Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[S:9]([CH2:12][C:13](=[O:15])[CH3:14])(=[O:11])=[O:10])=[CH:4][CH:3]=1.C1C=C[NH+]=CC=1.[Br:29][Br-]Br>C(O)(=O)C.ClCCl.C(OCC)(=O)C>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[S:9]([CH2:12][C:13](=[O:15])[CH2:14][Br:29])(=[O:10])=[O:11])=[CH:21][CH:20]=1
Reactant: CC(=O)CS(=O)(=O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(CBr)CS(=O)(=O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.9 %

Procedure:
To a solution of 1-[bis-(4-chloro-phenyl)-methanesulfonyl]-propan-2-one (Example 1, 0.63 g, 1.7 mmol) in a mixture of 10 mL of acetic acid and 60 mL of dichloromethane was added pyridine hydrobromide perbromide (0.62 g, 1.9 mmol) using a procedure such as those described in Grossert J. S. et al., Can. J. Chem. 1984; 62:798. The reaction mixture was stirred at room temperature for 18 hours and then evaporated to give an oil. The oil was dissolved in 200 mL of ethyl acetate, washed with three 50 mL portions of 5% aqueous sodium bicarbonate and then with 50 mL of brine. The organic layer was separated, dried (sodium sulfate), filtered, and then evaporated to afford an oil, which was chromatographed (silica gel, eluting with 30% ethyl acetate in hexane) to give 0.37 g (48%) of a white solid with mp 122–123° C.; 1H NMR (deuterochloroform): δ 4.03 (s, 2H), 4.09 (s, 2H), 5.64 (s, 1H), 7.33–7.41 (m, 4H), 7.51–7.58 (m, 4H); ms: m/z 435 (m−1) APCI-.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH:18]1([C:23](O)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([C:23]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C(O)C1CCCC1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)C4CCCC4)cc23)CC1

Procedure:
Beginning with 12.0 mg (0.05 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 11.0 mg (0.10 mMol) cyclopentanecarboxylic acid, 16.4 mg (100+%) of the title compound were recovered.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=2[C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[CH2:19][CH2:20][NH:21][CH2:22]3)=[CH:5][CH:4]=[N:3]1.O=C1N([S:33]([NH:36][C:37]2[N:42]=[CH:41][CH:40]=[CH:39][N:38]=2)(=[O:35])=[O:34])CCO1.C(N(CC)CC)C>C(#N)C>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:14])[F:15])[CH:10]=[CH:9][C:8]=2[C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[CH2:19][CH2:20][N:21]([S:33]([NH:36][C:37]2[N:42]=[CH:41][CH:40]=[CH:39][N:38]=2)(=[O:35])=[O:34])[CH2:22]3)=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1-c1cc(C(F)(F)F)ccc1-c1cccc2c1CCNC2
Reactant: O=C1OCCN1S(=O)(=O)Nc1ncccn1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cn1nccc1-c1cc(C(F)(F)F)ccc1-c1cccc2c1CCN(S(=O)(=O)Nc1ncccn1)C2
Temperature: 130 °C
Yield: 41.7 %

Procedure:
A microwave vial was charged with 5-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (Intermediate O, 55.90 mg, 0.156 mmol), 2-oxo-N-(pyrimidin-2-yl)oxazolidine-3-sulfonamide (Intermediate Q, 96 mg, 0.391 mmol), and acetonitrile (587 μl) to give a suspension. Triethylamine (218 μl, 1.564 mmol) was added resulting in the formation of a yellow solution. The vial was sealed and heated in a microwave reactor for 30 min at 130° C. The mixture was concentrated, then chromatographed on a 12 g silica gel column with 0 to 10% MeOH/DCM to provide 5-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (33.42 mg, 0.065 mmol) as a light-yellow solid. [M+H]+=515.2. 1H NMR (400 MHz, DMSO-d6) δ ppm=11.19 (br. s., 1H), 8.48 (d, J=4.9 Hz, 2H), 7.88 (dd, J=1.4, 8.1 Hz, 1H), 7.83 (br. s, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.22 (d, J=2.0 Hz, 1H), 7.20-7.10 (m, 2H), 7.03 (t, J=4.8 Hz, 1H), 6.89 (dd, J=1.3, 7.4 Hz, 1H), 5.88 (d, J=1.9 Hz, 1H), 4.62-4.49 (m, 2H), 3.59-3.52 (m, 1H), 3.48 (s, 3H), 3.23 (ddd, J=4.3, 8.0, 12.4 Hz, 1H), 2.59 (ddd, J=4.9, 8.3, 16.1 Hz, 1H), 2.28-2.19 (m, 1H).
Reaction SMILES: [Cl:1]C1C=CC(C[C:7]2[C:16]([C:17]([NH2:19])=[O:18])=[C:15]([OH:20])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:21]#[C:22][CH2:23][OH:24])[CH:13]=3)[N:8]=2)=CC=1.C([O-])([O-])=O.[K+].[K+].[ClH:33].[CH:34]([N:37]([CH2:41][CH2:42]Cl)[CH:38](C)C)(C)C.O>CN(C=O)C>[ClH:1].[Cl:33][C:9]1[CH:14]=[CH:13][C:12]([CH2:21][NH:19][C:17]([C:16]2[C:15](=[O:20])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:21]#[C:22][CH2:23][OH:24])[CH:13]=3)[N:8]([CH2:42][CH2:41][N:37]([CH3:34])[CH3:38])[CH:7]=2)=[O:18])=[CH:11][CH:10]=1
Reactant: CC(C)N(CCCl)C(C)C
Reactant: NC(=O)c1c(Cc2ccc(Cl)cc2)nc2ccc(C#CCO)cc2c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)ccc21
Temperature: 95 °C
Reaction time: 8 h

Procedure:
A solution of N-(4-chlorobenzyl-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide from Preparation No. 5 (0.515 g) is dissolved in DMF (10 mL), and K2CO3 (0.778 g) and diisoproplyaminoethyl chloride-hydrochloride (0.56 g) are added. The reaction mixture is heated to 95° C. for 14 h, then allowed to stir at room temperature overnight. The mixture is then poured into H2O and an oil formed, which is isolated by decanting the liquid. The oil is dissolved in MeOH/CH2Cl2, and etheral HCl is added to adjust the pH to 2. The mixture is concentrated in vacuo to give the title compound as the hydrochloride salt.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1.Br[CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.O>CN(C=O)C>[C:8]([C:7]1[CH:10]=[CH:11][C:4]([O:3][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:16][CH2:15]2)=[CH:5][CH:6]=1)#[N:9]
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Reactant: N#Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64.6 %

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil; 316 mg, 7.91 mmol) in DMF (10 mL) was added in portions 4-hydroxybenzonitrile (856 mg, 7.19 mmol). After stirring for 15 min at rt, tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (2.00 g, 7.19 mmol) was added, and the reaction mixture was stirred at 80° C. for 1 h and at 150° C. for a further 1 h. After cooling to rt, water was added, and the mixture was stirred for 15 min. The solid was filtered off, water was added again, and the mixture was stirred for further 15 min and then filtered again. This procedure was repeated once again. Finally, the solids obtained were dried in vacuo to give the title compound (1.47 g, 59%): ES-MS m/z 317, HPLC RT (Method F) 2.54 min.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]([CH3:20])[C:3]1=[O:21].[S:22]1[CH:26]=[CH:25][C:24]([C:27](Cl)=[O:28])=[CH:23]1>>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]1[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]([CH3:20])[C:3](=[O:21])[CH:2]([NH:1][C:27]([C:24]2[CH:25]=[CH:26][S:22][CH:23]=2)=[O:28])[N:8]=1
Reactant: O=C(Cl)c1ccsc1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2F)c2ccccc21
Product: CN1C(=O)C(NC(=O)c2ccsc2)N=C(c2ccccc2F)c2ccccc21

Procedure:
The procedure of Example 134 was carried out using equivalent amounts of 3(R,S)-amino-1,3-dihydro- 1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one and 3-thiophenecarbonyl chloride. The product was purified by chromatography on silica gel (5% (v/v) Et2O in CH2Cl2 elution). The combined product fractions were evaporated to dryness in vacuo to give the title compound which was dried at 65° C.
Reaction SMILES: [C:1]([O:5][OH:6])([CH3:4])([CH3:3])[CH3:2].[C:7](O)(=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9]>C(CC(C)(C)C)(C)C>[C:7]([O:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OO
Reactant: CC(C)(C)C(=O)O
Solvent: CC(C)CC(C)(C)C
Product: CC(C)(C)OOC(=O)C(C)(C)C

Procedure:
To a reaction vial with a TEFLON fluoropolymer magnetic stirring rod, 3 ml containing 0.2 M tert-butyl hydroperoxide and 0.2 M pivalic acid in isooctane was added. The reaction was started by addition of 200 mg of Rhizomucor miehei enzyme and about 10 mg of molsieves (3 grains). After sixty-seven hours, 13% conversion to tert-butyl peroxypivalate was obtained as measured with GC.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].I[CH3:19]>CN(C)C=O>[C:3]([O:7][C:8]([N:10]([CH3:19])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: Cc1cccc(NC(=O)OC(C)(C)C)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(N(C)C(=O)OC(C)(C)C)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 472.4 %

Procedure:
To a suspension of NaH (2.63 g 6.6 mmol) in 200 mL of N,N-dimethylformamide at 0° C. was added a solution of (tert-butoxy)-N-[6-methyl-(2-pyridyl)]carboxamide (12.3 g, crude), as prepared in the preceding step, in 50 mL of N,N-dimethylformamide. The reaction stirred at 0° C. for 15 min then at ambient temperature for 1 h. Then iodomethane (10.22 g, 7.2 mmol) was added and the mixture was stirred at ambient temperature overnight (16 h). The reaction mixture was concentrated in vacuo, diluted with saturated NH4Cl (400 mL), and extracted with ethyl acetate (2×250 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography on silica gel (10% ethyl acetate in hexane) to give the title compound as a yellow oil (7.56 g, 57%). 1H-NMR (400 MHz, DMSO-d6) δ 7.63 (t, J=7.2 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H), 6.97 (d, J=6.9 Hz, 1H), 3.27 (s, 2H), 2.42 (s, 3H), 1.45 (s, 9H).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2([C:23]3[C:14](=[CH:15][C:16]4[O:21][CH2:20][CH2:19][O:18][C:17]=4[CH:22]=3)[O:13][CH2:12]2)[C:4]1=[O:24].Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27]>CN(C)C=O>[O:24]=[C:4]1[C:5]2([C:23]3[C:14](=[CH:15][C:16]4[O:21][CH2:20][CH2:19][O:18][C:17]=4[CH:22]=3)[O:13][CH2:12]2)[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:3]1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: CCOC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)N1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.6 %

Procedure:
To a cooled (0° C.) suspension of sodium hydride (60% w/w in mineral oil, 0.16 g, 3.7 mmol) in anhydrous N,N-dimethylformamide (30 mL) was added 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.99 g, 3.39 mmol), followed by ethyl chloroformate (0.35 mL, 3.7 mmol). The reaction mixture was stirred at ambient temperature for 18 h and was concentrated in vacuo. The residue was purified by column chromatography and eluted with a 5% to 66% gradient of ethyl acetate in hexanes to afford ethyl 2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-1′(2′H)-carboxylate (0.68 g, 55%) as a colourless solid: mp 198-200° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ7.96 (d, J=7.7 Hz, 1H), 7.39-7.34 (m, 1H), 7.19-7.18 (m, 2H), 6.50 (s, 1H), 6.27 (s, 1H), 4.93 (d, J=9.1 Hz, 1H), 4.63 (d, J=9.1 Hz, 1H), 4.49 (q, J=7.1 Hz, 2H), 4.21-4.18 (m, 2H), 4.13-4.10 (m, 2H) 1.45 (t, J=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ175.7, 155.1, 150.8, 144.9, 138.7, 138.4, 130.7, 129.2, 125.5, 123.8, 121.0, 115.2, 111.7, 99.4, 80.8, 64.5, 63.9, 63.7, 58.6, 14.2; MS (ES+) m/z 367.7 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([C:8]2[CH:27]=[CH:26][C:11]([CH2:12][S:13][C:14]3[N:15]=[C:16]4[CH:25]=[CH:24][CH:23]=[CH:22][N:17]4[C:18](=[O:21])[C:19]=3[CH3:20])=[CH:10][CH:9]=2)=[O:7])=[CH:4][N:3]=1.[N:30]1([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[ClH:1].[ClH:1].[ClH:1].[CH3:20][C:19]1[C:18](=[O:21])[N:17]2[CH:22]=[CH:23][CH:24]=[CH:25][C:16]2=[N:15][C:14]=1[S:13][CH2:12][C:11]1[CH:26]=[CH:27][C:8]([C:6](=[O:7])[C:5]2[CH:28]=[CH:29][C:2]([N:39]3[CH2:40][CH2:41][CH:36]([N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)[CH2:37][CH2:38]3)=[N:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: Cc1c(SCc2ccc(C(=O)c3ccc(Cl)nc3)cc2)nc2ccccn2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(SCc2ccc(C(=O)c3ccc(N4CCC(N5CCCCC5)CC4)nc3)cc2)nc2ccccn2c1=O
Product: Cl
Yield: 18.6 %

Procedure:
A solution of 2-[4-(6-chloronicotinoyl)benzylthio]-3-methyl-4H-pyrido[1,2-a]-pyrimidin-4-one (287 mg), 4-piperidinopiperidine (137 mg) and potassium carbonate (194 mg) in DMF (10 ml) was stirred at 80° C. for 24 hours. This reaction mixture was concentrated and the residue was dissolved in chloroform. The solution was washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (chloroform-methanol =9:1) and treated with hydrogen chloride/ethyl acetate to provide the title compound as colorless solid (28 mg).
Reaction SMILES: [C:1]1([C:7]#[C:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrCCC1C=CC=[C:20]2[C:21]([NH:23]C(=O)C=12)=O.C([O-])([O-])=O.[K+].[K+]>C(#N)C.C(OCC)(=O)C>[C:1]1([C:7]#[C:8][CH:9]2[CH2:10][CH2:11][N:12]([CH2:20][CH2:21][NH2:23])[CH2:13][CH2:14]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1NC(=O)c2c(CCBr)cccc21
Reactant: C(#CC1CCNCC1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: NCCN1CCC(C#Cc2ccccc2)CC1
Reaction time: 3 h

Procedure:
4-(Phenylethynyl)piperidine (0.5 mmol, 92 mg) was dissolved in acetonitrile (anhydrous 4 Å, 4 mL) together with bromoethylphtalimide (0.5 mmol, 128 mg) and K2CO3 (2 mmol, 276 mg). The reaction mixture was heated to reflux for 3 hours, diluted with ethyl acetate (50 mL) and washed with HCl/aq (1M, 50 mL). The organic phase was dried over Na2SO4, filtered and evaporated to dryness. The protection group was removed by stirring the compound in methylamine (33% in ethanol, 5 mL) for another 3 hours. The mixture was evaporated, diluted with ethyl acetate (50 mL) and washed with NaOH (1M, 50 mL). The organic phase was dried over Na2SO4, filtered and evaporated to dryness. The crude product was used without further purification.
Reaction SMILES: [CH2:1]([C@@H:3]1[O:5][CH2:4]1)[Cl:2].F[C:7](F)(F)C(O)=O.[N:13]1([S:19](N)(=[O:21])=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>C(O)C>[Cl:2][CH2:1][C@H:3]([OH:5])[CH2:4][N:16]1[CH2:17][CH2:18][N:13]([S:19]([CH3:7])(=[O:21])=[O:20])[CH2:14][CH2:15]1
Reactant: O=C(O)C(F)(F)F
Reactant: NS(=O)(=O)N1CCNCC1
Reactant: ClC[C@H]1CO1
Solvent: CCO
Product: CS(=O)(=O)N1CCN(C[C@@H](O)CCl)CC1
Reaction time: 18 h
Yield: 61.7 %

Procedure:
(R)-Epichlorohydrin (3.10 mL, 39.5 mmol) was added to a stirred solution of piperazine sulfonamide trifluoroacetic acid (10.0 g, 35.9 mmol) and NN-diisopropyl-ethylamine (6.26 mL, 35.9 mmol) in ethanol (150 mL) at room temperature. The reaction mixture was stirred for 18 h and a further amount of (R)-epichlorohydrin was added (0.28 mL, 3.6 mmoL) and stirred for an additional 3 h. The reaction mixture was concentrated under vacuum and the white solid was suspended in ethanol (150 mL) and stirred for 2 days. The solid was collected by filtration and washed with cold ethanol to yield (R)-1-chloro-3-(4-methylsulfonyl-1-piperazinyl)-2-propanol (5.69 g) as a white solid which was used without further purification. (m/z): [M+H]+ calcd for C8H17ClN2O3S, 257.07; found 257.2. 1H-NMR (DMSO-d6): δ (ppm) 2.37 (dd, 1H), 2.45 (dd, 1H), 2.50-2.58 (m, 4H), 2.86 (s, 3H), 3.09 (m, 4H), 3.55 (dd, 1H), 3.65 (dd, 1H), 3.84 (m, 1H), 5.09 (d, 1H).
Reaction SMILES: [C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](O)([C:17]3[CH:26]=[CH:25][C:20]4[O:21][CH2:22][CH2:23][O:24][C:19]=4[C:18]=3[OH:27])[C:9]2=[O:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C2C=1C(O)(C1C(O)=CC3OCCC=3C=1)C(=O)N2C(C1C=CC=CC=1)C1C=CC=CC=1>>[C:30]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[CH:26]=[CH:25][C:20]4[O:21][CH2:22][CH2:23][O:24][C:19]=4[C:18]=3[OH:27])[C:9]2=[O:29])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1ccc2c(c1O)OCCO2
Agent: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(Cl)c2C1(O)c1cc2c(cc1O)OCC2
Product: O=C1C(c2ccc3c(c2O)OCCO3)c2ccccc2N1C(c1ccccc1)c1ccccc1

Procedure:
Following the procedure as described in PREPARATION 4C, and making non-critical variations using 1-(diphenylmethyl)-3-hydroxy-3-(5-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one to replace 4-chloro-1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one, 1-(diphenylmethyl)-3-(5-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one was obtained (82%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ 9.11 (s, 1H), 7.39-7.24 (m, 9H), 6.95-6.79 (m, 3H), 6.58 (d, J=8.0 Hz, 1H), 6.35-6.30 (m, 2H), 4.21 (s, 4H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:14]3[C:9]([C:10]([NH2:15])=[N:11][CH:12]=[N:13]3)=[C:8]([C:16]3[CH:17]=[CH:18][C:19]4[C:23]([CH:24]=3)=[N:22][N:21]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:20]=4)[CH:7]=2)[CH2:2]1.[CH3:32][N:33]([CH3:38])[CH2:34][C:35](O)=[O:36].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:25]([N:21]1[CH:20]=[C:19]2[C:23]([CH:24]=[C:16]([C:8]3[CH:7]=[C:6]([CH2:5][CH:3]4[CH2:4][N:1]([C:35](=[O:36])[CH2:34][N:33]([CH3:38])[CH3:32])[CH2:2]4)[N:14]4[C:9]=3[C:10]([NH2:15])=[N:11][CH:12]=[N:13]4)[CH:17]=[CH:18]2)=[N:22]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CN(C)CC(=O)O
Reactant: Nc1ncnn2c(CC3CNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CC(=O)N1CC(Cc2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 21.2 %

Procedure:
A mixture of 7-(azetidin-3-ylmethyl)-5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (80 mg, 0.20 mmol), N,N-dimethylglycine (24 mg, 0.23 mmol), EDCl (41 mg, 0.22 mmol), HOBt (29 mg, 0.22 mmol), and N,N-diisopropylethylamine (102 μL, 0.59 mmol) in DMF (1.8 mL) was stirred at rt for 16 h. The crude mixture was purified by preparative HPLC using a gradient elution from 15% to 30% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 21 mg (22%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1 H), 7.90 (s, 1 H), 7.79 (d, 1 H), 7.58 (s, 1 H), 7.26-7.39 (m, 5 H), 7.13 (dd, 1 H), 6.62 (s, 1 H), 5.65 (s, 2 H), 4.26 (t, 1 H), 4.00 (t, 1 H), 3.90 (dd, 1 H), 3.66 (dd, 1 H), 3.31-3.21 (m, 4 H), 2.99-3.11 (m, 1 H), 2.30 (s, 6 H); ES-MS m/z 495.47 [M+H]+, HPLC RT (min) 2.03.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][C:21]([NH2:30])=[C:20]([OH:31])[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl[CH2:43][C:44](Cl)=[O:45]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:32])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:22][C:21]4[NH:30][C:44](=[O:45])[CH2:43][O:31][C:20]=4[N:19]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc(O)c(N)cc3-c3ccccc3)cc2)CCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CO4)cc2)CCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 42 %

Procedure:
To a solution of tert-butyl(1-(4-(5-amino-6-hydroxy-3-phenylpyridin-2-yl)phenyl)cyclobutyl)carbamate (1.8 g, 4.17 mmol), DIPEA (3.63 ml, 20 mmol) in DCM (100 ml) at 0° C. was added a solution of chloroacetyl chloride (0.465 ml) in DCM (20 ml). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated to dryness under reduced pressure. To the residue was added MIBK (120 ml) and saturated sodium bicarbonate (120 ml). The resulting mixture was heated at 115° C. for 16 h. After cooled down to room temperature, the MIBK was removed under reduced pressure. The residue was extracted with ethyl acetate (75 ml). The layers were separated and the aqueous phase extracted into ethyl acetate (2×50 ml). The combined organic phases were washed with water (150 ml) and brine (150 ml), dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The resulting residue was purified by Biotage silica gel chromatography (gradient 0 to 2% methanol in DCM) to give the title compound (0.82 g, 42%). LCMS (Method A): RT=6.55 min, M+1=472. 1H NMR (500 MHz, CDCl3): 7.3-7.0 (10H, m), 4.96 (1H, br), 4.82 (2H, s), 2.55-2.25 (4H, m), 2.1-1.9 (1H, m), 1.8-1.65 (1H, m), 1.35-1.1 (9H, br).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:28](O)=[O:29])[N:18]([CH3:27])[C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)=[CH:11][CH:10]=1>>[CH:1]1([NH:7][C:28]([C:17]2[N:18]([CH3:27])[C:19]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)=[C:15]([C:12]3[CH:11]=[CH:10][C:9]([CH3:8])=[CH:14][CH:13]=3)[N:16]=2)=[O:29])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: Cc1ccc(-c2nc(C(=O)O)n(C)c2-c2ccc(C)cc2)cc1
Product: Cc1ccc(-c2nc(C(=O)NC3CCCCC3)n(C)c2-c2ccc(C)cc2)cc1

Procedure:
Using essentially the same procedure as Example 9, Step B, but using cyclohexylamine (0.020 mL), 4,5-di-(4-methylphenyl)-1-methylimidazole-2-carboxylic acid (25 mg, 0.08 mmol) from Example 9, Step A was converted to the title compound.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]([O:16][C:17]([N:19]1[C@@H:23]([CH2:24][CH2:25][OH:26])[CH2:22][O:21][C:20]1([CH3:28])[CH3:27])=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[C:12]([O:16][C:17]([N:19]1[CH:23]([CH2:24][CH2:25][O:26][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:22][O:21][C:20]1([CH3:28])[CH3:27])=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1[C@@H](CCO)COC1(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCC2COC(C)(C)N2C(=O)OC(C)(C)C)cc1
Yield: 90.6 %

Procedure:
Dry, freshly crystallised p-toluenesulphonyl chloride (1.86 g, 9.8 mmol) and 4-dimethylaminopyridine (10 mg, 0.082 mmol) were added to a solution of alcohol 5 (2.00 g, 8.15 mmol) and triethylamine (2.6 ml, 18.75 mmol) in dichloromethane (20 ml) at 5° C. with stirring. The resulting solution was protected from moisture and kept at 5° C. until all the starting material 5 had reacted (33 h, TLC). A colourless solid, presumably triethylamine hydrochloride, crystallised out of the reaction, and was filtered away. The filtrate was diluted with dichloromethane to a volume of 90 ml, and washed with water (2×20 ml), brine (20 ml), dried over Na2SO4, and concentrated to give the crude tosylate 7 as white solid. This material was purified by dissolving in ether (ca. 330 ml), filtering through celite 545 on a wad of cotton wool to give 2.95 g (90%) of 7. 1H NMR (200 MHz, CDCl3) 7.78 (m, 2H), 7.35 (d, 2H), 4.09 (m, 2H), 4.09 (m, 2H), 3.90 (m, 2H), 3.73 (m, 1H), 2.95 (m, 2H), 1.51 (s, 6H), 1.44 (s, 9H).