Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: CCOC(=O)CCCCCNc1c([N+](=O)[O-])cnc2ccccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCCCCNc1c(N)cnc2ccccc12
Reaction time: 15 h
Yield: 75.3 %

Procedure:
A Parr hydrogenation vessel was charged with ethyl 6-(3-nitroquinolin-4-ylamino)hexanoate (14.4 g, 43.2 mmol), 10% palladium on carbon catalyst (1.0 g), and ethanol (250 mL); placed on a Parr shaker; and the system pressurized to 40 psi (2.7×105 Pa) hydrogen. After shaking for 15 hours, the reaction mixture was filtered through CELITE filter agent and concentrated under reduced pressure to provide ethyl 6-(3-aminoquinolin-4-ylamino)hexanoate as a dark oil (9.8 g) that was used directly in the next step without further purification. This step was repeated several times to provide material for the subsequent step.
Reaction SMILES: C([O:8][C:9]1[CH:24]=[CH:23][C:12]([O:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[NH:20][CH:21]=[CH:22][C:15]=23)=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].CO>[NH:20]1[C:16]2=[N:17][CH:18]=[CH:19][C:14]([O:13][C:12]3[CH:23]=[CH:24][C:9]([OH:8])=[CH:10][CH:11]=3)=[C:15]2[CH:22]=[CH:21]1
Reactant: c1ccc(COc2ccc(Oc3ccnc4[nH]ccc34)cc2)cc1
Agent: [Pd]
Solvent: CO
Product: Oc1ccc(Oc2ccnc3[nH]ccc23)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-(4-Benzyloxy-phenoxy)-1H-pyrrolo[2,3-b]pyridine (Step a, 9.0 g, 28.4 mmol, 1.0 eq.) was suspended into MeOH (200 mL) and the atmosphere was replaced by argon. 10% Pd/C (3 g total), was added and the argon was replaced by a H2 atmosphere. The mixture was stirred for 16 h at 60 psi at RT (using Parr shaker). The reaction showed about 50% conversion to product (monitored by HPLC). More 10% Pd/C was added and reacted another 16 h at 60 psi. More 10% Pd/C was added and reacted another 16 h at 60 psi. TLC showed reaction done. The Pd/C was filtered, the MeOH removed and the obtained 4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenol was used crude in the next step.
Reaction SMILES: [CH2:1]([N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][CH2:10]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCCCC1.S(Br)([Br:27])=O.C(=O)([O-])O.[Na+]>CN(C=O)C>[CH2:1]([N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][CH2:10][Br:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCN(Cc1ccccc1)Cc1ccccc1
Reactant: O=S(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCCCC1
Product: BrCCN(Cc1ccccc1)Cc1ccccc1
Reaction time: 15 h
Yield: 70.9 %

Procedure:
To N,N-dibenzyl-2-aminoethanol (80.68 g) were added cyclohexane (500 ml) and DMF (12.9 ml), and thereto was added dropwise thionyl bromide (83.4 g). The mixture was stirred for 15 hours, and to the reaction solution was added an saturated aqueous sodium hydrogen carbonate solution in an ice-bath, and the mixture was extracted with ethyl acetate. The organic layer was washed with water (three times) and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (72.1 g).
Reaction SMILES: Cl[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:9][O-:10].[Na+]>CO>[CH3:9][O:10][C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccnc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nccnc1N
Temperature: 130 °C
Yield: 58.5 %

Procedure:
A mixture of 3-chloro-2-pyrazinamine (200 mg, 1.544 mmol) and sodium methoxide (250 mg, 4.63 mmol) in methanol (3.9 ml) was heated to 130° C. via a microwave reactor for 60 min. The crude product mixture was purified by RP-HPLC to give 3-(methyloxy)-2-pyrazinamine (113 mg, 0.903 mmol, 59% yield). MS (ES+) m/z 125.8 (MH+).
Reaction SMILES: Cl.FC1C=CC(C2(C3C4C(=CC=C(OCCN[S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])C=4)CCN3)CCC2)=CC=1.[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2([C:44]3[C:53]4[C:48](=[CH:49][CH:50]=[C:51]([O:54][CH2:55][CH2:56][NH2:57])[CH:52]=4)[C:47]([CH3:59])([CH3:58])[CH2:46][N:45]=3)[CH2:43][CH2:42][CH2:41]2)=[CH:36][CH:35]=1>>[ClH:33].[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2([CH:44]3[C:53]4[C:48](=[CH:49][CH:50]=[C:51]([O:54][CH2:55][CH2:56][NH:57][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:52]=4)[C:47]([CH3:59])([CH3:58])[CH2:46][NH:45]3)[CH2:43][CH2:42][CH2:41]2)=[CH:36][CH:35]=1
Reactant: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(F)cc3)CCC1)NCC2
Reactant: CC1(C)CN=C(C2(c3ccc(Cl)cc3)CCC2)c2cc(OCCN)ccc21
Agent: Cl
Product: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)NCC2(C)C

Procedure:
N-[2-({1-[1-(4-Chlorophenyl)cyclobutyl]-4,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl}oxy)ethyl]propane-1-sulfonamide hydrochloride was prepared analogously to N-[2-({1-[1-(4-fluorophenyl)cyclobutyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}oxy)ethyl]propane-1-sulfonamide hydrochloride (cf. example 65) using 2-({1-[1-(4-chlorophenyl)cyclobutyl]-4,4-dimethyl-3,4-dihydroisoquinolin-7-yl}oxy)ethanamine in place of 2-({1-[1-(4-fluorophenyl)cyclobutyl]-3,4-dihydroisoquinolin-7-yl}oxy)ethanamine.
Reaction SMILES: C1C(=O)N([Cl:8])C(=O)C1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:20][C:19]([CH:21]3[CH2:25][CH2:24][CH2:23][N:22]3[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[N:18][CH:17]=2)=[CH:12][CH:11]=1>CN(C=O)C>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:20][C:19]([C@@H:21]3[CH2:25][CH2:24][CH2:23][N:22]3[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[N:18][C:17]=2[Cl:8])=[CH:12][CH:11]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(Br)cc2)[nH]1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(Cl)c(-c2ccc(Br)cc2)[nH]1
Temperature: 50 °C
Yield: 95.6 %

Procedure:
NCS (0.51 g, 3.82 mmol) was added to a solution of tert-butyl 2-(5-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (1.0 g, 2.55 mmol) in DMF (25 mL) and the mixture was heated at 50° C. overnight. The volatiles were removed under vacuum. The residue was purified by flash column chromatography (BIOTAGE®), eluting with a gradient of 0 to 10% EtOAc/DCM to afford the partially pure (S)-tert-butyl 2-(5-(4-bromophenyl)-4-chloro-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (1.04 g) as yellow foam. LC-MS retention time 1.99 min; m/z 427.12 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5u C18 4.6×30 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 4 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% TFA and Solvent B was 10% H2O/90% MeOH/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (500 MHz, MeOD) δ ppm 7.63 (s, 4H), 4.74-4.81 (m, 1H), 3.64-3.72 (m, 1H), 3.45-3.55 (m, 1H), 2.27-2.42 (m, 1H), 2.00-2.15 (m, 2H), 1.90-2.00 (m, 1H), 1.48 (m, 3H), 1.27 (m, 6H).
Reaction SMILES: C([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH:18]=[CH:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[O:21]C(=O)C)=[CH:16][C:15](=O)[CH2:14][CH2:13]4)C.C[Mg]Br.Cl>O1CCCC1>[CH2:6]([C@:5]12[CH2:14][CH2:13][C@@H:12]3[C@@H:17]4[C:16]([CH2:15][CH:8]([CH3:19])[C@H:9]3[C@@H:10]1[CH2:11][CH2:3][C@@H:4]2[OH:21])=[CH:5][C:4](=[O:21])[CH2:3][CH2:18]4)[CH3:7]
Reactant: CC[C@]12CC[C@H]3[C@@H](C=CC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2OC(C)=O
Agent: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CC[C@]12CC[C@H]3[C@@H](C(C)CC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Reaction time: 0.33 h

Procedure:
Add dl-13-ethyl-17β-acetoxygona-4,6-dien-3-one (2.0 g) in tetrahydrofuran (30 cc) to tetrahydrofuran (20 cc) containing 3 moles methyl magnesium bromide (16 cc) and cuprous chloride (299 mg) at 0°. Stir for 20 minutes and pour into ice-cold brine saturated with hydrogen chloride. Extract with ether and chromatograph on Grade 2.5 neutral alumina. To obtain the title compound, recrystallize from ethyl acetate-hexane (0.56 g), m.p. 152°-154°; λmax. KBr 2.98, 6.02 μ; λmax. EtOH 242 mμ (ε16,730).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][C:4]=1[CH:12]1[C:25]2[C:24](=[O:26])[CH2:23][C:22]([CH3:28])([CH3:27])[CH2:21][C:20]=2[O:19][C:18]2[CH2:17][C:16]([CH3:30])([CH3:29])[CH2:15][C:14](=[O:31])[C:13]1=2.Cl[C:33]1[N:38]=[C:37]([C:39]#[N:40])[CH:36]=[CH:35][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:33]2[N:38]=[C:37]([C:39]#[N:40])[CH:36]=[CH:35][CH:34]=2)=[CH:5][C:4]=1[CH:12]1[C:25]2[C:24](=[O:26])[CH2:23][C:22]([CH3:28])([CH3:27])[CH2:21][C:20]=2[O:19][C:18]2[CH2:17][C:16]([CH3:30])([CH3:29])[CH2:15][C:14](=[O:31])[C:13]1=2
Reactant: COc1ccc(B(O)O)cc1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Reactant: N#Cc1cccc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(-c2cccc(C#N)n2)cc1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Temperature: 90 °C
Reaction time: 0.75 h
Yield: 95.3 %

Procedure:
A suspension of the [4-methoxy-3-(3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthen-9-yl)phenyl]boronic acid produced in Example 1-1 (1.01 g, 2.37 mmol), 6-chloropyridine-2-carbonitrile (342 mg, 2.37 mmol), sodium carbonate (1.01 g, 9.48 mmol), and tetrakis(triphenylphosphine)palladium(0) (137 mg, 0.12 mmol) in 1,2-dimethoxyethane (20.1 ml) and water (8.7 ml) was prepared at room temperature, and the suspension thus prepared was then stirred at 90° C. for 45 minutes. After air-cooling, water was added to the reaction solution, and the mixed solution was then extracted with ethyl acetate. The organic layer thus obtained was dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the residue thus obtained was then purified by silica gel column chromatography (ethyl acetate:hexane=1:1, v/v). The solid thus obtained was washed with a mixed solution of diethyl ether and hexane, followed by collection by filtration and drying, to obtain the title compound (1.09 g, yield: 95%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][NH:20][C:21]3=[O:24])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:25]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C.C(Cl)(Cl)Cl>C(Cl)(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:23]([Cl:25])=[C:22]3[C:17]([CH2:18][CH2:19][NH:20][C:21]3=[O:24])=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)C(=O)NCC3)CC1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2Cl)C(=O)NCC3)CC1
Temperature: 90 °C
Reaction time: 1 h
Yield: 12.2 %

Procedure:
The compound (6.63 g) prepared in step (a) of Example 125 was dissolved in carbon tetrachloride (200 ml). N-Chlorosuccinimide (3.47 g) and AIBN (0.66 g) were added to the solution, and the mixture was heated at 90° C. with stirring for one hr. The temperature of the reaction solution was returned to room temperature. Chloroform was then added to the reaction solution, and the mixture was washed with water, followed by drying over anhydrous MgSO4 The solvent was then removed by distillation under the reduced pressure. The residue was crudely purified by column chromatography on silica gel (ethyl acetate). The solvent was removed by distillation under the reduced pressure. Chloroform was added to the residue, and the precipitated crystal was collected by filtration (and washed with diethyl ether) to give 7-(4-tert-butoxycarbonyl-piperazin-1-yl)-8-chloro-3,4-dihydro-2H-isoquinolin-1-one (0.89 g).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12]2[C:13](=O)[C:14](=[O:19])[C:15]=2[O:16]CC)[CH:2]=1.[C:21]([NH2:25])([CH3:24])([CH3:23])[CH3:22]>C(O)C>[C:21]([NH:25][C:13]1[C:14](=[O:19])[C:15](=[O:16])[C:12]=1[NH:11][C:3]1[CH:2]=[N:1][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)N
Reactant: CCOc1c(Nc2cnc3ccccc3c2)c(=O)c1=O
Solvent: CCO
Product: CC(C)(C)Nc1c(Nc2cnc3ccccc3c2)c(=O)c1=O
Temperature: 60 °C
Yield: 84.6 %

Procedure:
To the product from Example 13, Step 1 (0.30 g, 1.12 mmol) in ethanol (8 mL) was added tert-butylamine (0.35 mL, 3.36 mmol) and the resulting mixture was heated at 60° C. overnight. The mixture was concentrated, and the residue was dissolved in ethylacetate. Addition of hexanes induced precipitation of product which was filtered and triturated with diethylether/hexanes. Filtration and drying afforded 0.28 g (85%) of the title compound as a yellow solid, three -quarter hydrate: mp 257°-260° C.; 1H NMR (DMSO-d6) d 10.00 (br d, 1H), 8.9 (d, 1H), 8.4 (m, 1H), 8.02 (d, 1H), 7.96 (br d, 1H), 7.86 (dd, 1H), 7.66-7.54 (m, 2H), 1.45 (s, 9H). IR (KBr) 3400, 3200, 2980, 1785, 1680cm-1 ; MS (m/z) 296 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][O:5][C@H:4]([CH2:8][OH:9])[CH2:3]1.[H-].[Na+].[N+](C1C=CC([O:21][C:22]([N:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=3[F:37])[CH2:26][CH2:25]2)=O)=CC=1)([O-])=O>C1COCC1>[F:37][C:31]1[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:30]=1[N:27]1[CH2:28][CH2:29][N:24]([C:22]([O:9][CH2:8][C@H:4]2[O:5][CH2:6][CH2:7][N:2]([CH3:1])[CH2:3]2)=[O:21])[CH2:25][CH2:26]1
Reactant: CN1CCO[C@H](CO)C1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCN(c2ccc(F)cc2F)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCO[C@H](COC(=O)N2CCN(c3ccc(F)cc3F)CC2)C1
Reaction time: 0.5 h
Yield: 38.5 %

Procedure:
(S)-(4-Methylmorpholin-2-yl)-methanol (Intermediate 10; 100 mg, 0.76 mmol) was added to a suspension of NaH (60% dispersion in oil; 90.0 mg, 2.28 mmol) in anhydrous THF (7 mL) and stirred under nitrogen for 30 min. 4-(2,4-Difluorophenyl)-piperazine-1-carboxylic acid 4-nitrophenyl ester (Intermediate 12, 330 mg, 0.91 mmol) was added and the reaction mixture was stirred at room temperature for 48 h. The reaction mixture was filtered through celite and the solid washed with THF (10 mL). The filtrates were combined and the solvent removed in vacuo. The residue was purified by column chromatography (normal phase silica, 5 g Isolute-Si column, gradient 1-5% MeOH in DCM) and the solvents were removed in vacuo to give [(2S)-4-methylmorpholin-2-yl]methyl 4-(2,4-difluorophenyl)-piperazine-1-carboxylate (104 mg, 38%) as a colourless gum.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH2:7]([O:14][C:15]([NH:17][C:18]1[N:26]=[CH:25][N:24]=[C:23]2[C:19]=1[N:20]=[CH:21][N:22]2CC(O)=O)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>ClCCl>[CH2:7]([O:14][C:15]([NH:17][C:18]1[N:26]=[CH:25][N:24]=[C:23]2[C:19]=1[N:20]=[CH:21][N:22]2[CH2:1][C:2]([Cl:4])=[O:3])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cn1cnc2c(NC(=O)OCc3ccccc3)ncnc21
Solvent: ClCCl
Product: O=C(Cl)Cn1cnc2c(NC(=O)OCc3ccccc3)ncnc21
Reaction time: 2 h

Procedure:
Oxalyl chloride (6.3 g, 50 mmol) is added dropwise over 5 minutes to a solution of N6 -(benzyloxycarbonyl)-9-(carboxymethyl)adenine (16.6 g, 50 mmol) dissolved in dichloromethane (200 mL). The reaction is stirred until gas evolution has ceased and then for an additional 2 hours. The reaction mixture is evaporated to an oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([CH2:20][C:21](OCC)=[O:22])[N:9]=1.[NH:26]([CH2:30][CH2:31][OH:32])[CH2:27][CH2:28][OH:29]>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([CH2:20][C:21]([N:26]([CH2:30][CH2:31][OH:32])[CH2:27][CH2:28][OH:29])=[O:22])[N:9]=1
Reactant: CCOC(=O)Cn1nc(-c2ccccc2O)nc1-c1ccccc1O
Reactant: OCCNCCO
Solvent: CCO
Product: O=C(Cn1nc(-c2ccccc2O)nc1-c1ccccc1O)N(CCO)CCO

Procedure:
2.0 g of ethyl [3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]acetate (Example 2) and 6.5 g of diethanolamine are boiled under reflux for 2 h in 5 ml of ethanol. The mixture is cooled, poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is chromatographed on silica gel. After concentration and drying, 2-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]-N,N-bis(2-hydroxyethyl)acetamide is obtained as a colorless foam. Rf value: 0.28 (silica gel 60, methylene chloride/methanol=9/1). 1H-NMR (DMSO-d6): 3,2-3,6 (m, 8H) 4.4-5.1 (b, 2H), 5.35 (s, 2H), 7.0 (m, 4H), 7.4 (m. 3H), 7.95 (d, 1H), 10.4 (bs, 1H), 11.05 ppm (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:30]=[CH:29][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][C:17]=3Br)=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:39][S:40]([C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1)(=[O:42])=[O:41]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:30]=[CH:29][C:14]([O:15][C:16]3[C:17]([C:46]4[CH:47]=[CH:48][C:43]([S:40]([CH3:39])(=[O:42])=[O:41])=[CH:44][CH:45]=4)=[CH:18][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:20][CH:21]=3)=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(Br)c1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(-c2ccc(S(C)(=O)=O)cc2)c1
Temperature: 55 °C
Reaction time: 12 h
Yield: 43.9 %

Procedure:
Ethyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-bromophenyl)acetate (Example 46 step C; 40 mg, 0.077 mmol), K2CO3 (32 mg, 0.23 mmol) and 4-(methylsulfonyl)phenylboronic acid (23 mg, 0.12 mmol) were diluted with dioxane (1 mL)/water (300 μL) followed by the addition of Pd(PPh3)4 (8.9 mg, 0.0077 mmol). The reaction was purged with nitrogen and stirred at 55° C. for 12 hours. The reaction was cooled and concentrated. The residue was taken up in minimal DCM and purified by silica gel chromatography, eluting with hexanes:ethyl acetate (1:1) to yield ethyl 2-(6-(4-(4-chlorophenethylcarbamoyl)phenoxy)-4′-(methylsulfonyl)biphenyl-3-yl)acetate (20 mg, 44% yield) as a clear oil.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[S:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.C([O-])(=O)C.[K+]>CC(N(C)C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: c1ccsc1
Reactant: O=Cc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=Cc1ccc(-c2cccs2)cc1
Temperature: 150 °C
Reaction time: 16 h

Procedure:
3.7 g (20 mmol) of 4-bromobenzaldehyde, 9.5 ml (120 mmol) of thiophene, 2.94 g (30 mmol) of potassium acetate and 1.16 g (1 mmol) of tetrakis(triphenylphosphine)palladium (Fluka, Buchs, Switzerland) in 50 ml of dimethylacetamide are placed in a pressure reactor and stirred at 150° C. under nitrogen for 16 hours. The reaction mixture is concentrated by evaporation; the residue is taken up in water and extracted three times with methylene chloride. After removal of the solvent, the residue is chromatographed on silica gel (hexane/ethyl acetate 4:1). The title compound is obtained in the form of a yellow solid. TLC: Rf =0.36 (hexane/ethyl acetate 4:1). HPLC20-100 : tRet =15.26. 1H-NMR (CD3OD; 200 MHz): 9.98/s (1 H); 7.93 and 7.85/each d, J=9.5 (2×2 H); 7.60/d, J=2.5 (1 H); 7.52/d, J=5 (1 H); 7.17/dxd, J=2.5 and 5 (1 H).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:19][S:20]([O:1][CH2:2][C:3]1([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5]1)(=[O:22])=[O:21]
Reactant: CCOC(=O)CC1(CO)CC1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CC1(COS(C)(=O)=O)CC1
Temperature: -50 °C
Reaction time: 1 h

Procedure:
253 mg of compound 14b and 225 μl triethylamine were dissolved in 10 ml dichloromethane and cooled to −50° C. 140 μl methanesulfonylchloride was added and the mixture was stirred for one hour allowing the temperature to increase to 0° C. Saturated aqueous sodium bicarbonate was added and the mixture was extracted twice with dichloromethane. The organic extracts were combined and dried with sodium sulfate. Evaporation of the solvent gave 308 mg of the title compound as an almost colorless liquid.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35]Cl)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][N:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNC1
Reactant: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCl
Product: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCN1CCCC1
Yield: 17.1 %

Procedure:
To the intermediate 1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(2-chloro-ethoxy)-6-methoxy-quinazolin-4-ylsulfanyl]-phenyl}-urea (225 mg, 0.426 mmol) from Example 79A was added pyrrolidine (0.105 mL, 1.278 mmol) in the manner described in Example 80 to yield 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-(pyrrolidin-1-yl)ethoxy)quinazolin-4-ylthio)phenyl)urea (41 mg, 18%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.55 (s, 1H), 8.85 (s, 1H), 8.30 (s, 1H), 7.65-7.50 (m, 2H), 7.35-7.05 (m, 4H), 6.50 (s, 1H), 4.30 (m, 2H), 4.00-3.75 (m, 7H), 2.55 (m, 2H), 1.98 (m, 4H), 1.30 (s, 9H); LC-MS (ESI)m/z 563 (M+H)+.
Reaction SMILES: C([NH:8]C1C=C(C=C(S(Cl)(=O)=O)C=1C1C=CC=CC=1)C(O)=O)C1C=CC=CC=1.[CH2:28]([O:32][C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([S:48](Cl)(=[O:50])=[O:49])[C:41]=1[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]([OH:38])=[O:37])[CH2:29][CH2:30][CH3:31]>>[CH2:28]([O:32][C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([S:48](=[O:50])(=[O:49])[NH2:8])[C:41]=1[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]([OH:38])=[O:37])[CH2:29][CH2:30][CH3:31]
Reactant: O=C(O)c1cc(NCc2ccccc2)c(-c2ccccc2)c(S(=O)(=O)Cl)c1
Reactant: CCCCOc1cc(C(=O)O)cc(S(=O)(=O)Cl)c1-c1ccccc1
Product: CCCCOc1cc(C(=O)O)cc(S(N)(=O)=O)c1-c1ccccc1

Procedure:
By replacing in Example 1, step G, 3-benzylamino-5-chlorosulfonyl-4-phenylbenzoic acid with 3-n-butoxy-5-chlorosulfonyl-4-phenylbenzoic acid, and following the procedure described, 3-n-butoxy-4-phenyl-5-sulfamylbenzoic acid is obtained crystallizing with 0.25 mole of water with a melting point of 129°-131° C.