Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:37])[CH:15]([C:20]1[CH:21]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[CH:23]=[C:24]([OH:26])[CH:25]=1)[CH2:16][CH:17]([CH3:19])[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:41]=1[C:47]([F:50])([F:49])[F:48].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:37])[CH:15]([C:20]1[CH:21]=[C:22]([C:27]2[CH:28]=[CH:29][C:30]([C:33]([F:34])([F:36])[F:35])=[CH:31][CH:32]=2)[CH:23]=[C:24]([O:26][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:41]=2[C:47]([F:49])([F:48])[F:50])[CH:25]=1)[CH2:16][CH:17]([CH3:19])[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CC(C(=O)N1C(=O)OCC1Cc1ccccc1)c1cc(O)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: Fc1ccc(CBr)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)CC(C(=O)N1C(=O)OCC1Cc1ccccc1)c1cc(OCc2ccc(F)cc2C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-benzyl-3-[2-(5-hydroxy-4′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoyl]-oxazolidin-2-one (as prepared in Example 1, step (k))(0.400 g, 0.78 mmol) in acetonitrile (3.9 mL) was added 1-bromomethyl-4-fluoro-2-trifluoromethyl-benzene (0.181 mL, 1.17 mmol) and Cs2CO3 (0.508 g, 1.56 mmol). The resulting white suspension was stirred at room temperature for 1 h. The white solid was filtered off and the solvent was removed in vacuo to obtain relatively pure 4-benzyl-3-{2-[5-(4-fluoro-2-trifluoromethyl-benzyloxy)-4′-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoyl}-oxazolidin-2-one.
Reaction SMILES: [Li][CH3:2].[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C:5](=[O:11])[CH2:4]2.O>C(OCC)C>[CH3:2][C:5]1([OH:11])[CH:6]2[CH2:9][CH2:10][N:3]([CH2:8][CH2:7]2)[CH2:4]1
Reactant: [Li]C
Reactant: O=C1CN2CCC1CC2
Solvent: O
Solvent: CCOCC
Product: CC1(O)CN2CCC1CC2
Temperature: -78 °C
Reaction time: 18 h
Yield: 70.8 %

Procedure:
To a well-stirred solution of MeLi [3.0M/diethyl ether](67.0 mL, 201 mmol) in anhydrous diethyl ether (150 mL) at −78° C. was added, dropwise, a solution of quinuclidin-3-one (12.5 g, 100 mmol) in diethyl ether (100 mL). The resulting solution was maintained at −78° C. for 1 hour, then at room temperature for 18 hours. Water (60 mL) was added dropwise at 0° C. and the mixture was concentrated in vacuo to give a residue, which was purified by neutral aluminum oxide column chromatography (0-20% MeOH in CHCl3) to give 3-methylquinuclidin-3-ol (10.0 g, 71%) as a light yellow solid. To stirred acetonitrile (250 mL) at 0° C. was slowly added concentrated sulfuric acid (100 mL). The resulting solution was added dropwise to a mixture of 3-methylquinuclidin-3-ol (9.10 g, 64.5 mmol) in acetonitrile (250 mL) at 0° C. The reaction mixture was stirred at room temperature for 60 hours, then cooled with an ice bath and basified with aqueous sodium hydroxide solution to pH 10. The mixture was extracted with 5:1 (v/v) CHC3/i-PrOH. The organic layer was concentrated to afford a residue which was diluted with 2N aq. HCl and washed with 5:1 (v/v) CHC3/i-PrOH. The remaining aqueous layer was then basified with 2N NaOH and extracted with 5:1 (v/v) CHCl3/i-PrOH. The combined organic layers were washed with water, dried (Na2SO4) and concentrated to give 9.5 g (82%) of the desired compound as a light yellow oil. The 2 enantiomers of the above intermediate are separated from each other by using chiral column on supercritical fluid chromatography (SFC) system.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.O.N1(O)C2C=CC=CC=2N=N1.Cl.[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH:35][CH:36]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:37]([OH:39])=[O:38].[N:46]12[CH2:53][CH2:52][CH:49]([CH2:50][CH2:51]1)[C@@H:48](O)[CH2:47]2>C1COCC1>[N:46]12[CH2:53][CH2:52][CH:49]([CH2:50][CH2:51]1)[C@@H:48]([O:38][C:37](=[O:39])[CH:36]([NH:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[F:28])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:47]2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: O=C(O)C(Nc1ccccc1F)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(Nc1ccccc1F)c1ccccc1
Yield: 16.3 %

Procedure:
A solution of DCC (534 mg, 0.71 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (217 mg, 1:42 mmol), (2-fluoro-phenylamino)-phenyl-acetic acid hydrochloride (I247) (200 mg, 0.71 mmol) and (R)-quinuclidin-3-ol (271 mg, 2.13 mmol) in THF (10 mL) is stirred at RT for 2 days. The solvent is evaporated and the residue is taken up with EtOAc, washed with sat NaHCO3, water and brine. The organic layer is collected, dried over Na2SO4, filtered and evaporated to dryness. The residue is purified by preparative HPLC. The organic solvent is evaporated and the acid aqueous phase is basified with Na2CO3 and extracted with EtOAc. The organic layer is dried (Na2SO4), filtered and evaporated to afford the title compound as yellow oil (41 mg, 16% yield).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[K+].Cl.O.[NH:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1>CO>[NH:14]1[CH2:15][CH:16]=[C:17]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:18][CH2:19]1
Reactant: O=C1CCNCC1
Reactant: c1ccc2[nH]ccc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C1=C(c2c[nH]c3ccccc23)CCNC1
Temperature: 25 °C

Procedure:
30 g (0.26 mol) of indole were dissolved in a solution of potassium hydroxide (77.6 g, 1.38 mol) in methanol (692 ml). 4-piperidone monohydrate hydrochloride (102.3 g, 0.66 mol) was added in one portion and the mixture was heated to reflux for 5 h. Potassium chloride precipitated upon cooling at room temperature and it was filtered off. The liquid phase was concentrated until only one third of the liquid remained in the round-bottom flask. The solid formed during the concentration of the liquid phase was filtered and washed thoroughly with ethanol and, finally, with ethyl ether. 31.9 g (63% of yield) of the final product were obtained.
Reaction SMILES: [C:1]([CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:6][C:7]#[N:8])(OC)=[O:2].[BH4-].[Na+].Cl>C(COC)OC.CCOCC>[OH:2][CH2:1][CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:6][C:7]#[N:8]
Reactant: COC(=O)C(CC#N)c1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: COCCOC
Product: N#CCC(CO)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
β-(Carbomethoxy)-β-phenylpropionitrile (144 g, 0.76 mol) is dissolved in dimethoxyethane (1500 mL) and NaBH4 (63.5 g, 1.67 mol) is cautiously added. The reaction mixture is stirred for 30 minutes and then heated at reflux for 2 hours. After this time the resulting solution is allowed to cool to ambient temperature and is poured onto ice. The mixture is then treated with 2N HCl (1500 mL) and is subsequently diluted with Et2O (1500 mL). The organic phase is washed with H2O (1×1000 mL), saturated NaCl solution (2×1000 mL), dried over MgSO4 and concentrated in vacuo to yield β-(hydroxymethyl)-β-phenylpropionitrile.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].N[C:20]1[CH:21]=[CH:22][C:23]2[NH:27][CH:26]=[N:25][C:24]=2[CH:28]=1.[K+].[Br-]>C(Cl)Cl.CO>[NH:25]1[C:24]2[CH:28]=[C:20]([NH:13][C:12]3[C:11]4[C:10](=[CH:9][CH:8]=[C:6]5[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]5=4)[N:14]=[CH:15][N:16]=3)[CH:21]=[CH:22][C:23]=2[N:27]=[CH:26]1
Reactant: Nc1ccc2[nH]cnc2c1
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Agent: [Br-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: N#Cc1nc2ccc3ncnc(Nc4ccc5nc[nH]c5c4)c3c2s1
Yield: 98 %

Procedure:
Prepared from VII and 6-aminobenzimidazole. Flash chromatography eluent (DCM-MeOH 8:2). Yield: 98%; yellow solid; mp>260° C.; IR (KBr) νmax/cm−1 3084, 2226, 1615, 1557, 1464, 1376, 1347, 1248, 1147, 967, 939, 809; 1H NMR (300 MHz, DMSO-d6) δ 8.48 (d, 1H, J=8.7 Hz), 8.15-8.10 (m, 2H), 8.02 (m, 1H), 7.75 (d, 1H, J=8.7 Hz), 7.56 (m, 1H), 7.04 (m, 1H); HRMS calcd for C17H10N7S (M+H+): 344.0718, found 344.0705.
Reaction SMILES: C(O[C:4]([C:6]1[S:10][C:9]([O:11][CH2:12][C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:15][O:16][C:17]=2[CH3:18])=[N:8][CH:7]=1)=[O:5])C.[NH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[O:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:4]([C:6]2[S:10][C:9]([O:11][CH2:12][C:13]3[C:14]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:8][CH:7]=2)=[O:5])[CH2:27][CH2:28]1
Reactant: CCOC(=O)c1cnc(OCc2c(-c3ccccc3)noc2C)s1
Reactant: NC1CCOCC1
Product: Cc1onc(-c2ccccc2)c1COc1ncc(C(=O)NC2CCOCC2)s1
Yield: 56 %

Procedure:
As described for example 127, 2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-thiazole-5-carboxylic acid ethyl ester (100 mg, 0.28 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (65 mg, 56%) which was obtained as a white solid after purification by chromatography (silica, 0 to 3% methanol in dichloromethane). MS: m/e=398.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[NH2:21])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:10][CH:9]=1)=[O:6].C[O:23][C:24](=[O:39])[C:25]([CH3:38])([CH3:37])[CH2:26][C:27]1[CH:32]=[C:31]([CH3:33])[C:30]([CH:34]=O)=[C:29]([CH3:36])[CH:28]=1>>[C:14]([C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5]([C:4]2[CH:18]=[CH:19][C:20]3[N:21]=[C:34]([C:30]4[C:29]([CH3:36])=[CH:28][C:27]([CH2:26][C:25]([CH3:37])([CH3:38])[C:24]([OH:39])=[O:23])=[CH:32][C:31]=4[CH3:33])[NH:1][C:2]=3[CH:3]=2)=[O:6])=[CH:9][CH:10]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1ccc(NC(=O)c2ccc(N)c(N)c2)cc1
Reactant: COC(=O)C(C)(C)Cc1cc(C)c(C=O)c(C)c1
Product: Cc1cc(CC(C)(C)C(=O)O)cc(C)c1-c1nc2ccc(C(=O)Nc3ccc(C(C)(C)C)cc3)cc2[nH]1

Procedure:
The title compound was prepared from 3,4-diamino-N-(4-tert-butylphenyl)-benzamide and 3-(4-formyl-3,5-dimethylphenyl)-2,2-dimethylpropionic acid methyl ester analogous to Example 6-26. 1H NMR (Methanol-d4, 400 MHz): δ 8.26 (s, 1H), 7.93 (d, 1H), 7.72 (m, 1H), 7.65 (m, 2H), 7.44 (m, 2H), 7.05 (s, 2H), 2.89 (s, 2H), 2.15 (s, 6H), 1.35 (s, 9H), 1.2 (s, 6H). MS (m/z) 498.2 (M+1); Retention time: 1.47 min (Method 10).
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:14](=O)[NH:13][CH:12]=[N:11][C:10]=3[O:9][C:8]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:25].C(=O)(O)[O-].[Na+]>O>[Cl:25][C:14]1[C:15]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:9][C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2oc(-c3ccccc3)c(-c3ccccc3)c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Clc1ncnc2oc(-c3ccccc3)c(-c3ccccc3)c12
Temperature: 60 °C
Yield: 63 %

Procedure:
A mixture of 5,6-diphenylfuro[2,3-d]pyrimidin-4(3H)-one (3 g) and POCl3 (30 mL) was heated at 55-65° C. for 3 h. Water was then added followed by sodium bicarbonate. The resulting mixture was extracted with ethyl acetate. The organic layer was concentrated and the crude compound was purified by silica gel column chromatography using a mixture of hexanes:ethyl acetate (95:5), to give white solid 4-chloro-5,6-diphenylfuro[2,3-d]pyrimidine (2 g, 63%). 1H NMR (300 MHz, CDCl3): δ 8.77 (s, 1H), 7.61-7.58 (m, 2H), 7.52-7.46 (m, 5H), 7.35-7.32 (m, 3H). LC-MS (ESI) m/z 307.0 (M+H).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:12]1[CH:18]2[CH:13]1[C:14]([CH3:21])([CH3:20])[CH2:15][C:16](=[O:19])[O:17]2.C(Cl)Cl.[CH3:25][OH:26]>>[CH3:25][O:26][CH:18]1[O:17][C:16](=[O:19])[CH2:15][C:14]([CH3:21])([CH3:20])[CH:13]1[OH:12]
Reactant: CC1(C)CC(=O)OC2OC21
Reactant: CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: COC1OC(=O)CC(C)(C)C1O
Temperature: -10 °C
Reaction time: 16 h

Procedure:
A drop of p-toluene sulfonic acid was added at -15° C. to a solution of 1.42 g of 5.6-epoxy-4,4-dimethyl-tetrahydro-pyr-2-one melting at ≃22° C., 14 ml of methylene chloride and 320 mg of methanol and the mixture was stirred for 31/2 hours at -10° C. 0.4 ml of methanol were added and the mixture was stirred at -10° C. for 16 hours. 40.4 ml of methanol and a little p-toluene sulfonic acid were added and the mixture was stirred for 48 hours while letting the temperature rise to room temperature. The mixture was decanted and the liquid phase was washed with aqueous saturated sodium bicarbonate solution, then with water, was dried and evaporated to dryness under reduced pressure. The 1.45 g of residue was chromatographed over silica and was eluted with a 1-1 mixture of hexane-ethyl acetate to obtain 1.42 g of dl 6-methoxy-5-hydroxy-4,4-dimethyl-tetrahydro-pyr-2-one melting at 72° C. and having a Rf=0.20.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([OH:28])[CH:20]=3)[CH:17]=[N:18][C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH:36](O)[CH3:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([O:28][CH:36]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[F:29])[CH3:37])[CH:20]=3)[CH:17]=[N:18][C:12]=2[CH:11]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sc(-n2cnc3cc(CO[Si](C)(C)C(C)(C)C)ncc32)cc1O
Reactant: CC(O)c1ccccc1F
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1sc(-n2cnc3cc(CO[Si](C)(C)C(C)(C)C)ncc32)cc1OC(C)c1ccccc1F

Procedure:
In a similar manner as described for example B31, 5.92 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3H-imidazo[4,5-c]pyridin-3-yl]-3-hydroxythiophene-2-carboxylate, 2.96 mg of 1-(2-fluorophenyl)ethanol, 7.39 g of triphenylphosphine (polymer bound, ˜3 mmol/g) and 6.49 g of di-tert-butyl azodicarboxylate in 200 ml anhydrous dichloromethane yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:17])=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5][NH:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9].[C:18](Cl)(Cl)=[S:19]>O1CCOCC1.O>[Cl:17][C:3]1[C:2]([N:1]=[C:18]=[S:19])=[C:15]([Cl:16])[CH:14]=[CH:13][C:4]=1[CH2:5][NH:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N)c1Cl
Reactant: S=C(Cl)Cl
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Reaction time: 8 h

Procedure:
A mixture of N-(3-amino-2,4-dichloro-benzyl)-2,2-dimethyl-propionamide (0.95 g, 3.4 mmol) in 4.0 mL dioxane is added to thiophosgene (0.45 mL, 5.8 mmol) in 2.5 mL water. The mixture is stirred overnight, extracted with DCM and the organic phase is washed with 5% aq NaHCO3 solution and water and dried with Na2SO4. After filtration and concentration, the crude product is diluted with DCM, filtered through a pad of silica gel and concentrated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[NH2:5].[CH2:17]([O:24][CH2:25][C@H:26]([NH:30]C(OC(C)(C)C)=O)[C:27](O)=[O:28])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[NH2:30][C@@H:26]([CH2:25][O:24][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:27]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[C:2]([Cl:1])[CH:3]=1)=[O:28]
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Reactant: Nc1ccc(Oc2ccc(Cl)cc2)c(Cl)c1
Product: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(Cl)cc2)c(Cl)c1
Yield: 89 %

Procedure:
Proceeding as in Reference 5, but substituting 3-chloro-4-(4-chlorophenoxy)aniline and (S)-3-(benzyloxy)-2-(tert-butoxycarbonylamino)propanoic acid, gave (S)-2-amino-3-(benzyloxy)-N-(3-chloro-4-(4-chlorophenoxy)phenyl)propanamide (80 mg, 89%).
Reaction SMILES: C[N:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([N+]([O-])=O)[C:3]1=O.[C:15]1(=O)[CH2:20]CC[CH2:17][CH2:16]1.N>CO>[N+:8]([C:6]1[CH:7]=[N:2][C:3]2[CH2:20][CH2:15][CH2:16][CH2:17][C:4]=2[CH:5]=1)([O-:10])=[O:9]
Reactant: Cn1cc([N+](=O)[O-])cc([N+](=O)[O-])c1=O
Reactant: O=C1CCCCC1
Agent: N
Solvent: CO
Product: O=[N+]([O-])c1cnc2c(c1)CCCC2
Yield: 94.5 %

Procedure:
A mixture of 1-methyl-3,5-dinitro-2-pyridone (2.4 g, 0.012 mole), cyclohexanone (1.18 g, 0.012 mole) and ammonia solution (2.0M, 120 mL) in methanol was refluxed overnight. The solvent was removed in vacuo and rhe residue was dissolved in ethyl acetate. The soluble portion was flash chromatographed over silica gel (eluent: 90:10 v/v ethyl acetate-hexane) to give a yellow solid (2.02 g, 94% yield).
Reaction SMILES: NN.[CH2:3]([O:28][C:29]1[CH:34]=[C:33]([O:35][CH3:36])[C:32]([C:37]([N:39]2[CH2:43][C:42](=[CH2:44])[CH2:41][C@H:40]2[CH2:45][OH:46])=[O:38])=[CH:31][C:30]=1[N+:47]([O-])=O)[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([C:15]([N:17]2[CH2:21][C:20](=[CH2:22])[CH2:19][CH:18]2[CH2:23][OH:24])=[O:16])=[CH:9][C:8]=1[N+:25]([O-])=O.C(Cl)(Cl)Cl.CO>CO.[Ni]>[CH2:5]([O:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([C:15]([N:17]2[CH2:21][C@@H:20]([CH3:22])[CH2:19][C@H:18]2[CH2:23][OH:24])=[O:16])=[CH:9][C:8]=1[NH2:25])[CH2:4][CH2:3][O:28][C:29]1[CH:34]=[C:33]([O:35][CH3:36])[C:32]([C:37]([N:39]2[CH2:43][CH:42]([CH3:44])[CH2:41][CH:40]2[CH2:45][OH:46])=[O:38])=[CH:31][C:30]=1[NH2:47]
Reactant: C=C1CC(CO)N(C(=O)c2cc([N+](=O)[O-])c(OCCCOc3cc(OC)c(C(=O)N4CC(=C)C[C@H]4CO)cc3[N+](=O)[O-])cc2OC)C1
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cc(OCCCOc2cc(OC)c(C(=O)N3C[C@@H](C)C[C@H]3CO)cc2N)c(N)cc1C(=O)N1CC(C)CC1CO
Temperature: 25 °C
Yield: 62 %

Procedure:
A solution of hydrazine (23 mg, 23 μL, 0.72 mmol) in MeOH (5 mL) was added dropwise to a solution of the diol 76 (95 mg, 0.145 mmol) and Raney Ni (20 mg) in MeOH (15 mL) heated at reflux. After 1 hour at reflux TLC (90% CHCl3/MeOH) revealed some amine formation. The reaction mixture was treated with further Raney Ni (20 mg) and hydrazine (23 mg, 23,L, 0.72 mmol) in MeOH (5 mL) and was heated at reflux for an additional 30 minutes at which point TLC revealed complete reaction. The reaction mixture was then treated with enough Raney Ni to decompose any remaining hydrazine and heated at reflux for a further 1.5 hours. Following cooling to room temperature the mixture was filtered through a sinter and the resulting filtrate evaporated in vacuo. The resulting residue was then treated with CH2Cl2 (30 mL), dried (MgSO4), filtered and evaporated in vacuo to provide the bis-amine (77) as a yellow oil (54 mg, 63%): 1H NMR (270 MHz, CDCl3) (diastereoisomers) δ6.73 (s, 2Harom), 6.32 (s, 2Harom), 4.60-4.30 (m, 2H, NCHCH2OH), 4.19 (t, 4H, J=5.87 Hz, OCH2CH2CH2O), 3.78-3.50 (m, 14H, NCHCH2OH, NCH2CHCH3 and OCH3), 2.40-1.55 (m, 8H, NCH2CHCH3, OCH2CH2CH2O and NCH2CHCH3CH2), 1.00-0. 95 (m, 6H, NCH2CHCH3); MS (EI), m/z (relative intensity) 600 (M+., 16), 459 (46), 345 (16), 206 (13), 186 (17), 180 (31), 166 (37), 149 (6), 142 (76), 100 (6), 98 (13), 97 (29), 84 (81), 69 (7), 55 (100).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][N+:8]([O-])=[C:7]([CH3:12])[C:6]=1[CH3:13])(=[O:4])=[O:3].C(O)(=[O:16])C.C(OC(=O)C)(=O)C>CO>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:12][OH:16])[C:6]=1[CH3:13])(=[O:4])=[O:3]
Reactant: Cc1c(S(C)(=O)=O)cc[n+]([O-])c1C
Reactant: CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: CO
Product: Cc1c(S(C)(=O)=O)ccnc1CO
Temperature: 80 °C

Procedure:
To a mixture of (4-Methanesulfonyl-2,3-dimethyl-pyridine)-1-oxide (24 g) and acetic acid (50 ml) was added acetic anhydride (28.2 ml), followed by heating to reflux and maintaining the same temperature for about 3 hrs. The reaction mass was cooled to 80° C. and methanol (25 ml) was added followed distilling off the solvent completely under vacuum. THF:methanol (125:25 ml), LiOH (7.5 g) was added to the crude at 25-30° C. followed by adding DCM (100 ml) to the reaction mixture and extraction with (2×150 ml) DCM. All the organic layers were combined and washed with saturated sodium chloride solution (25 ml). The organic layer was dried over sodium sulphate and distilled off completely under vacuum. Subsequently, n-hexane (100 ml) was added to the reaction mass, the compound filtered and washed with n-hexane (10 ml). The wet compound was then dried at 50-55° C. to yield 14 g of the title compound characterized by 1HNMR data (300 MHz): δ 2.58 (s, 3H), 3.13 (s, 3H), 4.62 (s, 1H), 4.80 (s, 2H), 7.86 (d, 1H), 8.68 (d, 1H) and mass [M]+: 202.06.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH3:18])=[C:5]2[CH2:19][C:20]([NH2:22])=[O:21].[H-].[Na+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CS(C)=O.O>[CH2:25]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH3:18])=[C:5]2[CH2:19][C:20]([NH2:22])=[O:21])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: Cc1c(CC(N)=O)c2cc(O)ccc2n1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1c(CC(N)=O)c2cc(OCc3ccccc3)ccc2n1Cc1ccccc1
Reaction time: 0.5 h
Yield: 82 %

Procedure:
5-Hydroxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetamide (400 mg, 1.4 mmol) was dissolved in 50 mL of DMSO, 40 mg (1.0 mmol) of 60% NaH/mineral oil added, stirred approximately 0.5 hour, 0.2 mL of benzyl bromide added and stirring maintained 2.5 hours. The mixture was diluted with water, extracted with EtOAc, the EtOAc solution washed with water, saturated NaCl solution, dried (Na2SO4), and concentrated at reduced pressure. The residue was chromatographed on silica (eluted with a gradient, CH2Cl2 →2% MeOH/CH2Cl2) and crystallized from CH2Cl2 /MeOH to give 440 mg (82% yield) of 5-benzyloxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetamide, mp, 118°-120° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([NH2:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.[Br:30][CH2:31]/[CH:32]=[CH:33]/[C:34](Cl)=[O:35]>O1CCCC1>[Br:30][CH2:31]/[CH:32]=[CH:33]/[C:34]([NH:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][C:16]=1[O:21][CH3:22])[N:13]=[CH:12][N:11]=[C:10]2[NH:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1)=[O:35]
Reactant: O=C(Cl)/C=C/CBr
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)/C=C/CBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a stirred solution of N4-(3-chloro-4-fluorophenyl)-7-methoxy-4,6-quinazolinediamine (8) (4.0 g, 12.5 mmol) in dry tetrahydrofuran (150 mL) under nitrogen was added triethylamine (19 mmol), followed by freshly prepared (2E)-4-bromo-2-butenoyl chloride (15 mmol) in dry tetrahydrofuran (50 mL). The resulting solution was then stirred at room temperature for 2 hours and concentrated under reduced pressure. Trituration from dichloromethane gave crude (2E)-4-bromo-N-[4-(3-chloro-4-fluoroanilino)-7-methoxy-6-quinazolinyl]-2-butenamide (4.6 g) that was used directly.