methylamine hydrochloride having a melting point of 184° C.-194° C. were obtained.
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]#[N:12])=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[OH:13])=[CH:4][CH:3]=1.[Cl:14]N1C(=O)CCC1=O.[BH4-].[Na+]>O1CCCC1>[NH2:1][C:2]1[C:10]([C:11]#[N:12])=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[OH:13])=[CH:4][C:3]=1[Cl:14]
Reactant: N#Cc1c(N)ccc2c1C(O)CC2
Reactant: O=C1CCC(=O)N1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1c(N)c(Cl)cc2c1C(O)CC2
Reaction time: 0.5 h
Yield: 47.9 %

Procedure:
A solution of 6-amino-7-cyanoindan-1-ol (700 mg, 4 mmol) in tetrahydrofuran (50 ml) is treated with N-chlorosuccinimide (530 mg, 4 mmol) in portions over 20 minutes, stirred for 30 minutes, treated with sodiumborohydride (270 mg), and stirred for one hour. The mixture is quenched with water (30 ml), evaporated to remove tetrahydrofuran, and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered, and evaporated to give 6-amino-5-chloro-7-cyanoindan-1-ol (400 mg) which is directly used in the next step; LC/MS: 209/211 (M+1)+.
Reaction SMILES: Cl[P:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[O:3]1.[CH:16]1([NH:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH:23]1([N:22]([P:2]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[C:5]3[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=3[O:3]2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: C1CCC(NC2CCCCC2)CC1
Reactant: ClP1Oc2ccccc2-c2ccccc21
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: c1ccc2c(c1)OP(N(C1CCCCC1)C1CCCCC1)c1ccccc1-2

Procedure:
35.1 g (0.15 mol) of 6-chloro-dibenz[c,e][1,2]oxaphosphorine, 27.1 g (0.15 mol) of dicyclohexylamine and 50 ml of triethylamine are kept at reflux temperature for 10 hours. Toluene is added to the solution; the triethylamine hydrochloride is then removed by filtration, and the filtrate is concentrated in vacuo. The crystalline product has a melting point of 162° C. (Compound I).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[CH:18][C:19]([CH2:33][OH:34])=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([C:28]([N:30]([CH3:32])[CH3:31])=[O:29])=[CH:24][CH:23]=5)[CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[C:35]1(C)C=CC(S(O)(=O)=O)=C[CH:36]=1>C(O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[CH:18][C:19]([CH2:33][O:34][CH2:35][CH3:36])=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([C:28]([N:30]([CH3:31])[CH3:32])=[O:29])=[CH:24][CH:23]=5)[CH:21]=4)=[O:14])[CH2:11][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CN(C)C(=O)c1ccc(-c2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2CO)cc1
Solvent: CCO
Product: CCOCc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(C(=O)N(C)C)cc1
Yield: 13.2 %

Procedure:
5′-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2′-(hydroxymethyl)-N,N-dimethylbiphenyl-4-carboxamide (49 mg, 0.10 mmol) and para-toluenesulfonic acid (38 mg, 0.2 mmol) were dissolved in ethanol (1.0 mL) and irradiated in the microwave at 140° C. for 10 minutes. Volatiles were removed in vacuo and crude product was purified by reverse phase HPLC to afford the pure product (6.4 mg, 13%). ESI-MS m/z calc. 486.2. found 487.5 (M+1)+; retention time 3.17 minutes.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([CH3:34])[C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([NH:14][C:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[O:17][C:16]=2[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=2)=[O:25])=[O:13])[CH2:8][CH2:7]1.C(N(CC)CC)C.[C:42](Cl)(=[O:44])[CH3:43].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[C:42]([NH:1][CH2:2][CH2:3][CH2:4][N:5]([CH3:34])[C@H:6]1[CH2:7][CH2:8][C@H:9]([C:12]([NH:14][C:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[O:17][C:16]=2[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=2)=[O:25])=[O:13])[CH2:10][CH2:11]1)(=[O:44])[CH3:43]
Reactant: CN(CCCN)[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3cccnc23)CC1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)NCCCN(C)[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3cccnc23)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-[({Trans-4-[(3-aminopropyl)(methyl)amino]cyclohexyl}-carbonyl)amino]-N-(5-chloropyridin-2-yl)furo[3,2-b]pyridine-2-carboxamide (113 mg) obtained in Example 121 and triethylamine (65 μl) are dissolved in chloroform (5 ml), and thereto is added acetyl chloride (25 μl) under ice-cooling. The mixture is warmed to room temperature and stirred for 1 hour. To the reaction solution is poured saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform. The organic layer is washed successively with water and saturated brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (eluent: ethyl acetate followed by ethyl acetate/methanol=10/1). The resulting solid is suspended in n-hexane-diisopropyl ether, and collected by filtration to give the title compound (90 mg).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:25][OH:26])[C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([O-:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:28]([O:31][CH2:32][CH3:33])(=[O:30])C.CN(C)[C:36](=[O:38])[CH3:37]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:25][OH:26])[C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([O:22][CH:36]([O:38][C:28]([O:31][CH2:32][CH3:33])=[O:30])[CH3:37])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: C=CC1=C(C(=O)[O-])N2C(=O)C(NC(=O)C(=NO)c3csc(N)n3)[C@H]2SC1
Reactant: CC(=O)N(C)C
Reactant: CCOC(C)=O
Agent: [Na+]
Product: C=CC1=C(C(=O)OC(C)OC(=O)OCC)N2C(=O)C(NC(=O)C(=NO)c3csc(N)n3)[C@H]2SC1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
1-DL-Iodoethyl ethyl carbonate (22 g) was added dropwise to a solution of sodium 7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (15 g) in N,N-dimethylacetamide (120 ml) at 5°-7° C., and the mixture was stirred at 5° C. for 30 minutes. To the reaction mixture was added ethyl acetate (200 ml), followed by filtration. The filtrate was washed with water and an aqueous sodium chloride, and then dried over magnesium sulfate. After removal of the solvent, the residue was washed with ethyl acetate and dried in vacuo to give DL-1-ethoxycarbonyloxyethyl 7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (7.4 g), mp 126°-130° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10]([NH:12][CH2:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=2[O:22][CH3:23])=[NH:11])[S:7][CH:8]=1.CN1CCOCC1.[CH3:31][O:32][C:33](Cl)=[O:34]>C1COCC1>[CH3:31][O:32][C:33](=[O:34])[NH:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10]([NH:12][CH2:13][C:14]2[C:15]([O:22][CH3:23])=[CH:16][CH:17]=[CH:18][C:19]=2[O:20][CH3:21])=[NH:11])[S:7][CH:8]=1
Reactant: COc1cccc(OC)c1CNC(=N)Nc1nc(CN)cs1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COC(=O)NCc1csc(NC(=N)NCc2c(OC)cccc2OC)n1

Procedure:
To 360 mg (1.12 mmol) N-[4-(aminomethyl)-1,3-thiazole-2-yl]-N′-(2,6-dimethoxybenzyl)guanidine hydrochloride, Example 154 free base, in 13.5 ml THF were added 0.2 ml NMM, and 0.1 ml chloroformic acid methyl ester in 1.5 ml THF were added drop-wise with stirring. Following completion of the reaction, the mixture was concentrated, was diluted with dichloromethane, was washed with saturated NaCl solution, was dried and was concentrated. Chromatography of the crude product on silica gel (dichloromethane/methanol 0-1%) yielded 140 mg; ESI-MS [M+H+]=380.05.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[CH:14]=1)=[CH:11][C:10]([O:16][CH3:17])=[CH:9][C:8]=2[Br:18])=[O:4].[H-].[Na+].[CH3:21][Si:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][O:25][CH2:26]Cl.O>CN1C(=O)CCC1>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][CH2:26][O:25][CH2:24][CH2:23][Si:22]([CH3:29])([CH3:28])[CH3:21])[C:12]2[C:7](=[C:8]([Br:18])[CH:9]=[C:10]([O:16][CH3:17])[CH:11]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1cc(=O)c2cc(OC)cc(Br)c2[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)c1cc(OCOCC[Si](C)(C)C)c2cc(OC)cc(Br)c2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 101.5 %

Procedure:
A brown solution of 8-bromo-6-methoxy-4-oxo-1,4-dihydro-quinoline-2-carboxylic acid methyl ester (6.73 g, 21.6 mmol) in 100 mL N-methyl pyrolidinone was treated with sodium hydride (60% dispersion in oil, 1.028 g, 25.7 mmol). Gas evolution and warming were observed. The reaction was stirred for 10 minutes at room temperature under nitrogen. Addition of 2-(trimethylsilyl)ethoxymethyl chloride (5.00 mL, 28.3 mmol) resulted in a slightly cloudy, light brown solution. After 2.5 hours at room temperature, the reaction mixture was poured into 800 mL water and stirred for 15 minutes. The resulting cream colored precipitate was isolated by filtration, washed with water, and dried under high vacuum to afford the product as a cream colored solid (9.70 g, quantitative yield). 1H NMR (300 MHz, DMSO, d6) δ 7.976 (d, 1 H, Jm=2.7 Hz, ArH7), 7.79 (s, 1 H, C═CH), 7.53 (d, 1 H, Jm=2.7 Hz, ArH5), 5.70 (s, 2 H, OCH2O), 3.99 (s, 6 H, OCH3 and CO2CH3), 3.88 (t, 2 H, J=8.0 Hz, OCH2CH2Si), 0.97 (t, 2 H, J=8.0 Hz, OCH2CH2Si), ), −0.04 (s, 9 H, Si(C H3)3; Mass Spec.: calc. for [C18H24BrNO5Si+H]+ Theor. m/z=442, 444; Obs. 442, 444.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[NH:13][N:12]=[C:11]([CH:14]3[CH2:16][CH2:15]3)[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Cl:17][C:18]1[CH:26]=[C:25]2[C:21]([CH:22]=[CH:23][NH:24]2)=[CH:20][C:19]=1[CH2:27][NH2:28].CCN(C(C)C)C(C)C>CC(O)C>[Cl:17][C:18]1[CH:26]=[C:25]2[C:21]([CH:22]=[CH:23][NH:24]2)=[CH:20][C:19]=1[CH2:27][NH:28][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH:14]3[CH2:16][CH2:15]3)[NH:12][N:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: NCc1cc2cc[nH]c2cc1Cl
Reactant: Clc1nccc(Nc2cc(C3CC3)n[nH]2)n1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cc2[nH]ccc2cc1CNc1nccc(Nc2cc(C3CC3)[nH]n2)n1
Temperature: 120 °C

Procedure:
A sealed vial was charged with 53 (80 mg, 0.34 mmol), 244 (45 mg, 0.25 mmol), DIPEA (100 mg, 0.75 mmol), and IPA (3.0 mL). The reaction mixture was heated at 120° C. for 18 h. The solution was concentrated and purified by preparative HPLC to afford 40 mg (42%) of I-93 as white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26](O)=[O:27])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:33][C:34]1[O:38][C:37]([C:39]2([NH2:42])[CH2:41][CH2:40]2)=[N:36][CH:35]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[C:25]([C:26](=[O:27])[NH:42][C:39]5([C:37]6[O:38][C:34]([CH3:33])=[CH:35][N:36]=6)[CH2:41][CH2:40]5)[C:24]([O:30][CH3:31])=[CH:23][C:22]=4[CH3:32])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:6][CH:7]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Reactant: Cc1cnc(C2(N)CC2)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncc(C)o5)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.2 g, 0.46 mmol, 1 eq), 1-(5-methyloxazol-2-yl)cyclopropanamine (0.06 g, 0.46 mmol, 1.0 eq), HOBT (0.062 g, 0.46 mmol, 1.0 eq), EDC.HCl (0.08, 0.46 mmol, 1.0 eq), in DCM at ambient temperature and under a nitrogen atmosphere was added diisopropylethylamine (0.19 ml, 1.3 mmol, 3.0 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by Combiflash column chromatography (4g flash column, CV 4.8 ml, 18 ml/min, max pressure 200 psi) using 0.5% Methanol/DCM. Yield: 0.030 g (11.76%). 1H NMR (400 MHz, CD3OD): δ 1.43-1.46 (m, 2H), 1.61-1.65 (m, 2H), 2.29 (d, 3H, J=0.8 Hz), 2.37 (s, 3H), 2.96 (s, 3H), 4.06 (s, 3H), 6.69 (s, 1H,), 7.14 (s, 1H), 7.28 (apparent t, 2H), 7.34 (dd, 1H, J=1.6, 8.4 Hz), 7.59 (d, 1H, J=1.2 Hz), 7.64 (d, 1H, J=8.4 Hz), 7.88 (s, 1H), 7.96-8.00 (m, 2H). LCMS: (ES+) m/z=554.2 (M+H)+
Reaction SMILES: [C:1]1([N:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:28])[N:17]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:12][CH:11]2[CH2:29][CH2:30]O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:38]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(#N)C>[C:1]1([N:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:28])[N:17]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:12][CH:11]2[CH2:29][CH2:30][Br:38])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCN(CCCCC)C(=O)N1CCN(C(=O)N(c2ccccc2)c2ccccc2)C(CCO)C1
Solvent: CC#N
Product: CCCCCN(CCCCC)C(=O)N1CCN(C(=O)N(c2ccccc2)c2ccccc2)C(CCBr)C1
Yield: 86 %

Procedure:
A solution of 312 mg (0.61 mmol) of (RS)-1-(N,N-diphenylcarbamoyl)-2-(2-hydroxyethyl)-4-(N,N-dipentylcarbamoyl)piperazine and 362 mL (0.86 mmol) of dibromotriphenylphosphorane in 15 mL of acetonitrile was stirred under nitrogen at 82° C. for 2 hours. The yellow solution was cooled and concentrated in vacuo. Flash chromatography on 35 g of silica gel using 1:1 v/v ethyl acetate/hexane as the eluant afforded 300 mg (85%) of a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[S:12][C:5]2[CH2:6][O:7][C:8]([CH3:11])([CH3:10])[CH2:9][C:4]=2[C:3]=1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[CH3:20][O:21][C:22]1[CH:32]=[CH:31][C:25]([C:26]([N:28]=[C:29]=[S:30])=[O:27])=[CH:24][CH:23]=1>C1COCC1>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([NH:28][C:29](=[S:30])[NH:1][C:2]2[S:12][C:5]3[CH2:6][O:7][C:8]([CH3:11])([CH3:10])[CH2:9][C:4]=3[C:3]=2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:27])=[CH:31][CH:32]=1
Reactant: COc1ccc(C(=O)N=C=S)cc1
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CC(C)(C)OC2
Solvent: C1CCOC1
Product: COc1ccc(C(=O)NC(=S)Nc2sc3c(c2C(=O)OC(C)(C)C)CC(C)(C)OC3)cc1
Temperature: 50 °C
Yield: 78.3 %

Procedure:
A solution of tert-butyl 2-amino-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate (1.0 mL, 0.083 M, 0.083 mmol) in THF was added to a solution of 4-methoxybenzoyl isothiocyanate (51 mg, 0.26 mmol) in THF (1 mL) and heated at 50° C. for 16 hours, then cooled to room temperature. The solvent was removed and EtOH (2 mL) was added. The product was filtered and rinsed with EtOH (3×5 mL). tert-Butyl 2-(3-(4-methoxybenzoyl)thioureido)-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate (31 mg, 0.065 mmol, 78% yield) was isolated as a white solid. 1H NMR (400 MHz, CDCl3) δ 14.65 (s, 1H), 8.98 (s, 1H), 7.83 (apparent d, J=8.9 Hz, 2H), 6.91 (apparent d, J=8.9 Hz, 2H), 4.66 (s, 2H), 3.81 (s, 3H), 2.69 (s, 2H), 1.56 (s, 9H), 1.24 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 173.90, 164.52, 164.49, 163.88, 147.40, 129.93, 129.13, 124.58, 123.65, 118.03, 114.34, 82.36, 70.79, 59.81, 55.62, 38.25, 28.49, 26.48.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([NH2:9])[CH2:7][NH2:8].C(N=[C:14]=[S:15])C=C>BrC1C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:7][NH:8][C:14](=[S:15])[NH:9]1
Reactant: C=CCN=C=S
Reactant: NCC(N)c1cccs1
Solvent: Brc1ccccc1
Product: S=C1NCC(c2cccs2)N1
Temperature: 25 °C
Yield: 86.8 %

Procedure:
. . A solution of 140 mg (1.0 mmol) of 2-thienyl-1,2-diaminoethane and allyl isothiocyanate (99 mg, 1 mmol) in bromobenzene (5 mL) was heated for 40 min and allowed to cool to room temperature and then cooled to −5° C. The title compound (160 mg, 83% yield) was obtained upon filtration and washing with hexane.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[CH:9]=[CH:8][C:7]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[CH:20][CH:19]=1.[CH3:27]O>>[CH3:5][C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[CH:9]=[CH:8][C:7]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=1
Reactant: Cc1cc(-c2cnccn2)ccc1-c1ccc(C(=O)O)cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(-c2ccc(-c3cnccn3)cc2C)cc1
Reaction time: 0.25 h
Yield: 65 %

Procedure:
Thionyl chloride (0.076 ml, 1.043 mmol) was added to methanol (7 ml) at 0° C. After 15 minutes, 2'-methyl-4'-pyrazinylbiphenyl-4-carboxylic acid (D85, 0.216 g, 0.745 mmol) was added and the mixture was heated to reflux. After 5 h, the reaction mixture was allowed to cool and was left at room temperature overnight. The reaction mixture was then evaporated under reduced pressure and the residue was partitioned between dichloromethane (25 ml) and 10% sodium carbonate solution (20 ml). The aqueous layer was then extracted with dichloromethane (1×10 ml), and the combined organic layers were then dried (Na2SO4) and evaporated under reduced pressure to give the title compound as a yellow/brown solid (0.146 g, 65%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9][C:10]1[C:18]([O:19]C2CCCCO2)=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[N:13][N:14]2C1CCCCO1.O>ClCCl>[CH3:8][S:9][C:10]1[C:18]([OH:19])=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[N:13][NH:14]2
Reactant: CSc1c(OC2CCCCO2)ccc2c1cnn2C1CCCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CSc1c(O)ccc2[nH]ncc12
Reaction time: 1 h
Yield: 127.1 %

Procedure:
Trifluoroacetic acid (1 ml) was added to a solution of 4-(methylthio)-1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-1H-indazole (0.0730 g, 0.21 mmol) in dichloromethane (1 ml) and stirred for 1 hour. The reaction solution was added to water and extracted three times with ethyl acetate and the extract solution was dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by a silica gel chromatography (hexane/ethyl acetate=2/1), crystallized from hexane/ethyl acetate and then dried up to obtain 4-(methylthio)-1H-indazol-5-ol (0.0481 g, >99%).
Reaction SMILES: [CH2:1]([C:8]1[N:12]([CH:13]([CH:23]2[CH2:28][CH2:27][CH2:26]CC2)[C:14]([NH:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:15])[C:11]2[CH:29]=[C:30]([Cl:34])[C:31]([F:33])=[CH:32][C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1([CH:41]=[O:42])CCCCC1.[S:43]1CCC(CC=O)[CH2:45][CH2:44]1.ClC1C=C(CC(O)=O)C=CC=1.COC(C1C=CC=CC=1)C(O)=O>>[Cl:34][C:30]1[C:31]([F:33])=[CH:32][C:10]2[N:9]=[C:8]([CH:1]([O:42][CH3:41])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:12]([CH:13]([CH2:23][CH:28]3[CH2:27][CH2:26][S:43][CH2:44][CH2:45]3)[C:14]([NH:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:15])[C:11]=2[CH:29]=1
Reactant: O=CCC1CCSCC1
Reactant: O=CC1CCCCC1
Reactant: O=C(NC1CCCCC1)C(C1CCCCC1)n1c(Cc2ccccc2)nc2cc(F)c(Cl)cc21
Agent: COC(C(=O)O)c1ccccc1
Agent: O=C(O)Cc1cccc(Cl)c1
Product: COC(c1ccccc1)c1nc2cc(F)c(Cl)cc2n1C(CC1CCSCC1)C(=O)NC1CCCCC1

Procedure:
The title compound was prepared in analogy to Example 1, replacing (2-amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester with (2-amino-4-chloro-5-fluoro-phenyl)-carbamic acid tert-butyl ester (([CAS RN 579474-50-3]), Example 47), cyclohexanecarbaldehyde with tetrahydro-2H-thiopyran-4-acetaldehyde ([CAS RN 372159-78-9]) and (3-chloro-phenyl)-acetic acid with DL- -methoxyphenylacetic acid ([CAS RN 7021-09-2]). MS (ISP): 544.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][CH2:9][CH2:8][CH2:7]2.[Cl:12][CH2:13][C:14](Cl)=[O:15].C(N(CC)CC)C>C(Cl)Cl>[Cl:12][CH2:13][C:14]([N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[CH3:1])[CH2:7][CH2:8][CH2:9]1)=[O:15]
Reactant: Cc1cccc2c1NCCC2
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc2c1N(C(=O)CCl)CCC2
Reaction time: 8 h
Yield: 97 %

Procedure:
To a solution of 8-methyl-1,2,3,4-tetrahydroquinolin (1) (8.0 g, 54.3 mmol) in dry CH2Cl2 (250 mL) at 0° C. was added chloroacetyl chloride (4.8 mL, 60.3 mmol) followed by addition of triethylamine (8.4 mL, 60.3 mmol). The reaction mixture was stirred overnight under N2 and then diluted with CH2Cl2 (300 mL), washed with 1M HCl (2×225 mL), H2O (2×250 mL) and brine. Dried over Na2SO4, filtered and concentrated under reduce pressure to 12.67 g of crude material which was purified by column chromatography (EtOAc/Hexanes). Obtained 11.76 g (52.6 mmol) of target 2 (off-white solid) in 97% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22]C)=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(N)cc1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(N)cc1
Yield: 94 %

Procedure:
To a mixture of methyl 2-(4-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxy late (500 mg, 1.61 mmol) in methanol (10 mL) and water (5 mL) was added a solution of sodium hydroxide (1100 mg, 27.4 mmol) in water (15 mL). The resultant mixture was heated for reflux until the complete of the reaction (monitored by thin layer chromatography). The methanol was removed under vacuum. The residue was acidified with 2 M hydrochloric acid to pH=1. The precipitates were collected by filtration to afford 2-(4-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a yellow solid, 430 mg, Yield 94%.