Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][O:8][C:9]2[N:14]=[C:13]([NH:15][C@H:16]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)[CH3:17])[N:12]=[C:11]([NH:25][C:26]3[CH:30]=[C:29]([O:31][CH:32]([CH3:34])[CH3:33])[NH:28][N:27]=3)[C:10]=2[F:35])[CH2:4][O:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.O>[F:35][C:10]1[C:9]([O:8][CH2:7][C@@H:5]([OH:6])[CH2:4][OH:3])=[N:14][C:13]([NH:15][C@H:16]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=2)[CH3:17])=[N:12][C:11]=1[NH:25][C:26]1[CH:30]=[C:29]([O:31][CH:32]([CH3:34])[CH3:33])[NH:28][N:27]=1
Reactant: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cn3)nc(OC[C@@H]3COC(C)(C)O3)c2F)n[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cn3)nc(OC[C@@H](O)CO)c2F)n[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.8 %

Procedure:
To a solution of 6-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-5-fluoro-N2-[(1S)-1-(5-fluoropyridin-2-yl)ethyl]-N4-(5-isopropoxy-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (Example 25; 0.21 g, 0.415 mmol) in methanol (5 ml) was added a few drops of water and then p-toluenesulfonic acid (0.119 g, 0.623 mmol). The mixture was stirred at room temperature for 16 hours. The solvent was removed in vacuo and the residue was subjected to silica gel chromatographic purification (by ISCO Combiflash with gradient EtOAc/hexanes) to afford the desired product as a white solid (0.075 g, yield 40%). LC-MS, 466 (M+1); 1H NMR δ 9.85 (br s, 1H), 8.30 (s, 1H), 7.60 (m, 1H), 7.30 (m, 1H), 5.25 (s, 1H), 4.80-4.90 (m, 2H), 4.60 (m, 2H), 4.0 (br s, 2H), 3.55 (m, 1H), 1.35 (d, 3H), 1.15 (d, 6H).
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3].O[C:24]1[CH:76]=[CH:75][C:27]([CH2:28][NH:29][C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33](/[N:40]=[N:41]/[C:42]3[C:51]4[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=4)[C:45](/[N:52]=[N:53]/[C:54]4[CH:73]=[CH:72][C:57]([C:58]([O:60][C:61]5[CH:66]=[CH:65][C:64]([CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])=[CH:63][CH:62]=5)=[O:59])=[CH:56][C:55]=4[CH3:74])=[CH:44][CH:43]=3)=[CH:32][CH:31]=2)=[CH:26][CH:25]=1>C1COCC1.C(N(CC)CC)C.CN(C1C=CN=CC=1)C>[C:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([O:20][C:24]2[CH:76]=[CH:75][C:27]([CH2:28][NH:29][C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:33](/[N:40]=[N:41]/[C:42]4[C:51]5[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=5)[C:45](/[N:52]=[N:53]/[C:54]5[CH:73]=[CH:72][C:57]([C:58]([O:60][C:61]6[CH:62]=[CH:63][C:64]([CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])=[CH:65][CH:66]=6)=[O:59])=[CH:56][C:55]=5[CH3:74])=[CH:44][CH:43]=4)=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)=[O:19])=[CH:21][CH:22]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CCCCCc1ccc(OC(=O)c2ccc(/N=N/c3ccc(/N=N/c4ccc(NCc5ccc(O)cc5)c5ccccc45)c4ccccc34)c(C)c2)cc1
Reactant: C=C(C)C(=O)OCCCCCCOc1ccc(C(=O)O)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCCCCCOc1ccc(C(=O)Oc2ccc(CNc3ccc(/N=N/c4ccc(/N=N/c5ccc(C(=O)Oc6ccc(CCCCC)cc6)cc5C)c5ccccc45)c4ccccc34)cc2)cc1
Temperature: -30 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
0.68 g of 4-{[6-(methacryloyloxy)hexyl]oxy}benzoic acid (2.20 mM) were dissolved in 20 ml of THF and 2.22 g of triethylamine (22.00 mM). The solution was cooled to −30° C. and 0.25 ml of methansulfochloride (2.20 mM) were added. The mixture was stirred for 1 h at this temperature, then 1.42 g of 4-pentylphenyl 4-{(E)-[4-((E)-{4-[(4-hydroxybenzyl)-amino]1-naphthyl}-diazenyl)-1-naphthyl]diazenyl}-3-methylbenzoate (2.00 mM) were added at once, followed by 50 mg of DMAP. The reaction mixture was stirred for 1 h at −30° C. and was allowed to warm to room temperature while stirred overnight. The next day, 10 g of celite filter aid were added and the resulting suspension was stirred for 15 min., filtered, the cake was washed with THF and the filtrate was evaporated to dryness. The residue was dissolved in 10 ml of dichloromethane and to this solution was then added approx. 30 ml of methanol dropwise at 0° C. The precipitated crystals were filtered off, washed with cooled methanol and dried to give 1.60 g (1.60 mM, 80%) of 4-pentylphenyl 4-[(E)-(4-{(E)-[4-({4-[(4-{[6-(methacryloyloxy)hexyl]oxy}benzoyl)oxy]benzyl}amino)-1-naphthyl]-diazenyl}-1-naphthyl)diazenyl]-3-methylbenzoate as dark crystals; λmax=571 nm, ε=35000 (THF). For total purification, the dye might be flash chromatographed on silica gel.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]2[CH2:10][CH2:9]2)=[CH:6][N:5]=[C:4]([C:11]#[N:12])[CH:3]=1.[F:13][CH2:14][CH2:15][OH:16].[H-].[Na+]>>[CH:8]1([C:7]2[C:2]([O:16][CH2:15][CH2:14][F:13])=[CH:3][C:4]([C:11]#[N:12])=[N:5][CH:6]=2)[CH2:10][CH2:9]1
Reactant: OCCF
Reactant: N#Cc1cc(Cl)c(C2CC2)cn1
Agent: [H-]
Agent: [Na+]
Product: N#Cc1cc(OCCF)c(C2CC2)cn1

Procedure:
The title compound was synthesized in analogy to Example 123c, using 4-chloro-5-cyclopropyl-pyridine-2-carbonitrile (example 145b), 2-Fluoro-ethanol (CAN 371-62-0) as starting materials and sodium hydride as reagent. The title compound was isolated (267 mg, 68%) as a yellow solid; MS (ESI, m/z): 207.1 (M+H+).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:15]2=[N:16][C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:19]=[C:14]2[C:13]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:31]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:15]2=[N:16][C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:19]=[C:14]2[C:13]([CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)=[C:12]1[Br:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc2c(C3CCCCC3)cn(CCOCc3ccccc3)c2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CCOCc3ccccc3)c2n1
Temperature: 25 °C
Yield: 55.9 %

Procedure:
To a solution of ethyl 1-(2-benzyloxyethyl)-3-cyclohexyl-1H-pyrrolo[2,3-b]pyridine-6-carboxylate (888 mg, 2.18 mmol) in carbon tetrachloride (20 ml) was added N-bromosuccinimide (505 mg, 2.84 mmol), and the mixture was heated under reflux for 12 hr. The mixture was allowed to cool to room temperature, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=6:1) to give ethyl 1-(2-benzyloxyethyl)-2-bromo-3-cyclohexyl-1H-pyrrolo[2,3-b]pyridine-6-carboxylate (592 mg, yield 56%).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([OH:12])=[O:11])[C:4]=2[CH:3]=[CH:2]1.Cl.[CH3:14]N(C)CCCN=C=NCC.CO>ClCCl>[NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:14])=[O:11])[C:4]=2[CH:3]=[CH:2]1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1cccc2[nH]ccc12
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
N,N-Dimethylaminopyridine (7.6 mg, 0.06 mmol) was added to a mixture of 1H-indole-4-carboxylic acid (100 mg, 0.62 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (131 mg, 0.68 mmol), and methanol (1 mL, 24.7 mmol) in dichloromethane (2 mL). The mixture was allowed to stir at room temperature overnight, then the solvent was evaporated and ethyl acetate (20 mL) was added. The solution was washed with 1 M HCl (2×15 mL), saturated sodium hydrogen carbonate (15 mL) and brine (10 mL), dried (MgSO4), filtered and evaporated to give 1H-indole-4-carboxylic acid, methyl ester (85.4 mg, 79%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:29]2[CH2:33][C@H:32]([CH2:34][NH:35][C:36](=[O:38])[CH3:37])[O:31][C:30]2=[O:39])[CH:5]=[CH:6][C:7]=1[C:8]1C(OC)=N[C:11]([O:14][C@@H:15]2[CH2:20][O:19][C:18]3=[N:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][N:17]3[CH2:16]2)=[N:12][CH:13]=1.[CH3:40][O:41][C:42](=[O:63])[C:43]1C=C(Br)C=N[C:44]=1O[C@@H]1COC2=NC([N+]([O-])=O)=CN2C1>>[CH3:40][O:41][C:42](=[O:63])[C:43]1[CH:44]=[C:8]([C:7]2[CH:6]=[CH:5][C:4]([N:29]3[CH2:33][C@H:32]([CH2:34][NH:35][C:36](=[O:38])[CH3:37])[O:31][C:30]3=[O:39])=[CH:3][C:2]=2[F:1])[CH:13]=[N:12][C:11]=1[O:14][C@@H:15]1[CH2:20][O:19][C:18]2=[N:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][N:17]2[CH2:16]1
Reactant: COC(=O)c1cc(Br)cnc1O[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Reactant: COc1nc(O[C@@H]2COc3nc([N+](=O)[O-])cn3C2)ncc1-c1ccc(N2C[C@H](CNC(C)=O)OC2=O)cc1F
Product: COC(=O)c1cc(-c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)cnc1O[C@@H]1COc2nc([N+](=O)[O-])cn2C1

Procedure:
(S,S)—N-(3-{3-Fluoro-4-[4-methoxy-2-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yloxy)-pyrimidin-5-yl]-phenyl}-2-oxo-oxazolidin-5-ylmethyl)-acetamide. The title compound was prepared by following the same procedure as described in the preparation of Example 7, except 5-bromo-2-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6(S)-yloxy)-nicotinic acid methyl ester was used in place of 6(S)-(5-bromo-pyridin-2-yloxy)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine. ESI MS m/z 571.5 (M+H+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH:8][C:9](=[O:13])[O:10]2)=[CH:5][CH:4]=1.C[N+]1([O-])CC[O:25]CC1>O1CCOCC1>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:7]2[C:6]3[C:11](=[CH:12][C:3]([CH:2]=[O:25])=[CH:4][CH:5]=3)[O:10][C:9](=[O:13])[CH:8]=2)=[CH:15][CH:16]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: O=c1cc(-c2ccc(F)cc2)c2ccc(CBr)cc2o1
Solvent: C1COCCO1
Product: O=Cc1ccc2c(-c3ccc(F)cc3)cc(=O)oc2c1
Temperature: 25 °C

Procedure:
7-(Bromomethyl)-4-(4-fluorophenyl)-2H-chromen-2-one can be prepared as described in Example 1A; its preparation is also described in U.S. Pat. No. 5,552,437. 7-(Bromomethyl)-4-(4-fluorophenyl)-2H-chromen-2-one (11.42 g, 34.3 mmol) and NMO (13.9 g, 102.8 mmol) in 110 mL of dioxane were heated to reflux for 6 h. The solution was cooled to rt and the solvent removed. The crude compound was diluted in EtOAc and washed with NH4Claq, water, brine and dried over MgSO4. The solvent was removed to yield the title compound. 1H NMR (400 MHz, acetone-d6): δ 10.20 (1H, s), 7.95 (1H, s), 7.85 (1H, m), 7.68 (3H, m), 7.38 (2H, m) and 6.51 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:24]=[C:25]([C:29]#[CH:30])[CH:26]=[CH:27][CH:28]=1.C(O)(=O)C1C=CC=CC=1>CO>[CH3:16][O:15][CH2:14][CH2:13][O:12][C:9]1[CH:10]=[C:11]2[C:2]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[CH:30])[CH:24]=3)=[N:3][CH:4]=[N:5][C:6]2=[CH:7][C:8]=1[O:17][CH2:18][CH2:19][O:20][CH3:21].[ClH:1]
Reactant: C#Cc1cccc(N)c1
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OCCOC
Agent: O=C(O)c1ccccc1
Solvent: CO
Product: C#Cc1cccc(Nc2ncnc3cc(OCCOC)c(OCCOC)cc23)c1
Product: Cl
Temperature: 27.5 °C
Reaction time: 4 h

Procedure:
10.0 g of 4-chloro-6,7-bis(2-methoxyethoxy) quinazoline was suspended in 300 ml methanol and 9.2 g of 3-aminophenyl acetylene was charged at 25-30° C. Further 2.0 ml of benzoic acid was added. The reaction mass was stirred at 25-30° C. for 4 hours. Solid obtained was filtered, washed with methanol and dried under vacuum. This solid was suspended in water and then basified with sodium hydroxide and stirred for 10 minutes. The resulting erlotinib base was isolated, washed with water and dried under vacuum. The base was suspended in water and acidified to pH 1.0-2.0 using hydrochloric acid. The reaction mixture was stirred for 2 hours, filtered, washed with water and dried to obtain 11.2 g of erlotinib hydrochloride.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:21]4=[N:22][C:23]([C:27]5[CH:32]=[CH:31][C:30]([C@@H:33]6[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35][CH2:34]6)=[CH:29][CH:28]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[N:56]([CH:59]([CH3:61])[CH3:60])=[C:57]=[O:58].N(CC)=C=O>CN(C)C1C=CN=CC=1.O1CCCC1>[CH:59]([NH:56][C:57](=[O:58])[O:39][C@H:36]1[CH2:37][CH2:38][C@@H:33]([C:30]2[CH:31]=[CH:32][C:27]([C:23]3[N:22]=[C:21]4[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:18]([O:17][C@@H:16]5[CH2:15][O:14][C@@H:13]6[C@H:9]([O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2])[CH2:10][O:11][C@H:12]56)=[N:19][C:20]4=[CH:25][C:24]=3[Cl:26])=[CH:28][CH:29]=2)[CH2:34][CH2:35]1)([CH3:61])[CH3:60]
Reactant: CC(C)N=C=O
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@@H](O)CC4)cc3)nc2n1COCC[Si](C)(C)C
Agent: CCN=C=O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)O[C@H]1CC[C@@H](c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O[Si](C)(C)C(C)(C)C)n4COCC[Si](C)(C)C)cc2)CC1
Reaction time: 12 h

Procedure:
(cis)-4-(4-(2-((3R,3aR,6R,6aS)-6-(tert-butyldimethylsilyloxy)hexahydrofuro[3,2-b]furan-3-yloxy)-6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)phenyl)cyclohexanol (50 mg), 4-dimethylamino-pyridine (DMAP, 1 mg) and triethylamine (30 μL) are dissolved in tetrahydrofurane (1 mL), treated with 2-isocyanatopropane (14 μL) and stirred for 12 hours. Triethylamine (60 μL) and isocyanatoethane (28 μL) are added and the mixture is stirred for 12 hours at 70° C. Again triethylamine (60 μL) and isocyanatoethane (28 μL) are added and the mixture is stirred for 12 hours at 70° C. The mixture is partitioned between ethylacetate and saturated aqueous NH4Cl solution. The organic phase is dried (MgSO4) and concentrated. The residue is used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:15]=[C:16]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([CH:36]=O)[CH:31]=2)[CH:17]=[C:18]([N:21]([CH2:28][CH3:29])[CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:19]=1[CH3:20])=[O:13].[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:15]=[C:16]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[CH:31]=2)[CH:17]=[C:18]([N:21]([CH2:28][CH3:29])[CH:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[C:19]=1[CH3:20])=[O:13]
Reactant: CCN(c1cc(-c2cccc(C=O)c2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCN(c1cc(-c2cccc(CN3CCOCC3)c2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3′-formyl-4-methyl-[1,1′-biphenyl]-3-carboxamide (270 mg, 0.53 mmol) and morpholine (94 mg, 1.07 mmol) in dichloroethane (5 mL), acetic acid (194 mg, 3.23 mmol) was added and reaction stirred at room temperature for 30 minutes. Then sodium triacetoxyborohydride (343 mg, 1.61 mmol) was added to the reaction mixture at 0° C., allowed to attain room temperature and stirring continued for overnight. On completion, reaction mixture was diluted with dichloromethane, washed with water, saturated aqueous sodium bicarbonate solution and dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the title compound (200 mg, 65%). LCMS: 573.25 (M+1)+; HPLC: 90.21% (@ 254 nm) (Rt; 4.048; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.45 (s, 1H), 8.20 (t, 1H), 7.52 (s, 1H), 7.49 (d, 2H, J=7.6 Hz), 7.39 (d, 1H, J=5.6 Hz), 7.29 (d, 1H, J=7.2 Hz), 7.20 (s, 1H), 5.85 (s, 1H), 4.28 (d, 2H, J=4.4 Hz), 3.82-3.84 (m, 2H), 3.56 (m, 4H), 3.52 (s, 2H), 3.22-3.30 (m, 2H), 3.08-3.10 (m, 2H), 3.01 (m, 1H), 2.37 (s, 4H), 2.24 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.65-1.67 (m, 2H), 1.51-1.54 (m, 2H), 0.83 (t, 3H, J=6.4 Hz).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])[C@@H:5]([C:16]([OH:18])=O)[CH2:4][CH2:3]1.[NH2:19][CH:20]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:21]([OH:25])[C:22]([NH2:24])=[O:23].O[NH-].O=[N-]>>[NH2:24][C:22](=[O:23])[C:21](=[O:25])[CH:20]([NH:19][C:16]([C@H:5]1[CH2:4][CH2:3][C:2](=[O:1])[N:6]1[CH2:7][C:8]1[C:9]([F:15])=[CH:10][CH:11]=[CH:12][C:13]=1[F:14])=[O:18])[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Reactant: O=C(O)[C@H]1CCC(=O)N1Cc1c(F)cccc1F
Agent: [N-]=O
Agent: [NH-]O
Product: NC(=O)C(=O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1c(F)cccc1F

Procedure:
Coupling of (R)-5-oxo-1-(2,6-difluorobenzyl)-pyrrolidine-2-carboxylic acid with 3-amino-2-hydroxy-4-phenylbutanamide and oxidation of the resulting hydroxyamide intermediate to the corresponding ketoamide.
Reaction SMILES: ClC(Cl)(OC(=O)[O:6][C:7]([Cl:10])(Cl)Cl)Cl.[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]2[CH2:25][NH:24][CH2:23][CH:22]2[CH:26]([O:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][N:30]=2)[CH3:27])[CH:17]=[CH:18][C:19]=1[Cl:20].N1C=CC=CC=1.CCOC(C)=O>C(Cl)Cl>[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]2[CH:22]([CH:26]([O:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:31][N:30]=3)[CH3:27])[CH2:23][N:24]([C:7]([Cl:10])=[O:6])[CH2:25]2)[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: CC(Oc1ccc(C(F)(F)F)cn1)C1CNCC1c1ccc(Cl)c(Cl)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(Oc1ccc(C(F)(F)F)cn1)C1CN(C(=O)Cl)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 104 %

Procedure:
To a stirred solution of carbonic acid ditrichloromethyl ester (triphosgene) (22 mg 0.074 mmol) in CH2Cl2 (3 mL) at −78° C., was added a solution of 2-{(SR)-1-[(3RS,4SR)-4-(3,4-dichloro-phenyl)pyrrolidin-3-yl]-ethoxy}-5-trifluoromethyl-pyridine (intermediate XV-B-3) (76 mg, 0.19 mmol) and pyridine (0.03 mL, 0.42 mmol) in CH2Cl2 (1 mL) over 30 minutes. The temperature was raised to RT, and stirring was continued over night. The organic phase was washed with H2O, dried over Na2SO4. Concentration under vacuo yielded and column chromatography (SiO2, EtOAc/H, 1:4) yielded 36 mg (41%) of the title compound as a viscous colorless oil.
Reaction SMILES: [S:1](=[O:38])(=[O:37])([O:3][CH2:4][C@@H:5]1[CH2:9][C@@H:8]([O:10][C:11]2[CH:16]=[C:15]([NH:17][C@@H:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][C@@H:19]3[O:27][CH3:28])[N:14]=[CH:13][N:12]=2)[CH2:7][C@@H:6]1[O:29][Si](C(C)(C)C)(C)C)[NH2:2].F.N1C=CC=CC=1>N1C=CC=CC=1.C1COCC1>[S:1](=[O:38])(=[O:37])([O:3][CH2:4][C@@H:5]1[CH2:9][C@@H:8]([O:10][C:11]2[CH:16]=[C:15]([NH:17][C@@H:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][C@@H:19]3[O:27][CH3:28])[N:14]=[CH:13][N:12]=2)[CH2:7][C@@H:6]1[OH:29])[NH2:2]
Reactant: CO[C@H]1Cc2ccccc2[C@H]1Nc1cc(O[C@@H]2C[C@@H](COS(N)(=O)=O)[C@@H](O[Si](C)(C)C(C)(C)C)C2)ncn1
Agent: F
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CO[C@H]1Cc2ccccc2[C@H]1Nc1cc(O[C@@H]2C[C@@H](COS(N)(=O)=O)[C@@H](O)C2)ncn1
Yield: 52.5 %

Procedure:
To a solution of {(1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(6-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyrimidin-4-yl)oxy]cyclopentyl}methyl sulfamate (0.239 g, 0.000423 mol) in pyridine (3.44 mL) and THF (3.44 mL) was added pyridine hydrofluoride (0.953 mL, 0.0106 mol) dropwise. After stirring the reaction for 2 hours, an additional amount of pyridine hydrofluoride (0.50 mL, 0.0055 mol) was added. After 2.75 hours the reaction was quenched by slow dropwise addition of saturated aqueous NaHCO3 and extracted with EtOAc (4×). The combined organic phases were dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (0 to 10% MeOH/CH2Cl2) and then by preparative plate chromatography (EtOAc) to obtain 100 mg (52%) of the title compound. 1H NMR (CD3OD, 400 MHz) δ: 8.15 (s, 1H), 7.24-7.15 (m, 4H), 5.98 (s, 1H), 5.34 (bs, 1H), 4.41-4.38 (m, 1H), 4.32 (dd, 1H, J=7.5, 9.7 Hz), 4.24-4.20 (m, 1H), 4.17 (dd, 1H, J=7.3, 9.8 Hz), 3.35 (s, 3H), 3.13-3.00 (m, 3H), 2.57-2.48 (m, 1H), 2.31-2.25 (m, 1H) 2.12-1.93 (m, 4H) ppm. LC/MS: Rt=1.33 min, ES+ 451 (FA standard).
Reaction SMILES: CC(C)(C)C([NH:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([Cl:13])=[CH:8][C:7]=1[O:14][CH3:15])=O.Cl>C(O)C>[Cl:13][C:9]1[C:10]([Cl:12])=[CH:11][C:6]([NH2:5])=[C:7]([O:14][CH3:15])[CH:8]=1
Reactant: COc1cc(Cl)c(Cl)cc1NC(=O)C(C)(C)C
Agent: Cl
Solvent: CCO
Product: COc1cc(Cl)c(Cl)cc1N
Yield: 100 %

Procedure:
The 2,2-dimethyl-N-(4,5-dichloro-2-methoxyphenyl)propanamide (3.70 grams, 0.01 mole) prepared in Part B was dissolved in ethanol: 12N HCl (1:1), the mixture heated under reflux overnight and then freed of volatiles under rotary evaporation. Partition between 2N HCl and dichloromethane gave an acid-soluble fraction which was worked up to give 1.1 grams (0.01 mole) of pure 4,5-dichloro-2-methoxyaniline as determined by thin layer chromatographic analysis. The dichloromethane fraction from above was freed of solvent giving starting material which was again refluxed overnight with ethanol: 12N HCl and worked up to give an additional 1.2 grams (0.01 mole) of pure 4,5-dichloro-2-methoxyaniline as determined by thin layer chromatographic analysis. NMR analysis of the product indicated the following:
Reaction SMILES: [O:1]1[CH2:4][CH:3]([CH2:5][OH:6])[CH2:2]1.[H-].[Na+].[Br:9][C:10]1[CH:15]=[CH:14][C:13](F)=[CH:12][CH:11]=1>CN(C=O)C>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([O:6][CH2:5][CH:3]2[CH2:4][O:1][CH2:2]2)=[CH:12][CH:11]=1
Reactant: Fc1ccc(Br)cc1
Reactant: OCC1COC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ccc(OCC2COC2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 15.3 %

Procedure:
To a solution of oxetan-3-ylmethanol (1.00 g, 11.3 mmol) in DMF (10 mL) was added NaH (300 mg, 13.6 mmol) at 0° C. The mixture was then stirred at 0° C. for 10 min. 1-Bromo-4-fluorobenzene (2.30 g, 13.6 mmol) was added to the solution. The mixture was stirred at 90° C. for 2 h. The mixture was partitioned between water and EtOAc (30 mL×3). The combined organics was dried and concentrated to give the title compound (420 mg, 15% yield) as a yellow oil.
Reaction SMILES: [CH:1]([C:4]1([CH3:21])[C:8](=[O:9])[N:7]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C:6]([CH3:20])=[N:5]1)([CH3:3])[CH3:2].N1C(=[O:27])CN=C1>C(Cl)Cl>[C:6]([NH:5][C:4]([CH3:21])([CH:1]([CH3:3])[CH3:2])[C:8]([NH:7][S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])=[O:9])(=[O:27])[CH3:20]
Reactant: CC1=NC(C)(C(C)C)C(=O)N1S(=O)(=O)c1ccc(C)cc1
Reactant: O=C1CN=CN1
Solvent: ClCCl
Product: CC(=O)NC(C)(C(=O)NS(=O)(=O)c1ccc(C)cc1)C(C)C

Procedure:
The reaction mixture is checked for completeness of formation of 4-isopropyl-2,4-dimethyl-1-(p-tolylsulfonyl)-2-imidazolin-5-one by infrared spectroscopy. The product imidazolin-5-one is then hydrolyzed by diluting the solution with 100 mL of methylene cloride and washing twice with water and once with HCl 10%. The organic layer is concentrated in vacuo and the resulting yellowish oily residue is shaken with ether and allowed to stand. Upon standing the title product precipitates as a white solid, which after filtration, washing and drying has a mp of 202°-203° C.