Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[S:13][C:12]([N:14]3[CH2:20][CH2:19][CH2:18][NH:17][C:16](=[O:21])[CH2:15]3)=[N:11][CH:10]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.Cl[C:23]1[N:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:29][C:26]1[CH:25]=[N:24][C:23]([NH:1][C:2]2[CH:3]=[C:4]([C:9]3[S:13][C:12]([N:14]4[CH2:20][CH2:19][CH2:18][NH:17][C:16](=[O:21])[CH2:15]4)=[N:11][CH:10]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=2)=[N:28][CH:27]=1
Reactant: Cc1cc(N)cc(-c2cnc(N3CCCNC(=O)C3)s2)c1
Reactant: Clc1cnc(Cl)nc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1cc(Nc2ncc(Cl)cn2)cc(-c2cnc(N3CCCNC(=O)C3)s2)c1
Temperature: 90 °C
Yield: 48 %

Procedure:
A sealed tube was charged with a stir bar, 4-[5-(3-amino-5-methylphenyl)-1,3-thiazol-2-yl]-1,4-diazepan-2-one (100 mg, 0.331 mmol), 2,5-dichloropyrimidine (49.3 mg, 0.331 mmol), potassium carbonate (91 mg, 0.661 mmol), Pd2 dba3 (30.3 mg, 0.033 mmol), and XPhos (79 mg, 0.165 mmol). The tube was evacuated and backfilled with argon three times. Fully degassed t-amyl alcohol (1.1 ml) was added, the tube was sealed and heated at 90° C. for overnight. The slurry was then cooled to room temperature, diluted with methanol, absorbed onto 2 g of silica, and purified via silica gel chromatography (0-20% methanol in ethyl acetate) to afford 4-(5-{3-[(5-chloropyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)-1,4-diazepan-2-one (66 mg, 0.159 mmol, 48.1% yield) as a bright yellow solid. MS APCI: [M+H]+ m/z 415.1. 1H NMR (500 MHz, DMSO) δ 9.80 (s, 1H), 8.55 (s, 2H), 7.60 (s, 2H), 7.46 (s, 1H), 7.41 (s, 1H), 6.93 (s, 1H), 4.16 (m, 2H), 3.78 (m, 2H), 3.20 (m, 2H), 2.26 (s, 3H), 1.78 (m, 2H). rhSyk=+++.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C1COCC1>[CH3:22][S:23]([O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)(=[O:25])=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 41.8 %

Procedure:
To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (5.0 g, 36 mmol) and triethyl amine (6.0 ml, 43 mmol) in 50 ml of THF at 0° C. under an atmosphere of nitrogen was added MsCl (3.4 ml, 43 mmol). The mixture was stirred at 0° C. for 3 h and quenched with aqueous sodium hydrogen carbonate (saturated, 100 mL). The mixture was extracted with ethyl acetate (3×100 mL). The combined organic fractions were washed with brine (1×100 mL), dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel Biotage 40M, eluting with EtOAc/isohexane to hexanes to afford the title compound as a colorless solid (4.2 g, 42%). 1H-NMR (500 MHz, CDCl3) δ 4.90 (s, 1H), 3.70 (m, 2H), 3.30 (m, 2H), 3.05 (s, 3H), 1.95 (m, 2H), 1.82 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:21]=3)[NH:16][N:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].C([O-])([O-])=O.[K+].[K+].[CH:38]1([NH2:42])[CH2:41][CH2:40][CH2:39]1.[I-].[Na+]>CN(C=O)C>[CH:38]1([NH:42][CH2:2][CH2:3][CH2:4][S:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[C:22]4[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH:21]=4)[NH:16][N:15]=3)[CH2:10][CH2:9]2)(=[O:7])=[O:6])[CH2:41][CH2:40][CH2:39]1
Reactant: NC1CCC1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)n[nH]c12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCNC4CCC4)CC3)n[nH]c12
Temperature: 120 °C
Reaction time: 0.02 h
Yield: 19 %

Procedure:
To a solution of 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-phenyl-1H-indazole-7-carboxamide (Intermediate 22) (20 mg, 0.0435 mmol) in DMF (1 mL) was added K2CO3 (27 mg, 0.174 mmol), cyclobutyl amine (18 uL, 0.217 mmol) and sodium iodide (0.8 mg, 0.00438 mmol). The reaction mixture was heated to 120° C. for 14 hrs. The solution was filtered and concentrated. The residue was purified by using a Gilson semi-preparative HPLC system with a YMC ODS-A (C-18) column 50 mm by 20 mm ID, eluting with 10% B to 80% B in 10 min, hold for 1 min where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to afford the title compound (4.1 mg, 19%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][CH:6]([CH:14]([OH:16])[CH3:15])[C:7](OC(C)(C)C)=[O:8].[BH4-].[Li+]>C(OCC)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][CH:6]([CH:14]([OH:16])[CH3:15])[CH2:7][OH:8]
Reactant: CC(O)C(Cc1ccc(Cl)c(Cl)c1)C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)C(CO)Cc1ccc(Cl)c(Cl)c1
Yield: 89.7 %

Procedure:
3.0 g of the alcohol compound thus obtained was dissolved in a liquid mixture of 30 ml of ethyl ether and 30 ml of tetrahydrofuran, and 1.2 g of lithium borohydride was added thereto with stirring under cooling with ice. The mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with ethyl ether, then washed with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The drying agent was separated by filtration, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (hexane/ethyl acetate=10/1) to obtain 2.1 g (yield: 90%) of (2RS, 3RS)-2-(3,4-dichlorobenzyl)-1,3-butanediol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([C:18](=[O:19])[NH:17][C:16](=[O:20])[NH:15]2)[C:7]1=[O:21].[H-].[Na+].Br[CH:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:31](=[O:32])[O:30]1.Cl>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([C:18](=[O:19])[NH:17][C:16](=[O:20])[N:15]2[CH:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:31](=[O:32])[O:30]2)[C:7]1=[O:21]
Reactant: O=C1NC(=O)C2(N1)C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccccc12
Reactant: O=C1OC(Br)c2ccccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1OC(N2C(=O)NC(=O)C23C(=O)N(Cc2ccc(Cl)c(Cl)c2)c2ccccc23)c2ccccc21
Reaction time: 0.5 h
Yield: 16.4 %

Procedure:
1'-(3,4-Dichlorobenzyl)-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione (1.8 g.) was stirred in anhydrous N,N-dimethylformamide (50 ml.) under an atmosphere of nitrogen at 25° C. Sodium hydride (0.25 g; 50% w/v oil dispersion) was added, and the mixture stirred for 30 minutes. 3-Bromophthalide (1.15 g.) was then added. The mixture was stirred for 16 hours and then poured into water (150 ml.). The mixture was acidified (concentrated hydrochloric acid) and then extracted with ethyl acetate (150 ml.). The extract was washed with water (2×150 ml.), brine (150 ml.) and then dried (MgSO4). The dry solution was evaporated onto silica gel (10 g., Merck type 7734) which was then added to the top of a column of silica gel (150 g., Merck type 7734) made up in toluene. The column was eluted with an increasing concentration of ethyl acetate in toluene up to 25% v/v. The fractions containing the major product [Relative flow value: 0.5 on Merck SiO2TLC plates No. 5715; eluant: EtOAc/toluene, 1:1 v/v] were collected and evaporated to give an oil which crystallised on treatment with ethyl acetate/petrol 60-80 to give 1'-(3,4-dichlorobenzyl)-3-phthalidyl-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione (0.4 g.), m.p. 154°-158° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]1([CH2:13][CH:14]=[CH:15][CH2:16][C@@H:17]([CH:21]([CH3:23])[CH3:22])[C:18](O)=[O:19])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH3:24][NH:25][CH3:26].N1C=CC=CC=1>C(Cl)Cl.CCOCC.CN(C=O)C.C1(C)C=CC=CC=1>[CH3:24][N:25]([CH3:26])[C:18](=[O:19])[C@H:17]([CH:21]([CH3:23])[CH3:22])[CH2:16][CH:15]=[CH:14][CH2:13][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CNC
Reactant: CC(C)[C@H](CC=CCC1CCCCC1)C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)[C@H](CC=CCC1CCCCC1)C(=O)N(C)C
Reaction time: 0.5 h

Procedure:
42.6 ml (0.49 mol) of oxalyl chloride are metered into a solution of 58.1 g (0.244 mol) of 6-cyclohexyl-2(S)-isopropyl-4-hexenoic acid in 270 ml of abs. toluene and 0.5 ml of DMF. When the addition is complete, the reaction mixture is boiled under reflux for 90 minutes, then concentrated in a rotary evaporator. The residue is dissolved in 270 ml of dry CH2Cl2 and added dropwise, at 0°, to a solution of 17.2 g (0.38 mol) of dimethylamine and 61.4 ml (0.76 mol) of pyridine in 270 ml of CH2Cl2. After stirring for 30 minutes at 0°, the mixture is diluted with ether and washed twice with 2N HCl, twice with saturated NaHCO3 solution and twice with brine. The combined organic phases are dried with MgSO4 and concentrated by evaporation. The residue is distilled at 124°-128°/0.04 mbar.
Reaction SMILES: [NH:1]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:2]([C:7]([NH:9][C@@H:10]([C:21]([O:23]C)=O)[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].O.[NH2:33][NH2:34].C(=O)=O>CN(C=O)C>[NH:1]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[C@H:2]([C:7]([NH:9][C@@H:10]([C:21]([NH:33][NH2:34])=[O:23])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: COC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Reactant: NN
Agent: O=C=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)NN
Reaction time: 8 h

Procedure:
To a solution of the compound obtained in (1) (430 mg) in DMF (10 ml) was added hydrazine monohydrate (1.0 ml) at room temperature and the solution was stirred overnight. To the reaction mixture was added dry-ice and the resulting solution was concentrated to give a residue, which was triturated with water to afford the product (406 mg). FAB-MS(m/e,(C22H33N5O4 +H)+):432
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7](O)=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.OS(O)(=O)=O.[NH3:17]>C(O)CCC.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH2:17])=[O:8]
Reactant: N
Reactant: O=C(O)c1cc(Br)ccc1O
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CCCCO
Product: NC(=O)c1cc(Br)ccc1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 82 %

Procedure:
To a stirred solution of 5-Bromosalicyclic acid (30 g, 135.5 mmol) in n-butylalcohol (60 mL) was added H2SO4 (95.6%, 289 μL, 5.42 mmol) in a 100 ml round bottom flask connected by a Dean-Stark trap/reflux condenser that was filled with 12 ml of n-butylalcohol. After heated to reflux for 2 days, the reaction was cooled down to R.T. and concentrated to give a pale yellow oil. The mixture was added 50 mL MeOH, followed by NH3 in MeOH (7 N, 116 mL). The reaction was stirred at R.T. for another 2 days, monitored by HPLC. After the reaction complete, it was concentrated to give a white solid. The crude solid was washed with small amount of EtOAc and hexane to afford 24 g of the product as a white crystalline solid (82% yield). 1H NMR (CDCl3) δ 12.15 (s, 1H), 7.54 (m, 2H), 6.97 (d, J=12 Hz, 1H), 6.00 (broad, 2H).
Reaction SMILES: [N+](C1C=CC=CC=1O)([O-])=O.[CH3:11][O:12][C:13]1[CH:25]=[CH:24][C:16]([C:17]([CH2:19][CH2:20][C:21]([OH:23])=O)=[O:18])=[CH:15][C:14]=1[F:26].CC(C)N=C=NC(C)C.[N:36]1[CH:41]=[CH:40][C:39]([N:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)=[CH:38][CH:37]=1>ClCC(Cl)C.CN(C=O)C.C(N(CC)CC)C>[F:26][C:14]1[CH:15]=[C:16]([C:17](=[O:18])[CH2:19][CH2:20][C:21]([N:45]2[CH2:46][CH2:47][N:42]([C:39]3[CH:40]=[CH:41][N:36]=[CH:37][CH:38]=3)[CH2:43][CH2:44]2)=[O:23])[CH:24]=[CH:25][C:13]=1[O:12][CH3:11]
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: COc1ccc(C(=O)CCC(=O)O)cc1F
Agent: CC(C)N=C=NC(C)C
Agent: O=[N+]([O-])c1ccccc1O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CC(Cl)CCl
Product: COc1ccc(C(=O)CCC(=O)N2CCN(c3ccncc3)CC2)cc1F
Temperature: 25 °C
Reaction time: 13 h
Yield: 718.3 %

Procedure:
To the polymeric nitrophenol (1.5 g, approx. 1 mmol) was added a solution of 3-(4-methoxy-3-fluorobenzoyl)propionic acid (1.66 g, 7.34 mmol) in a mixture of 1,2-dichloropropane (15 ml) and DMF (6 ml), followed by the addition of DIC (0.78 ml, 5.01 mmol). The mixture was shaken at room temperature for 13 hours, filtered, and the polymer was extensively washed with DCM, DMF, and 1,2-dichloropropane. To the polymer was added 1,2-dichloropropane (5 ml), a solution of 1-(4-pyridyl)piperazine (116 mg, 0.71 mmol) in 1,2-dichloropropane (10 ml), and triethylamine (0.2 ml). The resulting mixture was shaken at room temperature for 21 hours, filtered, and the polymer was carefully washed with DCM and methanol. The combined filtrates were concentrated to yield the crude product as an oil (0.38 g). Crystallization from acetonitrile (2 ml) at −20° C. yielded 0.19 g (5.1 mmol, 72%) of the title compound as almost colourless solid.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[NH2:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[C:10]([C:26](=[O:30])[C:27]([NH2:29])=[O:28])=[C:11]([CH2:24][CH3:25])[N:12]2[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.O>[CH3:6][O:5][C:3](=[O:4])[CH2:2][NH:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[C:10]([C:26](=[O:30])[C:27]([NH2:29])=[O:28])=[C:11]([CH2:24][CH3:25])[N:12]2[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCc1c(C(=O)C(N)=O)c2c(N)cccc2n1Cc1ccccc1
Reactant: COC(=O)CBr
Solvent: O
Solvent: CN(C)C=O
Product: CCc1c(C(=O)C(N)=O)c2c(NCC(=O)OC)cccc2n1Cc1ccccc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
Methyl bromoacetate (0.07 ml, 0.78 mmol) was added to 250 mg (0.78 mmol) of 4-Amino-2-Ethyl-α-oxo-1-(phenylmethyl)-1H-indole-3-Acetamide in 4 ml of DMF, stirred at 60° C. for 0.5 hour, and then at room temperature for 20 hours. The mixture was diluted with water and extracted with EtOAc. The EtOAC solution was washed with brine, dried over MgSO4, and evaporated in vacuo. The residue was chromatographed over silica gel eluting with Hexane/50 to 100% EtOAc to give 196 mg (64%) of [[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]amino]acetic acid methyl ester melting at 188°-193° C.
Reaction SMILES: [N:1]1([C:7](=[O:24])[CH2:8][CH:9]([CH2:13][S:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:16])=[O:15])[C:10]([OH:12])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.OC(C(F)(F)F)=O.[NH2:32][CH:33]([CH2:47][CH3:48])[CH:34]([C:36]1[O:37][C:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[N:39][N:40]=1)[OH:35].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CN1CCOCC1>C(Cl)Cl>[OH:35][CH:34]([C:36]1[O:37][C:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[N:39][N:40]=1)[CH:33]([NH:32][C:10](=[O:12])[CH:9]([CH2:13][S:14]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:16])=[O:15])[CH2:8][C:7]([N:1]1[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1)=[O:24])[CH2:47][CH3:48]
Reactant: O=C(O)C(CC(=O)N1CCOCC1)CS(=O)(=O)Cc1ccccc1
Reactant: CCC(N)C(O)c1nnc(-c2ccccc2)o1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(NC(=O)C(CC(=O)N1CCOCC1)CS(=O)(=O)Cc1ccccc1)C(O)c1nnc(-c2ccccc2)o1
Reaction time: 14 h
Yield: 107.9 %

Procedure:
To a stirred mixture of 4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyric acid (177 mg, 0.5 mmol), 2-amino-1-(5-phenyl-[1,3,4]oxadiazol-2-yl)-1-butanol TFA salt (175 mg), prepared as in reference 16, and HOBt (92 mg, 0.6 mmol) in MeCl2 (5 ml), was added EDC (144 mg, 0.75 mmol) and N-methylmorpholine (0.35 ml) at room temperature. After stirring for 14 hours, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated NaHCO3, brine, dried with MgSO4 and concentrated to yield 308 mg of N-{1-[Hydroxy-(5-phenyl-[1,3,4]oxadiazol-2-yl)-methyl]-propyl}-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide. Without further purification, the crude product was used for next reaction; MS: 569.6(M−1), 571.4(M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH2:9][C:10](O)=[O:11])=[C:4]([F:13])[CH:3]=1.S(Cl)([Cl:16])=O.CN(C=O)C>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH2:9][C:10]([Cl:16])=[O:11])=[C:4]([F:13])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1c(F)cc(Br)cc1F
Solvent: CN(C)C=O
Product: O=C(Cl)Cc1c(F)cc(Br)cc1F
Temperature: 60 °C
Reaction time: 2 h
Yield: 69.6 %

Procedure:
To a solution of 2-(4-bromo-2,6-difluorophenyl)acetic acid (0.3 g, 1.195 mmol) in sulfurous dichloride (5 mL, 1.195 mmol) was added DMF (9.25 μL, 0.120 mmol). The resulting mixture was stirred at 60° C. After 2 h, LCMS analysis showed the starting material had disappeared and the solvent was removed in vacuo to give 2-(4-bromo-2,6-difluorophenyl)acetyl chloride (0.35 g, 0.832 mmol, 69.6% yield). To a solution of 4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)aniline (0.347 g, 1.113 mmol) and Et3N (0.225 g, 2.227 mmol) in DCM (30 mL) was added 2-(4-bromo-2,6-difluorophenyl)acetyl chloride (0.3 g, 1.113 mmol). The resulting mixture was stirred at 25° C. After LCMS analysis showed the starting material had disappeared, the mixture was washed with H2O (20 mL) and brine (20 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by preparative TLC (PE/EA=3/1) to give N-(4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-bromo-2,6-difluoro phenyl)acetamide (110 mg, 0.196 mmol, 17.6% yield): 1H NMR (400 MHz, CD3OD) δ 7.81 (d, J=2.8 Hz, 1H), 7.68 (d, J=2.4 Hz, 1H), 7.32-7.25 (m, 7H), 7.15 (d, J=8.8 Hz, 1H), 4.61 (s, 2H), 4.23 (t, J=4.6 Hz, 2H), 3.84 (t, J=4.6 Hz, 2H), 3.77 (s, 2H); ES-LCMS m/z 546.0 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][OH:17])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([O-])(=[O:20])C.[Na+]>C(O)(=O)C>[OH:17][CH2:16][CH2:15][CH2:14][CH:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:4]=[CH:3][C:2](=[O:20])[NH:7][N:6]=2)[CH2:9][CH2:10]1
Reactant: OCCCC1CCN(c2ccc(Cl)nn2)CC1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=c1ccc(N2CCC(CCCO)CC2)n[nH]1
Reaction time: 4 h

Procedure:
A mixture of 6 parts of 1-(6-chloro-3-pyridazinyl)-4-piperidinepropanol, 1.9 parts of sodium acetate and 150 parts of acetic acid was stirred for 4 hours at reflux temperature. The reaction mixture was evaporated and the residue was taken up in 200 parts of a hydrochloric acid solution 10%. After stirring for 1 hour at reflux temperature, the whole was evaporated. The residue was taken up in water and treated with ammonium hydroxide. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated, yielding a first fraction of 6-[4-(3-hydroxypropyl)-1-piperidinyl]-3(2H)-pyridazinone; From the remaining aqueous layer, the precipitated product was filtered off and crystallized from 2-propanol. The product was filtered off and dried at 60° C., yielding a second fraction of the desired intermediate.
Reaction SMILES: [N+](C1C=CC(O[C:11]([C:13]2[C:21]3[O:20][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[N:18][C:17]=3[C:16]([O:28][CH3:29])=[CH:15][CH:14]=2)=[O:12])=CC=1)([O-])=O.[NH2:30][C:31]1[N:35]([CH3:36])[N:34]=[CH:33][C:32]=1[C:37]#[N:38]>C(OCC)C>[C:37]([C:32]1[CH:33]=[N:34][N:35]([CH3:36])[C:31]=1[NH:30][C:11]([C:13]1[C:21]2[O:20][C:19]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[N:18][C:17]=2[C:16]([O:28][CH3:29])=[CH:15][CH:14]=1)=[O:12])#[N:38]
Reactant: COc1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2oc(N3CCOCC3)nc12
Reactant: Cn1ncc(C#N)c1N
Solvent: CCOCC
Product: COc1ccc(C(=O)Nc2c(C#N)cnn2C)c2oc(N3CCOCC3)nc12
Yield: 68.9 %

Procedure:
Starting from 4-methoxy-2-(morpholin-4-yl)-benzooxazole-7-carboxylic acid 4-nitro-phenyl ester (200 mg) and 5-amino-1-methyl-1H-pyrazole-4-carbonitrile (122 mg). Purification by column chromatography on silica eluting with 80% ethyl acetate in heptane followed by 1% methanol in dichloromethane afforded, after trituration with diethyl ether, the title compound as a white solid (132 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:18]([CH2:19][O:20][CH3:21])[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[NH:10][C:9]=2[CH2:8][NH:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.ClOC(C)(C)C>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1NCc2[nH]c3cccc(OCc4ccccc4)c3c2C1COC
Agent: CC(C)(C)OCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ncc2[nH]c3cccc(OCc4ccccc4)c3c2c1COC
Temperature: -15 °C
Reaction time: 0.08 h
Yield: 75 %

Procedure:
10 mmol of 5-benzyloxy-4-methoxymethyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid ethyl ester is dissolved in 45 ml of methylene chloride. The solution is cooled to -15° C. and 4.6 ml of triethylamine is added Then a solution of 3.6 ml of tert-butyl hypochlorite in 45 ml of methylene chloride is added within about 10 minutes and stirred for 5 minutes more. After further addition of 3.8 ml of triethylamine, heating to ambient temperature and stirring at this temperature for 4 hours takes place. The solvent is distilled off in vacuum (bath temperature +30° C.) and condensed to dryness at +60° C. bath temperature. The residue is taken up in methylene chloride, filtered over silica gel, rewashed with methylene chloride, the product is eluted with ethyl acetate, the eluate is condensed and washed with ice water. The precipitate is filtered off and wahsed with ice-cold ethyl acetate. 2.93 g of 5-benzyloxy-4-methoxymethyl-β-carboline-3-carboxylic acid ethyl ester (80.5% of theory) with melting point 190.0° C. is obtained.
Reaction SMILES: [C:1](Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:9]([C:13]1[CH:39]=[CH:38][C:16]([CH2:17][O:18][C:19]2[CH:20]=[C:21]([CH:35]=[CH:36][CH:37]=2)[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31](=[O:34])(=[O:33])[NH2:32])=[O:23])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>CN(C)C1C=CN=CC=1.O1CCCC1>[C:9]([C:13]1[CH:39]=[CH:38][C:16]([CH2:17][O:18][C:19]2[CH:20]=[C:21]([CH:35]=[CH:36][CH:37]=2)[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([NH:32][C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])(=[O:34])=[O:33])=[O:23])=[CH:15][CH:14]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CCCCCC(=O)Cl
Reactant: CC(C)(C)c1ccc(COc2cccc(C(=O)Nc3ccccc3S(N)(=O)=O)c2)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCCCCC(=O)NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccc(C(C)(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
In a stream of nitrogen and at 0° C., 0.16 ml (1.10 mmol) of hexanoyl chloride was added to an anhydrous tetrahydrofuran (10 ml) solution containing 438 mg (1.00 mmol) of 3-(4-t-butylbenzyloxy)-N-(2-sulfamoylphenyl)benzamide produced in Reference Example 2 and 249 mg (2.00 mmol) of 4-dimethylaminopyridine, the mixture was stirred at room temperature for 1 hour and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography to obtain 488 mg (yield: 91.0%) of the title compound.