Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[C:5]([NH2:20])=[CH:4][CH:3]=1.[N:21]([O-])=O.[Na+].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C(O)(=O)C.O>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:9][C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][CH:14]=[CH:13]4)[N:21]=[N:20][C:5]2=[CH:4][CH:3]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(Cl)nc1NCc1ccc2ncccc2c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Clc1ccc2nnn(Cc3ccc4ncccc4c3)c2n1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
Intermediate 9 (0.220 g, 0.772 mmol) was dissolved in acetic acid (1.3 ml) and cooled to 5° C. Sodium nitrite (0.063 g, 0.927 mmol) in 0.35 ml water was added slowly followed by sulphuric acid (0.09 ml). The reaction mixture was warmed to RT and stirred for 30 min. The reaction mixture was poured into ice water and pH adjusted to ca. 8 with sodium bicarbonate solution, extracted with ethyl acetate, washed with brine, dried over sodium sulphate and concentrated to afford the title compound as a brown solid (0.220 g, 96%). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 8.88 (s, 1H), 8.69 (d, J=8.6 Hz, 1H), 8.35 (d, J=8.1 Hz, 1H), 8.01 (d, J=8.6 Hz, 1H), 7.90 (s, 1H), 7.74 (d, J=8.5 Hz, 1H), 7.61 (d, J=8.5 Hz, 1H), 7.53 (dd, J=8.0, 4.0 Hz, 1H), 6.12 (s, 2H).
Reaction SMILES: N12CCCN=C1CCCCC2.[C:12]([O:16][C:17]([N:19]1[C:27]2[CH:26]=[CH:25][N:24]=[CH:23][C:22]=2[CH:21]=[C:20]1[CH2:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]#[C:37][C:38]2[CH:39]=[N:40][CH:41]=[CH:42][C:43]=2[NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:31][C:30]1=[O:52])=[O:18])([CH3:15])([CH3:14])[CH3:13]>CC#N>[C:12]([O:16][C:17]([N:19]1[C:27]2[CH2:26][CH2:25][NH:24][CH2:23][C:22]=2[CH:21]=[C:20]1[CH2:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[N:44]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C:43]3[CH:42]=[CH:41][N:40]=[CH:39][C:38]=3[CH:37]=2)[CH2:31][C:30]1=[O:52])=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)Nc1ccncc1C#CCN1CCN(Cc2cc3cnccc3n2C(=O)OC(C)(C)C)C(=O)C1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)n1c(CN2CCN(Cc3cc4cnccc4n3C(=O)OC(C)(C)C)CC2=O)cc2c1CCNC2
Temperature: 50 °C
Reaction time: 4 h
Yield: 107.5 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (42 mg, 0.27 mmol) is added to a suspension containing 2-{4-[3-(4-tert-butoxycarbonylamino-pyridin-3-yl)-prop-2-ynyl]-2-oxo-piperazin-1-ylmethyl}-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (77 mg, 0.14 mmol) in anhydrous CH3CN (10 mL) and the mixture is warmed to 50° C. After 4 h, the reaction mixture is concentrated to dryness and the residue is partitioned between CH2Cl2 (50 mL) and water (50 mL) and the layers are separated. The aqueous layer is extracted twice with CH2Cl2 (25 mL) and the combined organic phase is washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to provide 85 mg of the title compound as a crude solid which is used directly without further purification. 1H NMR (300 MHz, CDCl3) δ1.68 (s, 9H), 1.70 (s, 9H), 2.91 (m, 2H), 3.41 (s, 2H), 3.49 (m, 2H), 4.26 (s, 2H), 4.95 (d, J=1.1 Hz, 2H), 6.39 (d, J=0.7 Hz, 1H), 6.68 (d, J=0.7 Hz, 1H), 7.86 (m, 1H), 8.41 (m, 1H), 8.76 (br s, 1H), 8.82 (br s, 1H) ppm: MS (EI): m/z 561 (M+H).
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[CH:6]=1)[CH2:3][OH:4].C(N(CC)CC)C.[Cl:20][CH2:21][C:22](Cl)=[O:23]>C(Cl)Cl>[Cl:20][CH2:21][C:22]([NH:1][C@H:2]([C:5]1[CH:6]=[C:7]([F:12])[CH:8]=[C:9]([F:11])[CH:10]=1)[CH2:3][OH:4])=[O:23]
Reactant: N[C@@H](CO)c1cc(F)cc(F)c1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)N[C@@H](CO)c1cc(F)cc(F)c1
Reaction time: 0.33 h

Procedure:
To a solution of (2R)-2-amino-2-(3,5-difluorophenyl)ethanol from Step B (630 mg, 3.64 mmol) and triethylamine (0.51 mL, 3.64 mmol) in CH2Cl2 (40 mL) at 0° C. was added chloroacetyl chloride (0.29 mL, 3.64 mmol). After 20 min, the reaction mixture was quenched with saturated aqueous NaHCO3 (15 mL) and extracted with CH2Cl2 (2×25 mL). The combined organic extracts were washed with 10% citric acid, then brine, then dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=250 (M+1).
Reaction SMILES: [BH4-].[Na+].[NH2:3][C:4]1[C:9]([C:10](=[O:16])[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])=[CH:8][C:7]([Br:17])=[CH:6][N:5]=1>CO>[NH2:3][C:4]1[C:9]([CH:10]([OH:16])[C:11]([N:13]([CH3:14])[CH3:15])=[O:12])=[CH:8][C:7]([Br:17])=[CH:6][N:5]=1
Reactant: CN(C)C(=O)C(=O)c1cc(Br)cnc1N
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(C)C(=O)C(O)c1cc(Br)cnc1N
Reaction time: 0.08 h
Yield: 56.9 %

Procedure:
Sodium borohydride (85.5 mg, 2.25 mmol) was added to methanol (5 mL) at 0° C. After 5 min, 2-(2-amino-5-bromo-pyridin-3-yl)-N,N-dimethyl-2-oxo-acetamide (408 mg, 1.50 mmol) in MeOH (15 mL) was added. After 1 h, the reaction was quenched by addition of saturated NH4Cl and the mixture was concentrated in vacuo. The residue was extracted with ethyl acetate, dried over Na2SO4 and purified by silica gel chromatography using DCM and MeOH to afford 2-(2-amino-5-bromo-pyridin-3-yl)-2-hydroxy-N,N-dimethyl-acetamide (234 mg, 57.1%) as a brown oily solid. The material was used in the next step. MS: m/z 274 (M+H+).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:12]2[N:11]([CH3:13])[C:10]3[CH2:14][CH2:15][NH:16][C:17](=[O:18])[C:9]=3[C:8]=2[CH:7]=[CH:6][CH:5]=1.Cl[CH2:20][C:21]1[O:25][CH:24]=[N:23][C:22]=1[CH3:26].O>COCCOC>[F:3][C:4]1[C:12]2[N:11]([CH3:13])[C:10]3[CH2:14][CH2:15][N:16]([CH2:20][C:21]4[O:25][CH:24]=[N:23][C:22]=4[CH3:26])[C:17](=[O:18])[C:9]=3[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1ncoc1CCl
Reactant: Cn1c2c(c3cccc(F)c31)C(=O)NCC2
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ncoc1CN1CCc2c(c3cccc(F)c3n2C)C1=O
Reaction time: 6 h
Yield: 76.6 %

Procedure:
Sodium hydride (73% dispersion in oil; 167 mg) was added to a stirred suspension of 6-fluoro-2,3,4,5-tetrahydro-5-methyl-1H-pyrido[4,3-b]indol-1-one (500 mg) in dry DME (150 ml), and the suspension was stirred at 60° under nitrogen for 6 h. 5-Chloromethyl-4-methyloxazole (440 mg) was then added and the mixture was stirred overnight at 60°. A further quantity of sodium hydride (73% dispersion in oil; 84 mg) was added and the mixture was stirred for 3 h, and then cooled (0°). Water (200 ml) was added, and the mixture was extracted with dichloromethane (3×200 ml). The combined organic extracts were concentrated in vacuo and the residue was purified by FCC eluting with System A (100:8:1) to give the title compound (550 mg) as a solid, m.p. 158°-161°.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][N:6]=1>C(O)C>[NH:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][N:6]=1)[NH2:3]
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNc1ccc(C(=O)O)cn1
Yield: 71 %

Procedure:
Hydrazine monohydrate (101 g) was added to a solution of 6-chloronicotinic acid (20 g) in ethanol (20 ml) at room temperature and stirred under reflux. After completion of the reaction, the solvent was evaporated, ethanol was added and the solid was collected by filtration to give 6-hydrazinonicotinic acid (13.8 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:6])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: C1CCNCC1
Agent: ClCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)c1ccc(C(=O)N2CCCCC2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, piperidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 4.45 minutes; C22H22Cl2N4O2 (445.35); mass spectrum: (M−H)−=444/446/448 (chlorine isotope).
Reaction SMILES: [N:1]1([NH:7][C:8]([C:10]2[C:14]([NH2:15])=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:12]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[N:11]=2)=[O:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:30](OC(OCC)OCC)C>C1(C)C=CC=CC=1.O>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:13]2[N:12]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[N:11]=[C:10]3[C:8](=[O:9])[N:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[CH:30]=[N:15][C:14]=23)=[CH:21][CH:20]=1
Reactant: CCOC(OCC)OCC
Reactant: Nc1c(C(=O)NN2CCOCC2)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=c1c2nn(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2ncn1N1CCOCC1
Temperature: 25 °C

Procedure:
A solution of 4-amino-1-(2-chlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylic acid morpholin-4-ylamide (I-10A-1a, 200 mg, 0.46 mmol) and triethylorthoformate (116 microliters, 0.7 mmol) in toluene (2.5 ml) was heated at 100° C. for 0.45 h and at 120° C. for 2 h. The reaction mixture was cooled to room temperature, diluted with H2O, and extracted with EtOAc (2×). The combined organic extracts were washed with 1 M K2CO3 and saturated aqueous brine, dried, and concentrated under vacuum. The crude residue was purified via radial chromatography (1 mm plates, 50% EtOAc/hexanes as eluant) to give the desired product 10A-1 as an amorphous solid: MS 442.1 (M+1)+; 1H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.53–7.50 (m, 1H), 7.47–7.39 (m, 3H), 7.35–7.28 (m, 4H), 4.25 (bm, 2H), 3.95 (bm, 2H), 3.75 (bm, 2H), 3.00 (bm, 2H).
Reaction SMILES: [N:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:12]1[CH:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([S:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=2[F:29])[N:13]=1>>[F:29][C:23]1[C:24]([F:28])=[CH:25][CH:26]=[CH:27][C:22]=1[CH2:21][S:20][C:14]1[N:13]=[C:12]([NH:10][S:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)(=[O:9])=[O:8])[CH:17]=[C:16]([O:18][CH3:19])[N:15]=1
Reactant: NS(=O)(=O)N1CCOCC1
Reactant: COc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Product: COc1cc(NS(=O)(=O)N2CCOCC2)nc(SCc2cccc(F)c2F)n1

Procedure:
The title compound was prepared from morpholine-4-sulfonamide (prepared according to patent WO 2004/011443, 0.20 g) and 4-Chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-methoxypyrimidine (the product of Example 35, step i) (0.25 g) according to the procedure outlined in Example 1, step iv). The crude material was purified by column chromatography using EtOAc/isohexane (2:8) as eluent. Yield: 0.26 g.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([CH3:31])=[C:20]([C:32]([OH:34])=O)[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.[NH2:35][C@H:36]1[CH2:41][CH2:40][C@H:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:38][CH2:37]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:29])([CH3:30])[CH3:28])[C:21]([CH3:31])=[C:20]([C:32]([NH:35][C@H:36]4[CH2:41][CH2:40][C@H:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:47])([CH3:46])[CH3:48])[CH2:38][CH2:37]4)=[O:34])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c1
Product: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-ethylphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c14) and commercially available tert-butyl trans-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow foam.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]O)=[CH:20][CH:19]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].CN(C=O)C>C(Cl)Cl>[CH2:5]([O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][Cl:3])=[CH:20][CH:19]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCCCCOc1ccc(CO)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCOc1ccc(CCl)cc1
Reaction time: 0.12 h

Procedure:
Thionyl chloride (38.8 g, 328 mmol) was added dropwise to a 0° C. solution of 4-Dodecyloxybenzyl alcohol (80.0 g, 274 mmol) in dry CH2Cl2 (900 mL) with a catalytic amount of DMF. Upon addition, reaction was allowed to stir for 5-10 minutes, while monitoring through TLC (CH2Cl2) for completion. Reaction mixture was concentrated under reduced pressure and the resulting residue re-crystallized from acetone to give the title benzyl chloride, decomposes upon melting. 77g (92%).
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH:17]=O.[OH-].[Na+]>CO>[Cl:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:2][C:1]([C:4]2[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=2)=[O:3])[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(C(=O)C=Cc2ccc(Cl)c(Cl)c2)cc1
Reaction time: 19 h
Yield: 96 %

Procedure:
To a stirred suspension at room temperature of 4-acetylbenzoic acid (1.71 g, 10.44 mmol), 3,4-dichlorobenzaldehyde (2.05 g, 11.49 mmol) or aldehyde (1.1 equiv.) in MeOH (50 ml) was added a solution of NaOH (26.1 ml, 1N in H2O). After 19 h, the reaction mixture was filtered off, rinsed with MeOH and dried to afford the title compound IIa (3.22 g, 10.03 mmol, 96% yield) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ(ppm): 8.35 (s, 1H), AB system (δA=8.13, δB=8.01, J=8.4 Hz, 4H), 8.12 (d, J=15.8 Hz, 1H), 7.93 (d, J=7.9 Hz, 1H), 7.76 (d, J=8.3 Hz, 1H, 7.73 (d, 15.8 Hz, 1H).
Reaction SMILES: [C:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1[C:17]([OH:19])=[O:18])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:20][Si](C=[N+]=[N-])(C)C>C(Cl)Cl.CO>[C:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1[C:17]([O:19][CH3:20])=[O:18])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C1c2ccccc2CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of N-BOC-1,3-dihydro-2H-isoindol-1-carboxylic acid (SNPE, 10 g, 38 mmol) in CH2Cl2 (100 mL) and MeOH (100 mL) at 0° C. was added trimethylsilyldiazomethane dropwise until the yellow color persisted. After stirring at rt for 15 min, the reaction mixture was concentrated in vacuo. The residue was azeotroped with toluene to afford N-BOC-1,3-dihydro-2H-isoindol-1-carboxylic acid, methyl ester which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:13]2[C:21]3[C:16](=[C:17]([N:22]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[S:23]([CH3:26])(=[O:25])=[O:24])[CH:18]=[CH:19][CH:20]=3)[CH:15]=[N:14]2)([CH2:11][CH3:12])[CH2:9][OH:10])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:13]2[C:21]3[C:16](=[C:17]([N:22]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:32])[CH3:34])[S:23]([CH3:26])(=[O:24])=[O:25])[CH:18]=[CH:19][CH:20]=3)[CH:15]=[N:14]2)([CH2:11][CH3:12])[CH:9]=[O:10])=[CH:4][CH:3]=1
Reactant: CCC(CO)(c1ccc(Cl)cc1)n1ncc2c(N(COCC[Si](C)(C)C)S(C)(=O)=O)cccc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O
Solvent: ClCCl
Product: CCC(C=O)(c1ccc(Cl)cc1)n1ncc2c(N(COCC[Si](C)(C)C)S(C)(=O)=O)cccc21
Reaction time: 1.5 h

Procedure:
A solution of N-(1-(2-(4-chlorophenyl)-1-hydroxybutan-2-yl)-1H-indazol-4-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)methanesulfonamide (560 mg, 1.07 mmol) in DCM (10 mL) was added to Dess-Martin periodinane (590 mg, 1.39 mmol) in portion at 0° C. and stirred for 1.5 h. The mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography (PE/EA=8/1) to afford the title compound as a yellow solid. LC/MS m/z=522.1 [M+H]+.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:10](OC(=O)C)(=[O:12])[CH3:11].[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10](=[O:12])[CH3:11])[CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc2c(c1)CCC2
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)CCC2
Temperature: 25 °C
Reaction time: 15 h
Yield: 88.1 %

Procedure:
A mixture of 2,3-dihydro-1H-indene (100.0 g, 0.85 mol) and acetic anhydride (104.2 g, 1.35 mol) was added drop-wise to a slurry of AlCl3 (272.0 g, 2.04 mol) in CH2Cl2 (1000 ml) at 0° C. over a period of 3 h. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 15 h. Then the reaction mixture was poured into ice water (500 mL) and extracted with ethyl acetate (500 mL×3). The combined organic layers were washed with brine (500 mL), dried over Na2SO4 and evaporated in vacuo. The residue that was purified by column chromatography (petroleum ether:ethyl acetate=20:1) to give the product (120.0 g, 88%). 1H NMR (400 MHz, CDCl3) δ 2.08-2.15 (m, 2H), 2.58 (s, 3H), 2.95 (t, J=7.2, 4H), 7.28 (d, J=8.0, 1H), 7.75 (d, J=8.0, 1H) 7.82 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[Cl:13]N1C(=O)CCC1=O>CN(C=O)C>[Cl:13][C:6]1[C:2]([CH3:1])=[C:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:4][C:5]=1[CH3:7]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1[nH]c(C)cc1C
Solvent: CN(C)C=O
Product: CCOC(=O)c1[nH]c(C)c(Cl)c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 29 %

Procedure:
To a solution of ethyl 3,5-dimethyl-1H-pyrrole-2-carboxylate (0.100 g, 0.598 mmol) in DMF (2 ml) was added N-chlorosuccinimide (0.120 g, 0.897 mmol). The reaction mixture was stirred at RT for 4 h. The solvent was evaporated and purification by column chromatography (hexanes/EtOAc) afforded ethyl 4-chloro-3,5-dimethyl-1H-pyrrole-2-carboxylate (0.035 g, 29%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.68 (br. s., 1H) 4.22 (q, 2H) 2.19 (s, 3H) 2.15 (s, 3H) 1.28 (t, 3H). MS: m/z 202.3 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([CH2:10][NH2:11])[N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]1[CH:21]=[C:22]([NH:29][C:30](=O)[O:31]C2C=CC=CC=2)[CH:23]=[CH:24][C:25]=1[CH2:26][CH2:27][OH:28]>CC#N>[C:1]([C:5]1[CH:9]=[C:8]([CH2:10][NH:11][C:30]([NH:29][C:22]2[CH:23]=[CH:24][C:25]([CH2:26][CH2:27][OH:28])=[C:20]([F:19])[CH:21]=2)=[O:31])[N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(CN)n(-c2cccc(Cl)c2)n1
Reactant: O=C(Nc1ccc(CCO)c(F)c1)Oc1ccccc1
Solvent: CC#N
Product: CC(C)(C)c1cc(CNC(=O)Nc2ccc(CCO)c(F)c2)n(-c2cccc(Cl)c2)n1
Reaction time: 16 h
Yield: 92.3 %

Procedure:
To a stirred solution of (3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methanamine (synthesis described for example A141) (102 mg, 0.387 mmol, 1.0 eq) in MeCN (9 mL) was added TEA (0.214 mL, 1.55 mmol, 4.0 eq) followed by phenyl 3-fluoro-4-(2-hydroxyethyl)phenylcarbamate (108 mg, 0.395 mmol, 1.02 eq) and the mixture was stirred for 16 h at reflux. The reaction mixture was concentrated under vacuum and the residue purified by CC using EtOAc/hexane (2:1) as eluent to get 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(3-fluoro-4-(2-hydroxyethyl)phenyl)urea (159 mg; 92%, white solid).
Reaction SMILES: C(O[CH:6]([O:17]CCCC)[C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[N+:14]([O-])=O)CCC.[CH:22]([Mg]Br)=[CH2:23].[Cl-].[NH4+]>O1CCCC1>[CH3:13][C:11]1[CH:10]=[C:9]2[C:8](=[C:7]([CH:6]=[O:17])[CH:12]=1)[NH:14][CH:23]=[CH:22]2
Reactant: C=C[Mg]Br
Reactant: CCCCOC(OCCCC)c1cc(C)ccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(C=O)c2[nH]ccc2c1
Temperature: -40 °C
Reaction time: 0.67 h

Procedure:
Dissolve 2-Dibutoxymethyl-4-methyl-1-nitrobenzene (13.957 g, 47.373 mmol) in anhydrous tetrahydrofuran (474 mL) under nitrogen, and cool the solution to −40° C. Add vinylmagnesium bromide (190 mL, 190 mmol, 1.0 M in tetrahydrofuran) at 40° C. with stirring. Stir the reaction mixture for 40 minutes and add saturated aqueous ammonium chloride. Extract the aqueous layer with ethyl acetate. Combine the organic layers, dry over sodium sulfate, filter, and concentrate. Dissolve the residue in tetrahydrofuran (160 mL) and cool to 0° C. Add aqueous 0.5 molar hydrochloric acid (20 mL) and stir the mixture at 0° C. for 1 hour. Add saturated aqueous sodium hydrogen carbonate (200 mL) and extract the aqueous layer with ethyl acetate (3×200 mL). Combine the organic layers, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure and purify by flash column chromatography (silica gel, 5% ethyl acetate/hexane) to give the title compound as a white solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)[CH2:3][CH2:2]1.[N:14]1([S:20](Cl)(=[O:22])=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH:1]1([CH2:4][O:5][CH2:6][C:7]2[CH:8]=[CH:9][C:10]([NH:13][S:20]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)(=[O:22])=[O:21])=[N:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)N1CCCCC1
Reactant: Nc1ccc(COCC2CC2)cn1
Product: O=S(=O)(Nc1ccc(COCC2CC2)cn1)N1CCCCC1

Procedure:
This material was prepared in analogy to example 1 from 5-cyclopropylmethoxymethyl-pyridin-2-ylamine (0.089 g) and piperidine-1-sulfonyl chloride (0.142 g) as a light yellow gum (0.027 g). MS (ESI−): 324.2 ([M−H]−)
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl.[O:22]1[C:26]2[CH2:27][NH:28][CH2:29][CH2:30][C:25]=2[CH:24]=[CH:23]1>CCOCC.CS(Cl)(=O)=O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:28]2[CH2:29][CH2:30][C:25]3[CH:24]=[CH:23][O:22][C:26]=3[CH2:27]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCCCCCCc1ccccc1
Reactant: c1cc2c(o1)CNCC2
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: c1ccc(CCCCCCN2CCc3ccoc3C2)cc1
Reaction time: 0.17 h

Procedure:
To a solution of 0.39 g (2.2 mmol) of 6-phenylhexan-1-ol and 0.38 ml (2.7 mmol) of triethylamine in 20 ml of ether, methanesulfonyl chloride was added dropwise under ice-cooling, followed by stirring for 10 minutes. The ether solution was washed with water and saturated aqueous sodium chloride, after which it was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The residual oil (crude 6-phenylhexyl methanesulfonate) was dissolved in 30 ml of acetonitrile; 0.289 g (1.811 mmol) of 4,5,6,7-tetrahydrofuro[2,3-c]pyridine hydrochloride and 0.76 ml (5.4 mmol) of triethylamine were added, followed by refluxing for 3 hours. The solvent was distilled off from the reaction mixture under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=6/1) to yield the desired product.