Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:8]([O:9][CH3:10])[N:7]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:5]2[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:4]=2[N:3]=1.C1C[O:26][CH2:25][CH2:24]1.CC[O-].[Na+]>CCO>[Cl:22][C:19]1[CH:20]=[CH:21][C:4]2[N:3]=[C:2]([O:26][CH2:25][CH3:24])[CH:8]([O:9][CH3:10])[N:7]=[C:6]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:5]=2[CH:18]=1
Reactant: COC1N=C(c2ccccc2Cl)c2cc(Cl)ccc2N=C1Cl
Reactant: C1CCOC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5.40 g. (0.015 mol) of 2,7-dichloro-5-(o-chlorophenyl)-3-methoxy-3H-1,4-benzodiazepine in 25 ml. of THF is added a solution of NaOEt [from 0.34 g. (0.015 ml.) of Na] in 20 ml. of EtOH. The mixture is stirred for 21/2 hour at room temperature, poured into 500 ml. of ice water, and extracted twice with Et2O. The extracts are washed with saturated NaHCO3 and brine and dried. Concentration and crystallization gives 3 g. of the title compound; m.p. 110°-113°.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([F:38])[CH:37]=1)[CH2:33]Cl>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:33][C:32]2[CH:31]=[C:30]([F:29])[CH:37]=[C:36]([F:38])[CH:35]=2)=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Reactant: Fc1cc(F)cc(CCl)c1
Product: O=C1OC2(CCN(C(=O)c3cn(Cc4cc(F)cc(F)c4)c4cc(Cl)ccc34)CC2)c2ccc(F)cc21

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) with commercially available 3,5-difluorobenzyl chloride gave the title compound. ES-MS m/e (%): 525.4(M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:22])=O>>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][Cl:22])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1cc(CO)ccc1OCc1ccccc1
Product: O=[N+]([O-])c1cc(CCl)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under agitation, 58.3 g of 4-benzyloxy-3-nitrobenzyl alcohol is introduced in incremental portions into 250 ml of thionyl chloride, stirred for 30 minutes at room temperature, and concentrated under vacuum. The residue is recrystallized from diisopropyl ether while decolorizing with active carbon, thus producing 50.9 g of 4-benzyloxy-3-nitrobenzyl chloride, mp 60°-61° C.
Reaction SMILES: [Cl-].[CH2:2]([P+](CCCC)(CCCC)CCCC)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(Cl)C1C=CC=CC=1.[Cl:30][SiH:31]([Cl:33])[Cl:32]>>[CH2:2]([Si:31]([Cl:33])([Cl:32])[Cl:30])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCCC[P+](CCCC)(CCCC)Cc1ccccc1
Reactant: Cl[SiH](Cl)Cl
Agent: [Cl-]
Solvent: ClCc1ccccc1
Product: Cl[Si](Cl)(Cl)Cc1ccccc1
Yield: 802.5 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.26 g (0.79 mmol) of benzyltributylphosphonium chloride, 1.00 g (7.90 mmol) of benzyl chloride, and 3.21 g (23.7 mmol) of trichlorosilane were reacted at 150° C. for 2 hrs. The resulting mixture was distilled to give 1.43 g of benzyltrichlorosilane (yield; 80%).
Reaction SMILES: [OH:1][C@:2]1([C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32])[C@:18]2([CH3:19])[C@H:5]([C@H:6]3[C:15]([C@@H:16]([C:20]4[CH:25]=[CH:24][C:23]([CH:26]([OH:28])[CH3:27])=[CH:22][CH:21]=4)[CH2:17]2)=[C:14]2[C:9](=[CH:10][C:11](=[O:29])[CH2:12][CH2:13]2)[CH2:8][CH2:7]3)[CH2:4][CH2:3]1.[CH3:37][C:38]([CH3:44])([CH3:43])[CH2:39][C:40](Cl)=[O:41]>>[OH:1][C@:2]1([C:30]([F:35])([F:36])[C:31]([F:32])([F:33])[F:34])[C@:18]2([CH3:19])[C@H:5]([C@H:6]3[C:15]([C@@H:16]([C:20]4[CH:21]=[CH:22][C:23]([CH:26]([O:28][C:40](=[O:41])[CH2:39][C:38]([CH3:44])([CH3:43])[CH3:37])[CH3:27])=[CH:24][CH:25]=4)[CH2:17]2)=[C:14]2[C:9](=[CH:10][C:11](=[O:29])[CH2:12][CH2:13]2)[CH2:8][CH2:7]3)[CH2:4][CH2:3]1
Reactant: CC(C)(C)CC(=O)Cl
Reactant: CC(O)c1ccc([C@H]2C[C@@]3(C)[C@@H](CC[C@@]3(O)C(F)(F)C(F)(F)F)[C@@H]3CCC4=CC(=O)CCC4=C32)cc1
Product: CC(OC(=O)CC(C)(C)C)c1ccc([C@H]2C[C@@]3(C)[C@@H](CC[C@@]3(O)C(F)(F)C(F)(F)F)[C@@H]3CCC4=CC(=O)CCC4=C32)cc1
Yield: 63 %

Procedure:
In analogy to Example 1, 150 mg (0.29 mmol) of (8S,11R,13S,14S,17S)-17-hydroxy-11-[4-((RS)-1-hydroxyethyl)phenyl]-1 3-methyl-17-pentafluoroethyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one were converted using 3,3-dimethylbutyryl chloride and, after workup and purification, 113 mg (63%) of the title compounds were isolated as a colourless foam.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH2:33][N:34]4[CH:38]=[CH:37][N:36]=[CH:35]4)[CH:26]=3)[CH:16]=2)=[CH:11][C:10]=1[CH3:39])C1C=CC=CC=1.[H][H].C(O)C>C1COCC1.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH2:33][N:34]4[CH:38]=[CH:37][N:36]=[CH:35]4)[CH:26]=3)[CH:16]=2)=[CH:11][C:10]=1[CH3:39]
Reactant: Cc1cc(-c2cn(-c3cccc(OCCn4ccnc4)c3)c3ncnc(N)c23)ccc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(-c2cn(-c3cccc(OCCn4ccnc4)c3)c3ncnc(N)c23)ccc1O

Procedure:
0.4 g of 5-(4-benzyloxy-3-methylphenyl)-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]-4-amino-pyrrolo[2,3-d]pyrimidine are hydrogenated in a hydrogen atmosphere at normal pressure and about 40° C. for 10 h in 20 ml of THF and 10 ml of ethanol in the presence of 0.2 g of 5% palladium/carbon. After filtration through Celite and crystallization of the residue from methylene chloride, 5-(4-hydroxy-3-methylphenyl)-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine having an m.p. of 202°-204° C. is obtained.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[C:9](Cl)(=[O:14])[CH2:10][CH:11]([CH3:13])[CH3:12].Cl>[OH-].[Na+]>[C:9]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])(=[O:14])[CH2:10][CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)CC(=O)Cl
Reactant: O=C(O)[C@@H]1CCCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)CC(=O)N1CCC[C@H]1C(=O)O
Reaction time: 0.25 h

Procedure:
To a well stirred solution of L-proline (1.15 g; 0.01 mole) in 2N aq. NaOH (5 ml), 4N aq. NaOH (2.5 ml) and iso-valeryl chloride (1.4 ml; 0.012 mole) were added simultaneously dropwise maintaining the temperature near 0°-4° C. After 15 minutes, the mixture was acidified (pH 2-3) with 1N HCl and extracted with CHCL3. The combined organic extract was dried using MgSO4, and the solvent was removed. N-iso-valeryl-L-proline was obtained as an oil. Yield 0.85 g, Rf =0.66 (Silica gel, n-C4H9OH-AcOH-H2O, 5:1:2); [α]D20 -129.3° (c 0.6; CHCl3).
Reaction SMILES: [F:1][C:2]1([F:44])[CH2:7][C@H:6]([O:8][C:9]2[CH:14]=[C:13]([F:15])[C:12]([S:16]([N:19](CC3C=CC(OC)=CC=3OC)[C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:18])=[O:17])=[C:11]([F:37])[CH:10]=2)[C@@H:5]([C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)[CH2:4][CH2:3]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:44][C:2]1([F:1])[CH2:7][C@H:6]([O:8][C:9]2[CH:14]=[C:13]([F:15])[C:12]([S:16]([NH:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:17])=[O:18])=[C:11]([F:37])[CH:10]=2)[C@@H:5]([C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2c(F)cc(O[C@H]3CC(F)(F)CC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1CCC(F)(F)C[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)c(F)c1
Yield: 49.3 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 4-{[(1S*,2R*)-5,5-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (120 mg, 0.188 mmol) prepared in Example 109a, triethylsilane (0.15 mL), trifluoroacetic acid (1.5 mL) and dichloromethane (1.5 mL), to yield the title compound (45 mg, 49%) as a colorless solid.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[N:20]1([CH2:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][N:28]2[CH2:33][CH2:34][NH2:35])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C(#N)C>[N:20]1([CH2:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][N:28]2[CH2:33][CH2:34][NH:35][C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[CH:16]=[CH:17][CH:18]=[N:19][C:5]2=3)=[O:3])[CH2:21][CH2:22][O:23][CH2:24][CH2:25]1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: NCCN1CCCCC1CN1CCOCC1
Solvent: CC#N
Product: O=C1Nc2cccnc2N(C(=O)NCCN2CCCCC2CN2CCOCC2)c2ccccc21
Yield: 30 %

Procedure:
Prepared analogously to Example 2 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[2-[(morpholin-4-yl)methyl]-piperidin-l-yl]ethanamine in a yield of 30% of theory. Colourless crystals, m.p. 167° C. (acetonitrile using fuller's earth).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[H-].[Na+].[CH2:11](Br)[CH3:12]>O1CCCC1>[CH2:11]([O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[CH3:12]
Reactant: Oc1ccc(O)cc1
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1ccc(O)cc1

Procedure:
Hydroquinone can be added to a solution of sodium hydride (NaH) dissolved in tetrahydrofuran (THF) and combined with ethyl bromide yielding para-ethoxyphenol. The para-ethoxyphenol can be extracted and added to a solution of tosyl chloride (TsCl) dissolved in pyridine and tetrahydrofuran (THF) at room temperature, yielding para-ethoxytosyloxybenzene. The para-ethoxytosyloxybenzene can be extracted and added to a solution of diatomic iodine (I2) and potassium iodide trioxide (KIO3) dissolved in sulfuric acid (H2SO4) and acetic acid (CH3COOH) yielding 4-ethoxy-3-iodo-1-tosyloxybenzene. The 4-ethoxy-3-iodo-1-tosyloxybenzene is extracted and added to a solution of aqueous sodium hydroxide (NaOH) and tert-butanol, removing the tosylate protecting group and yielding 4-ethoxy-3-iodophenol. The 4-ethoxy-3-iodophenol can be extracted and exposed to resin-bound triphenyphosphine (PPh3) in a solution of azopyridine and methanol (CH3OH) in a salt bath at 0° C., yielding 4-ethoxy-3-iodomethoxybenzene. The 4-ethoxy-3-iodomethoxybenzene can be extracted and added to a solution of titanium tetrachloride (TiCl4) and 1,1-dichlorodimethylether (CHCl2OCH3) dissolved in dichloromethane (CH2Cl2) in a salt bath at −10° C., yielding 2-methoxy-4-iodo-5-ethoxybenzaldehyde. The 2-methoxy-4-iodo-5-ethoxybenzaldehyde can be extracted and half of the yield can be added to tri-iso-propylsilylacetylene (TIPS-acetylene) in an amine solvent such as triethylamine, diethylamine, piperidine, or di-iso-propylethylamine. This mixture can be passed over a palladium (Pd) catalyst bed, yielding 2-methoxy-5-ethoxy-4-((tri-iso-propylsilyl)ethynyl)benzaldehyde.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11].C([Li])CCC.CN(C)[CH:23]=[O:24].O>O1CCCC1>[F:1][C:2]1[C:7]([CH:23]=[O:24])=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11]
Reactant: CC(C)S(=O)(=O)Nc1ccc(F)cc1F
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)Nc1ccc(F)c(C=O)c1F
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To propane-2-sulfonic acid (2,4-difluoro-phenyl)-amide (48, 2.35 g, 9.95 mmol) in tetrahydrofuran (70 mL) under an atmosphere of nitrogen cooled with a dry ice/acetone bath was added 1.60 M of n-butyllithium (1.60 M in hexane, 6.53 mL, 10.45 mmol). The reaction was stirred for 40 minutes, and then another portion of n-butyllithium (1.60 M in hexane, 6.84 mL, 10.94 mmol). The reaction was stirred for 1 hour and N,N-dimethylformamide (0.92 mL, 11.9 mmol) was added. The reaction was allowed to warm to room temperature overnight. The reaction was poured into water extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtrated. The filtrate was concentrated and purified by silica gel column chromatography (dichloromethane/methanol 5%) to give the compound (49, 1.4 g, 53.4%). MS (ESI) [M−H+]−=263.4.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])([O-:3])=[O:2].N1C=CN=C1.[C:31]([Si:35]([CH3:38])([CH3:37])Cl)([CH3:34])([CH3:33])[CH3:32]>O1CCCC1>[C:31]([Si:35]([CH3:38])([CH3:37])[O:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:7][C:6]1[CH:17]=[CH:18][C:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=[N+]([O-])c1cc(OCCCCCCCCO)ccc1-c1ccccc1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCCCCCCOc1ccc(-c2ccccc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.1 %

Procedure:
8-(3-Nitro-4-phenylphenoxy)octan-1-ol (1.23 g, 3.5 mmol) and imidazole (408 mg, 6.0 mmol) were dissolved in tetrahydrofuran (15 mL) and a solution of tert-butyldimethylchlorosilane (750 mg, 5.0 mmol) in tetrahydrofuran (5 mL) was added thereto. After stirring the reaction mixture at room temperature for 18 hours, purified water was added to stop the reaction and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, a saturated aqueous solution of ammonium chloride, and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography to obtain tert-butyldimethyl{[8-(3-nitro-4-phenylphenoxy)octyl]oxy}silane (1.38 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1.[C:18]1([C:24]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN1C(=O)CCC1>[N+:15]([C:5]1[CH:4]=[CH:3][C:2]([N:29]2[CH2:30][CH2:31][N:26]([C:24]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:25])[CH2:27][CH2:28]2)=[CH:7][C:6]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(Br)cc1Nc1ccccc1
Reactant: O=C(c1ccccc1)N1CCNCC1
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(c1ccccc1)N1CCN(c2ccc([N+](=O)[O-])c(Nc3ccccc3)c2)CC1
Temperature: 25 °C
Yield: 67.6 %

Procedure:
A solution of N-(5-bromo-2-nitrophenyl)benzenamine (200 mg, 0.68 mmol) and phenyl(piperazin-1-yl)methanone (257 mg, 1.36 mmol) in NMP (1.5 mL) was heated to 110° C. for 16 h. The solution was cooled to room temperature to which was slowly added H2O (5 mL). The resulting yellow precipitate was filtered, washed with 2 mL of water, dried (high vacuum, 14 h) to furnish (4-(4-nitro-3-(phenylamino)phenyl)piperazin-1-yl)(phenyl)methanone (187 mg, 0.46 mmol), 68% yield. 1H NMR (500 MHz, CDCl3) d (ppm) 3.10-3.61 (m, 8H), 6.34 (dd, J=2.6, 9.7 Hz, 1H), 6.41 (d, J=2.6 Hz, 1H), 7.24-7.48 (m, 10H), 8.19 (d, J=9.7 Hz, 1H), 9.86 (s, 1H). 13C NMR (125 MHz, CDCl3): d (ppm) 171.0, 155.7, 145.8, 139.3, 135.5, 130.6, 130.2, 129.4, 129.1, 127.6, 126.1, 125.0, 106.2, 96.9, 46.7, 29.9.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[I-:19].[NH4+].OO>C(O)(=O)C>[NH2:1][C:2]1[C:3]([I:19])=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:14])([F:15])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Reactant: [I-]
Agent: OO
Agent: [NH4+]
Solvent: CC(=O)O
Product: C[C@]1(c2cc(N)c(I)cc2F)N=C(N)OCC1(F)F
Reaction time: 8 h

Procedure:
Intermediate XI-3 (R2a=F; R2b=I; R3=Me; R4 and R5=H): A solution of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) (500 mg, 1.9 mmol) and ammonium iodide (308 mg, 2.1 mmol) in acetic acid (9.6 ml) was treated at room temperature with an aqueous solution of hydrogen peroxide (35%, 0.19 ml, 2.1 mmol). After stirring overnight 50% of the starting material was left. Another equivalent of ammonium iodide and hydrogen peroxide was added and stirring continued at room temperature overnight. For the workup, the reaction mixture was filtered, the filtrate treated with sodium thiosulphate, then extracted with ethyl acetate (3×). The combined organic layers were washed with a saturated solution of sodium hydrogen carbonate, then dried over sodium sulphate and evaporated at reduced pressure. In order to eliminate residual acetic acid, the crude product was dissolved in dichloromethane and extracted again with a saturated solution of sodium hydrogen carbonate. The crude product was purified by chromatography on an Isolute flash NH2 column using a gradient of heptane/ethyl acetate=100/0 to 0/100 as the eluent. The (R)-4-(5-amino-2-fluoro-4-iodo-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine was obtained as a yellow solid (415 mg, 56% of theory). MS (ISP): m/z=386.0 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[C:42]([CH2:47][CH3:48])=[N:43][CH:44]=[CH:45][CH:46]=2)[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[C:42]([CH2:47][CH3:48])=[N:43][CH:44]=[CH:45][CH:46]=2)[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCc1ncccc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Product: CCc1ncccc1-c1cccc(C(=O)CC(=O)Nc2cc(C(F)(F)F)c(OCC(F)(F)F)cc2NC(=O)OC(C)(C)C)c1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (281 mg, 0.75 mmol) and 3-[3-(2-ethyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K31) (244 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous yellow substance (373 mg, 80%).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:17])[CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:20]1.C(N(CC)CC)C>CCCCO>[Br:1][C:2]1[C:3]([N:19]2[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:20]2)=[C:4]2[C:10]([NH:11][C:12](=[O:17])[CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: CC(C)CC(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: CC(C)CC(=O)Nc1c[nH]c2ncc(Br)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Yield: 39.2 %

Procedure:
A mixture of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methylbutanamide (177 mg, 0.563 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (339 mg, 1.69 mmol), and triethylamine (157 μL, 1.13 mmol) in n-BuOH (5 mL) was processed as in Example 56, Step B, and the crude was purified by C-18 reverse phase chromatography (Biotage 25M+) on Biotage SP4 unit eluting with a gradient of 15-85% CH3CN/water (25 CV) to provide (R)-tert-butyl 1-(5-bromo-3-(3-methylbutanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (109 mg, 39% yield) as a solid. LCMS (APCI+) m/z 494, 496 (M+H)+, Retention time=3.92 minutes (Method 2).
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][N:7]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH2:6][CH2:5][C:4]2[N:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:3]1=2.C1C(=O)N([I:27])C(=O)C1>C(O)(C(F)(F)F)=O.CC(O)=O>[I:27][C:17]1[C:16]([OH:19])=[N:15][C:4]2[CH2:5][CH2:6][N:7]([C:9](=[O:14])[C:10]([F:13])([F:11])[F:12])[CH2:8][CH:2]([CH3:1])[C:3]=2[CH:18]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2nc(O)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: CC1CN(C(=O)C(F)(F)F)CCc2nc(O)c(I)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.3 %

Procedure:
To a solution of 5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ol hydrobromide (1.76 g, 6.79 mmol) in DCM (50 ml) and DMF (10 ml) was added Et3N (2.90 ml, 20.7 mmol) and TFAA (1.00 ml, 6.90 mmol). The mixture was stirred for 2 h at ambient temperature, concentrated in vacuo and parted between sat. aq. NaHCO3 and EtOAc. The organic phase was dried, concentrated in vacuo and purified by column chromatography to yield 1.46 g (77%) of 5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ol. 1H-NMR (DMSO-d6) δ 11.43 (br s, 1H), 7.30 (m, 1H), 6.18 (m, 1H), 3.95-3.42 (m, 4H), 3.06-2.96 (m, 2H), 2.95-2.87 (m, 1H), 1.12 (2× d, 3H) ppm. A mixture of 5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ol (1.36 g, 4.96 mmol) and NIS (1.12 g, 4.96 mmol) in TFA (2 ml) and AcOH (36 ml) was stirred at room temperature for 16 h. Evaporation of TFA and AcOH followed by chromatographic purification of the resulting residue gave 1.95 g (98%) of 3-iodo-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ol. 1H-NMR (CDCl3) δ 7.86 (s, 1H), 4.17-3.41 (m, 4H), 3.20-2.94 (m, 3H), 1.26 (2× d, 3H) ppm. A mixture of 3-iodo-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ol (50.0 mg, 125 μmol) and K2CO3 (17.3 mg, 125 μmol) in MeOH (10 ml) was heated at reflux for 4 h. The reaction mixture was concentrated in vacuo and purified by column chromatography rendering 20.2 mg (53%) of 3-iodo-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ol. 1H-NMR (CDCl3) δ 7.90 (s, 1H), 3.09-2.80 (m, 7H), 1.28 (d, 3H) ppm.
Reaction SMILES: [OH:1][CH:2]([C:6]([O:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].CN(C=O)C.[H-].[Na+].[CH3:39][O:40][C:41]1[CH:46]=[C:45]([CH3:47])[N:44]=[C:43](S(C)(=O)=O)[N:42]=1>O>[CH3:39][O:40][C:41]1[CH:46]=[C:45]([CH3:47])[N:44]=[C:43]([O:1][CH:2]([C:6]([O:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]([OH:5])=[O:4])[N:42]=1
Reactant: COc1cc(C)nc(S(C)(=O)=O)n1
Reactant: COc1ccc(CCOC(c2ccccc2)(c2ccccc2)C(O)C(=O)O)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C)nc(OC(C(=O)O)C(OCCc2ccc(OC)c(OC)c2)(c2ccccc2)c2ccccc2)n1
Reaction time: 0.25 h
Yield: 52.3 %

Procedure:
1 g (2.3 mmol) of 2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-diphenylpropionic acid was introduced into 10 ml of DMF, and 340 mg of NaH (50% suspension) were added. After the mixture had been stirred for 15 minutes, 526 mg of 4-methoxy-6-methyl-2-methylsulfonylpyrimidine were added, and the mixture was stirred at room temperature for 3 hours. Water was added to the mixture, which was then extracted with ether. The aqueous phase was acidified with 1 N aqueous HCl, extracted with ether and dried over magnesium sulfate. The solvent was distilled off, the residue was purified by MPLC, and 655 mg (52%) of colorless powder were isolated after recrystallization from ether/n-hexane.