Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([N:34]3[CH2:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:35]3=[O:43])[CH:31]=[C:32]([Cl:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([N:34]3[CH2:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:35]3=[O:43])[CH:31]=[C:32]([Cl:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(Cl)cc(N3Cc4ccccc4C3=O)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2c(Cl)cc(N3Cc4ccccc4C3=O)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.butyl 4'-[(2-n-propyl-4-chloro-6-(1-oxo-isoindolin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:28])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.[OH:29][CH2:30][C:31]([CH3:35])([CH2:33]O)[CH3:32]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:28][CH2:32][C:31]([CH3:35])([CH3:33])[CH2:30][OH:29])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(CO)CO
Reactant: O=C1c2ccccc2C(O)(c2ccc(Cl)cc2)N1Cc1ccc([N+](=O)[O-])cc1
Product: CC(C)(CO)COC1(c2ccc(Cl)cc2)c2ccccc2C(=O)N1Cc1ccc([N+](=O)[O-])cc1
Yield: 55 %

Procedure:
The named compound was synthesised from 3-(4-Chlorophenyl)-3-hydroxy-2-(4-nitrobenzyl)-2,3-dihydroisoindol-1-one (400 mg, 1.01 mmol, 1 equiv.) and neopentyl glycol (526 mg, 5.05 mmol, 5 equiv.) using General Procedure A and obtained as an off-white solid (267 mg, 55%). 1H NMR (300 MHz, CDCl3): 8.02-7.98 (m, 2H, O2N—C—CH), 7.96-7.93 (m, 1H, C(O)═C═CH), 7.58-7.55 (m, 2H, Ar—H), 7.32-7.28 (m, 2H, Ar—H), 7.15-7.12 (m, 5 H, Ar—H), 4.58 and 4.44 (dd: AB, J=15.3 Hz, 2H, N—CH2), 3.39 (s, 2H, HO—CH2), 2.78 and 2.63 (dd: AB, J=8.7 Hz, 2H, N—CH2), 0.83 (d, J=3.9 Hz, CH3). 13C NMR (75 MHz, CDCl3): 168.30, 147.33, 145.19, 144.60, 137.31, 134.90, 133.08, 131.64, 130.17, 129.85, 128.61, 127.95, 123.81, 123.23, 123.16, 94.54, 69.57, 69.02, 42.42, 36.41, 21.75. m/z (ES): 481 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[C:5](I)=[CH:4][N:3]=1.[F:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18](B(O)O)[CH:19]=1.[NH2:23][C:24]1[N:25]=[C:26]([CH3:29])[S:27][CH:28]=1>>[F:13][C:14]1[CH:19]=[C:18]([C:5]2[C:6]3[S:10][C:9]([CH3:11])=[N:8][C:7]=3[C:2]([NH:23][C:24]3[N:25]=[C:26]([CH3:29])[S:27][CH:28]=3)=[N:3][CH:4]=2)[CH:17]=[N:16][CH:15]=1
Reactant: Cc1nc(N)cs1
Reactant: OB(O)c1cncc(F)c1
Reactant: Cc1nc2c(Cl)ncc(I)c2s1
Product: Cc1nc(Nc2ncc(-c3cncc(F)c3)c3sc(C)nc23)cs1

Procedure:
The title compound, MS: m/e=358.2 (M+H+), was prepared in accordance with the general method of example 2, step 1 and step 2 from 4-chloro-7-iodo-2-methyl-thiazolo[4,5-c]pyridine (Example B), 3-fluoro-5-pyridineboronic acid and 4-amino-2-methylthiazole (Example C).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:9]1[N:10]=[CH:11][C:12]([CH:36]2[CH2:38][CH:37]2[C:39]([OH:41])=O)=[N:13][C:14]=1[C:15]1[O:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH3:28])=[CH:22][CH:21]=2)=[N:18][N:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:49]1[CH2:53][CH2:52][C@@H:51]([NH:54][C:55](=[O:61])[O:56][C:57]([CH3:60])([CH3:59])[CH3:58])[CH2:50]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[C:45]([O:44][C:42]([N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[C:9]1[C:14]([C:15]2[O:16][C:17]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][N:27]([CH3:28])[C:29](=[O:30])[O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[CH:22][CH:21]=3)=[N:18][N:19]=2)=[N:13][C:12]([CH:36]2[CH2:38][CH:37]2[C:39]([N:49]2[CH2:53][CH2:52][C@@H:51]([NH:54][C:55]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:61])[CH2:50]2)=[O:41])=[CH:11][N:10]=1)=[O:43])([CH3:48])([CH3:46])[CH3:47]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: CN(Cc1ccc(-c2nnc(-c3nc(C4CC4C(=O)O)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)o2)cc1)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(Cc1ccc(-c2nnc(-c3nc(C4CC4C(=O)N4CC[C@@H](NC(=O)OC(C)(C)C)C4)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)o2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-[5-[bis(tert-butoxycarbonyl)amino]-6-[5-[4-[[tert-butoxycarbonyl(methyl)amino]methyl]phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]cyclopropanecarboxylic acid (100 mg, 0.15 mmol) and tert-butyl N-[(3R)-pyrrolidin-3-yl]carbamate (31 mg, 0.17 mmol) in DMF (0.6 mL) at room temperature was added HATU (57 mg, 0.15 mmol) followed by the addition of DIEA (48 mg, 65 μL, 0.37 mmol) and reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and washed with 1M HCl solution, and then with brine. The layers were separated and the organic layer was dried over Na2SO4, filtered and concentrated to obtain tert-butyl N-[[4-[5-[3-[bis(tert-butoxycarbonyl)amino]-6-[2-[(3R)-3-(tert-butoxycarbonylamino)pyrrolidine-1-carbonyl]cyclopropyl]pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]phenyl]methyl]-N-methyl-carbamate, which was dissolved in of 50% TFA-DCM (1 mL) mixture and stirred for 25 minutes at room temperature. The reaction mixture was concentrated under reduced pressure. The crude material was dissolved in DMSO (1 mL), filtered and purified using reverse phase HPLC (10 to 99% MeOH in H2O with HCl modifier) to obtain [2-[5-amino-6-[5-[4-(methylaminomethyl)phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]cyclopropyl]-[(3R)-3-aminopyrrolidin-1-yl]methanone.
Reaction SMILES: I[CH3:2].[F:3][C:4]([F:32])([F:31])[C:5]1[CH:30]=[CH:29][CH:28]=[CH:27][C:6]=1[C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:20]=[N:19][C:18]([N:21]3[CH2:25][CH2:24][NH:23][C:22]3=[O:26])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)=[O:8]>>[CH3:2][N:23]1[CH2:24][CH2:25][N:21]([C:18]2[N:19]=[N:20][C:15]([N:12]3[CH2:11][CH2:10][N:9]([C:7](=[O:8])[C:6]4[CH:27]=[CH:28][CH:29]=[CH:30][C:5]=4[C:4]([F:3])([F:31])[F:32])[CH2:14][CH2:13]3)=[CH:16][CH:17]=2)[C:22]1=[O:26]
Reactant: CI
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(N3CCNC3=O)nn2)CC1
Product: CN1CCN(c2ccc(N3CCN(C(=O)c4ccccc4C(F)(F)F)CC3)nn2)C1=O
Yield: 39 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 1-iodomethane in place of 1-iodo-3-methylbutane to react with 1-{6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]pyridazin-3-yl}imidazolidin-2-one, the title compound was obtained as a white solid in 39% yield (0.020 g). 1H NMR (300 MHz, CDCl3) δ 8.47-8.44 (m, 1H), 7.71 (d, J=7.8 Hz, 1H), 7.62-7.49 (m, 2H), 7.33 (d, J=7.8 Hz, 1H), 7.03-6.99 (m, 1H), 4.08 (t, J=7.8 Hz, 2H), 4.02-3.82 (m, 2H), 3.65-3.42 (m, 6H), 3.31-3.28 (m, 2H), 2.89 (m, 3H). 13C NMR (75 MHz, CD3OD) δ 170.4, 135.4, 133.9, 131.0, 128.8, 127.99, 127.91, 127.85, 47.8, 46.7, 46.6, 45.1, 42.5, 42.4, 31.01, 30.8. MS (ES+) m/z 435 (M+1).
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([N:14]3[CH2:17][CH:16]([NH2:18])[CH2:15]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C>ClC(Cl)C.ClCCl>[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:18][CH:16]2[CH2:15][N:14]([C:12]([N:8]3[CH2:9][CH2:10][CH2:11][N:5]([CH:1]4[CH2:4][CH2:3][CH2:2]4)[CH2:6][CH2:7]3)=[O:13])[CH2:17]2)=[O:25])=[CH:22][CH:21]=1
Reactant: NC1CN(C(=O)N2CCCN(C3CCC3)CC2)C1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NC1CN(C(=O)N2CCCN(C3CCC3)CC2)C1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 37 %

Procedure:
To a solution of 1-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]azetidin-3-amine (46 mg, 0.18 mmol) in dichloroethane (3 ml) was added 4-chlorobenzoyl chloride (20 μl, 0.18 mmol) and DIPEA (38 μl, 0.22 mmol). The reaction was stirred at room temperature for 3 hours and then diluted with dichloromethane (30 ml) and washed twice with saturated NaHCO3 (15 ml), dried (MgSO4), filtered and concentrated at reduced pressure. The residue was purified by FCC (DCM/MeOH/NH3 with gradient, 98:2:1 to 90:10:1) to provide the title compound as white solid (26 mg, 37%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].Cl[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1.CC(O)=O>CN(C=O)C.CC(O)(C)C>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: N#Cc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C#N)cc2)CC1
Temperature: 60 °C

Procedure:
Step-1: To a stirred solution of N—BOC 4-hydroxypiperidine (7.50 g, 0.0373 mol) in dry DMF (50 mL) was added 95% NaH solid (1.12 g, 0.047 mol) in small portions over 5-10 min. After the evolution of gas had subsided, 4-chlorobenzonitrile (5.18 g, 0.0376 mol) was added in one portion, and the mixture heated to 60° C. overnite. The mixture was diluted with tBuOH (about 5 mL) and neutralized to pH 7 using glacial AcOH. The DMF was concentrated in vacuo, and the crude product chromatographed over a 120 g Isco column using 20% DCM/hexanes to DCM as an eluent to get step-1 product, 4-(4-cyanophenoxy)piperidine-1-carboxylic acid tert-butyl ester, as a white solid (10.33 g, 92%): LC Rt=3.40; 1H NMR (300 MHz, CDCl3) δ 1.46 (s, 9H), 1.74-1.80 (m, 2H), 1.89-1.97 (m, 2H), 3.40 (ddd, J=10.3, 7.6, 4.0 Hz, 2H), 3.68 (ddd, J=10.3, 8.7, 4.0 Hz, 2H), 4.55 (septet, J=3.6 Hz, 1H), 6.94 (d, J=9.0 Hz, 2H), 7.58 (d, J=9.0 Hz, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1N[C:9]2=CN=C(Br)[CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:2].C(NC(C)C)(C)C.C[Si](C#C)(C)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[C:4]([O:3][CH2:1][CH3:2])(=[O:5])[CH3:6].[CH3:4][CH2:6][CH2:7][CH:8]([CH3:9])[CH3:13]
Reactant: CCOC(=O)c1cc2cc(Br)ncc2[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C#C[Si](C)(C)C
Solvent: C1COCCO1
Solvent: CC(C)NC(C)C
Product: CCCC(C)C
Product: CCOC(C)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 25 %

Procedure:
PdCl2(PPh3)2 (0.026 g, 0.037 mmol) and Cu(|)I (0.007 g, 0.037 mmol) were added sequentially to 5-bromo-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester (Preparation 26, 0.100 g, 0.370 mmol) under an argon atmosphere. 1,4-Dioxane (7 mL, anhydrous) followed by diisopropylamine (0.063 mL, 0.45 mmol) were added and the stirred mixture was purged with argon for 5 min. Trimethylsilylacetylene (0.064 mL, 0.45 mmol) was added dropwise and the resulting mixture stirred at rt for 24 h. The reaction mixture was partitioned between water (50 mL) and ethyl acetate (100 mL) and the layers separated. The aqueous phase was extracted with ethyl acetate (3×30 mL). The combined organics were washed with brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was dissolved in the minimum amount of dichloromethane and loaded onto a silica column. Purification via flash column chromatography (SiO2, dichloromethane then 25% ethyl acetate/isohexane) gave a pale yellow solid. δH (CDCl3): 0.28 (9H, s), 1.43 (3H, t), 4.45 (2H, q), 7.18 (1H, s), 7.83 (1H, s), 8.86 (1H, s), 9.21 (1H, br s).
Reaction SMILES: P(OCC)(OCC)(OCC)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[C:26]1(=[O:33])[CH2:31][CH2:30][CH2:29][C:28](=[O:32])[CH2:27]1.[F:34][C:35]1[CH:40]=[CH:39][C:38]([NH:41][C:42]([NH2:44])=[O:43])=[CH:37][C:36]=1[C:45]([F:48])([F:47])[F:46].[CH:49]([C:51]1[CH:58]=[CH:57][C:54]([C:55]#[N:56])=[CH:53][CH:52]=1)=O>COC(C)(C)C>[C:55]([C:54]1[CH:57]=[CH:58][C:51]([CH:49]([C:27]2[C:28](=[O:32])[CH2:29][CH2:30][CH2:31][C:26]=2[OH:33])[NH:44][C:42]([NH:41][C:38]2[CH:39]=[CH:40][C:35]([F:34])=[C:36]([C:45]([F:46])([F:47])[F:48])[CH:37]=2)=[O:43])=[CH:52][CH:53]=1)#[N:56]
Reactant: O=C1CCCC(=O)C1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: NC(=O)Nc1ccc(F)c(C(F)(F)F)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCOP(=O)(OCC)OCC
Solvent: COC(C)(C)C
Product: N#Cc1ccc(C(NC(=O)Nc2ccc(F)c(C(F)(F)F)c2)C2=C(O)CCCC2=O)cc1
Temperature: 50 °C

Procedure:
A mixture of triethyl phosphate (620 μL, 3.66 mmol) and phosphorous pentoxide (346 mg, 2.44 mmol) is heated at 50° C. over night and dilutet with tert-butyl methyl ether (7 mL). Cyclohexane-1,3-dione (513 mg, 4.57 mmol), 1-(4-fluoro-3-(trifluoromethyl)phenyl)urea (677 mg, 3.05 mmol) and 4-formylbenzonitrile (400 mg, 3.05 mmol) are added, and the mixture is heated at 55° C. for 3 h. All volatiles are removed under reduced pressure. The residue is dissolved in methanol, and the mixture is purified by reversed phase HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% formic acid). Yield: 551 mg; ESI mass spectrum [M+H]+=448; Retention time HPLC: 1.04 min (Z018_S04).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])([OH:16])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:26]I.O>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])([O:16][CH3:26])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CI
Reactant: COc1ccc(Cl)cc1C1(O)CCN(C(=O)OC(C)(C)C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1C1(OC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
To a suspension of NaH (0.7 g, 60% in mineral oil, 17.5 mol) in DMF (30 mL) was added dropwise a solution of 4-(5-chloro-2-methoxy-phenyl)-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester 5b (4.0 g, 11.7 mol) in DMF (10 mL) at 0° C. After being stirred at this temperature for 30 min, MeI (0.9 ml 0.0145 mol) was added dropwise. The reaction mixture was stirred at 0° C. for 30 min and then warmed to room temperature. Water (100 mL) was added and the mixture was extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated to obtain crude 4-(5-chloro-2-methoxy-phenyl)-4-methoxy-piperidine-1-carboxylic acid tert-butyl ester 5c (3.8 g), which was used directly in next step.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([C:31](O)=[O:32])=[CH:25]2>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:31]([C:26]1[NH:27][C:28]2[C:24]([CH:25]=1)=[CH:23][C:22]([O:21][CH3:20])=[CH:30][CH:29]=2)=[O:32]
Reactant: COc1ccc2[nH]c(C(=O)O)cc2c1
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Product: COc1ccc2[nH]c(C(=O)Nc3ccc(N4CCC(N5CCCC5C)C4)cc3C)cc2c1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 5-methoxy-1H-indole-2-carboxylic acid. MS: 433.2 (M+H).
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[CH3:26][S:27]([O:11][CH2:10][C@@H:9]([NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:12][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)(=[O:29])=[O:28]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CC1CCCCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)CC1CCCCC1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
A solution of (S)—N-Boc-2-amino-3-cyclohexylpropanol (20 g, 0.078 mol) in CH2Cl2 (400 mL) and triethylamine (19.6 g, 0.195 mol) was cooled to −20° C. Methanesulfonyl chloride (19.5 g, 0.171 mol) was added with fast dropwise addition maintaining the internal temperature at −20° C. The reaction mixture was stirred at −20° C. for an additional 30 min then for 1 h at 0° C. and then quenched with ice-cold water (200 mL). The mixture was extracted with CH2Cl2 (3×100 mL), washed with water (3×50 mL), dried over Na2SO4, concentrated to give the crude (S)-2-(tert-butoxycarbonylamino)-3-cyclohexylpropyl methanesulfonate (23.3 g, 90%), which was used for the next reaction without further purification. 1H NMR (400 MHz, CDCl3): 4.93 (m, 1H), 4.60 (d, J=7.6 Hz, 1H), 3.67 (m, 2H), 3.12 (s, 3H), 1.87-1.50 (m, 5H), 1.45 (s, 9H), 1.40-0.72 (m, 8H), MS (E/Z): 336 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[C:21]([F:28])=[C:22]([CH2:26][OH:27])[CH:23]=[CH:24][CH:25]=1>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][OH:27])[C:21]=1[F:28])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: OCc1cccc(Br)c1F
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#Cc1cccc(CO)c1F

Procedure:
Following the general method as outlined in Intermediate 19, starting from tert-butyl(4-chloro-2-ethynylphenoxy)acetate (Intermediate 3) and (3-bromo-2-fluorophenyl)methanol (Intermediate 11), the title compound was obtained as a dark brown sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [CH2:1]([N:3]([CH2:10][CH:11]1C[O:12]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[CH3:14][O-:15].[Na+].[C:17]([O-])(O)=O.[Na+]>CO>[CH2:1]([N:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:10][CH:11]([OH:12])[CH2:14][O:15][CH3:17])[CH3:2]
Reactant: C[O-]
Reactant: CCN(CC1CO1)c1ccccc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCN(CC(O)COC)c1ccccc1
Temperature: 25 °C
Yield: 97 %

Procedure:
A solution of ethyl-oxiranylmethyl-phenyl-amine (1.72 g, 9.65 nmol) and NaOMe (1.04 g, 2.0 eq.) in MeOH (8 mL) was heated at reflux for over weekend. After cooling to room temperature, the mixture was diluted with sat NaHCO3 (20 mL) and extracted with 3×20 mL of EtOAc. The combined extracts were dried over Na2SO4, filtered and concentrated and the product was purified by chromatography (30% EtOAc-hexanes) to give 1-(ethyl-phenyl-amino)-3-methoxy-propan-2-ol (1.95 g, 97%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[O:9][CH3:10].Cl.Cl[C:13](Cl)(Cl)[CH:14]([OH:16])O.[O-]S([O-])(=O)=O.[Na+].[Na+].[NH2:26][OH:27].Cl>O.O1CCOCC1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:14](=[O:16])/[CH:13]=[N:26]/[OH:27])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COc1cc(N)ccc1Br
Reactant: OC(O)C(Cl)(Cl)Cl
Reactant: NO
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(NC(=O)/C=N/O)ccc1Br
Temperature: 50 °C
Yield: 111.2 %

Procedure:
A mixture of 4-bromo-3-(methyloxy)aniline (50 g, 247 mmol), HCl (100 mL) and dioxane (150 mL) in H2O (500 mL) was stirred at 50° C. 2,2,2-Trichloro-1,1-ethanediol (81.7 g, 494 mmol), Na2SO4 (526 g, 3705 mmol) and H2O (1 L) were added to the mixture followed by NH2OH.HCl (103 g, 1482 mmol in 100 mL of H2O). The mixture was stirred at 80° C. for 1 h, cooled to room temperature, filtered and washed with H2O to yield (2E)-N-[4-bromo-3-(methyloxy)phenyl]-2-(hydroxyimino)ethanamide (75 g) as a yellow solid. MS (m/z) 273 (M+H+).
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl[C:11]1[N:16]=[C:15]([NH:17][C:18]2[C:19]([O:24][CH3:25])=[N:20][CH:21]=[CH:22][CH:23]=2)[C:14]([N+:26]([O-:28])=[O:27])=[CH:13][CH:12]=1.Cl.[F:30][C:31]1[CH:32]=[CH:33][C:34]([C@@H:37]([NH2:39])[CH3:38])=[N:35][CH:36]=1>C(O)CCC.C(OCC)(=O)C>[F:30][C:31]1[CH:32]=[CH:33][C:34]([C@@H:37]([NH:39][C:11]2[N:16]=[C:15]([NH:17][C:18]3[C:19]([O:24][CH3:25])=[N:20][CH:21]=[CH:22][CH:23]=3)[C:14]([N+:26]([O-:28])=[O:27])=[CH:13][CH:12]=2)[CH3:38])=[N:35][CH:36]=1
Reactant: C[C@H](N)c1ccc(F)cn1
Reactant: COc1ncccc1Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncccc1Nc1nc(N[C@@H](C)c2ccc(F)cn2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
Diisopropylethylamine (0.49 mL, 2.81 mmol) was added to a solution of 6-chloro-N-(2-methoxypyridin-3-yl)-3-nitropyridin-2-amine (Preparation 22a, 0.26 g, 0.69 mmol) and (S)-1-(5-fluoropyridin-2-yl)ethanamine hydrochloride (prepared according to the method described in WO2006/82392A1, 0.13 g, 0.74 mmol) in butanol (5 mL) and the resulting mixture was stirred at 80° C. overnight. Subsequently, the reaction was cooled down, diluted with ethyl acetate and washed with brine (×3). The organic phase was separated, dried over anhydrous magnesium sulphate and the solvent removed under reduced pressure. The residue was purified by flash chromatography (hexanes 100% to 1:1 hexanes/ethyl acetate) to give the title compound (253 mg, 94%) as a yellow solid.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Cl:10][C:11]1[C:12]([F:32])=[C:13]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH2:28]Cl)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:14]=[CH:15][CH:16]=1.[NH2:33][C:34]([C:36]1([NH:47][CH3:48])[CH2:39][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:37]1)=[O:35].O>CN(C)C=O>[NH2:33][C:34]([C:36]1([N:47]([CH2:28][C:25]2[CH:26]=[C:27]3[C:22](=[CH:23][C:24]=2[O:30][CH3:31])[N:21]=[CH:20][N:19]=[C:18]3[NH:17][C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([Cl:10])[C:12]=2[F:32])[CH3:48])[CH2:39][N:38]([C:40]([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:41])[CH2:37]1)=[O:35]
Reactant: CNC1(C(N)=O)CN(C(=O)OC(C)(C)C)C1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CCl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
N,N-diisopropylethylamine (0.22 ml, 1.24 mmol) was added to a solution of N-(3-chloro-2-fluorophenyl)-6-(chloromethyl)-7-methoxyquinazolin-4-amine (160 mg, 0.41 mmol prepared as described in Example 62) in dimethylformamide (1 ml). After 5 minutes of stirring, the reaction mixture became homogeneous and tert-butyl 3-(aminocarbonyl)-3-(methylamino)azetidine-1-carboxylate (98 mg, 0.43 mmol) was added. After 30 minutes of stirring at 80° C., the reaction mixture was cooled down to room temperature, water was added and the aqueous layer was extracted with ethyl acetate (×2). The combined organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residues were purified by column chromatography on silica eluting with increasingly polar mixtures of methanol/dichloromethane (0/100-5/95) to give tert-butyl 3-(aminocarbonyl)-3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]azetidine-1-carboxylate as a yellow solid, (100 mg, 44%); 1H NMR Spectrum: (CDCl3) 1.46 (s, 9H), 2.39 (s, 3H), 3.82 (s, 2H), 3.99 (s, 3H), 4.17 (d, 2H), 4.25 (brd, 2H), 5.47 (brs, 1H), 6.79 (brs, 1H), 7.17 (m, 2H), 7.29 (s, 1H), 7.66 (brs, 1H), 7.83 (s, 1H), 8.49 (brs, 1H), 8.75 (s, 1H); Mass Spectrum: (M+H)+ 545.