Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([C:18]2[NH:23][C:22](=[O:24])[C:21]([C:25]([O:27]C)=[O:26])=[CH:20][C:19]=2[CH2:29][CH3:30])=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1>[CH2:1]([O:8][C:9]1[C:17]([C:18]2[NH:23][C:22](=[O:24])[C:21]([C:25]([OH:27])=[O:26])=[CH:20][C:19]=2[CH2:29][CH3:30])=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1cc(C(=O)OC)c(=O)[nH]c1-c1ccc2c(ccn2C)c1OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1cc(C(=O)O)c(=O)[nH]c1-c1ccc2c(ccn2C)c1OCc1ccccc1
Temperature: 50 °C

Procedure:
To a solution of methyl 6-(4-(benzyloxy)-1-methyl-1H-indol-5-yl)-5-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylate (0.0888 g, 0.21 mmol) in THF (1.5 mL) was added a solution of LiOH (1M aqueous saturated, 0.60 ml, 0.60 mmol). The reaction mixture was heated at 50° C. for 1 h until starting material was consumed. The reaction was then cooled to room temperature and acidified with 1M HCl to pH˜2. The product was extracted with DCM (3×10 mL). The combined organic phases were washed with brine and dried over Na2SO4. Upon removal of the solvent product (0.0757 g, 88%) was obtained as yellow solid.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[CH:15]=[C:14]([O:17][CH2:18][CH2:19][CH2:20][C:21](OCC)=[O:22])[CH:13]=[CH:12]2)(=[O:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[OH:22][CH2:21][CH2:20][CH2:19][CH2:18][O:17][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[CH:9][CH:8]=[C:7]2[CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])=[CH:12][CH:13]=1
Reactant: CCOC(=O)CCCOc1ccc2cccc(CCNC(C)=O)c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(=O)NCCc1cccc2ccc(OCCCCO)cc12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
In a 250 ml round-bottomed flask, the ester obtained in Step A (0.009 mol) is dissolved in 100 ml of anhydrous ether. 0.009 mol of lithium aluminum hydride is added in portions, and the reaction mixture is stirred for 6 hours at room temperature. The reaction mixture is then hydrolysed with a few drops of 1M NaOH, and the precipitate that forms is filtered off. The filtrate is dried over MgSO4 and evaporated under reduced pressure. The resulting residue is precipitated from an Et2O/petroleum ether mixture (1/1), suctioned off and recrystallised. White solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:4][N:3]=1.[Cl-].[NH4+]>C(O)C.C(OCC)(=O)C.[BH4-].[Na+].[C].[Pd]>[NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nccc(-c2cccs2)c1[N+](=O)[O-]
Agent: [Pd]
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1nccc(-c2cccs2)c1N
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
To a mixture of Compound 2 (2.06 g, 9.3 mmol) and 466 mg palladium carbon (10% by weight) in ethanol (130 ml) and ethyl acetate (65 ml), 28 ml of 1 M aqueous sodium borohydride was added at 0° C. The resulting mixture was stirred at 0° C. for 1 hour. To the mixture, 43 ml of 5% aqueous ammonium chloride was added. The mixture was filtered through celite. The filtrate was diluted with 500 ml water. After evaporation of ethanol and ethyl acetate, the mixture was extracted with ethyl acetate (250 ml×3). After drying over Na2SO4, the solvent was distilled off. The residue was purified by flash silica gel chromatography using methylene chloride:ethyl acetate (19:1 to 93:7) as an elution solvent to give 1.46 g of Compound 3 (Rf 0.24 on methylene chloride:ethyl acetate=9:1) in a yield of 82%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd-2](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.C(#N)C>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C:2]2[CH:3]=[C:4]3[C:10]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[O:17][CH3:18])=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1
Reactant: COc1ccccc1-c1c[nH]c2ncc(Br)cc12
Reactant: COc1ccc(COc2ccc(B3OC(C)(C)C(C)(C)O3)cc2OC)cc1
Agent: Cl[Pd-2](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(COc2ccc(-c3cnc4[nH]cc(-c5ccccc5OC)c4c3)cc2OC)cc1
Yield: 48.7 %

Procedure:
A Personal Chemistry® microwave vial (2-5 ml size) was charged with 5-bromo-3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine (98 mg, 0.33 mmol), 2-[3-methoxy-4-(4-methoxy-benzyloxy)-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (148 mg, 0.400 mmol), 6.5 mg (9.3 μmol, 5 mol %) of dichlorobis(triphenylphosphino)palladium(II), 1 ml of acetonitrile and 1 ml of a 2 M aqueous solution of sodium carbonate. The vial was sealed, evacuated and purged three times with nitrogen, then irradiated in a Personal Chemistry® microwave reactor with a temperature setting of 150° C. for 30 minutes. Ethyl acetate (50 ml) was added, and the layers were separated. The aqueous fraction was extracted three times with ethyl acetate, and the combined organic fractions were washed with brine, dried (Na2SO4), filtered and concentrated. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in hexanes gave 75 mg (50%) of 5-[3-methoxy-4-(4-methoxy-benzyloxy)-phenyl]-3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine as a light yellow solid. 1H-NMR (d6-DMSO) δ=12.12 (br.s, 1H), 8.51 (d, 1H), 8.11 (d, 1H), 7.70 (d, 1H), 7.57 (dd, 1H), 7.38 (d, 2H), 7.27 (t, 1H), 7.25 (d, 1H), 7.18 (dd, 1H), 7.11 (m, 2H), 7.02 (t, 1H), 6.95 (d, 2H), 5.03 (s, 2H), 3.85 (s, 3H), 3.82 (s, 3H), 3.75 (s, 3H); MS m/z: 467 [MH]+.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:14][C:15]1[CH:16]=[C:17]([CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)[CH:18]=[CH:19][C:20]=1[Cl:21].CCN(CC)CC>C(#N)C>[Cl:14][C:15]1[CH:16]=[C:17]([CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]([NH:32][C:2]3[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=3[C:4]([OH:6])=[O:5])=[CH:30][CH:31]=2)[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Reactant: Nc1ccc(CCCCc2ccc(Cl)c(Cl)c2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(O)c1cc([N+](=O)[O-])ccc1Nc1ccc(CCCCc2ccc(Cl)c(Cl)c2)cc1
Yield: 30 %

Procedure:
A mixture of 2-fluoro-5-nitrobenzoic acid (1.85 g, 0.01 mol), 4-[4-(3,4-dichlorophenyl)butyl]-phenylamine (2.94 g, 0.01 mol) and Et3N (2.80 mL) in acetonitrile (110 mL) was heated to reflux for 48 hours. The reaction mixture was cooled and concentrated in vacuo to remove the solvent. The residue was dissolved in CH2C2 and washed with diluted HCl. The organic layer was dried Na2SO4), concentrated in vacuo to give a crude solid. Purification by flash chromatography (silica gel, CH2Cl2) yielded 1.40 g (0.003 mol, 30%) of the desired product.
Reaction SMILES: [H-].[Na+].[C:3]1([N:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:30]4[C:26](=[N:27][NH:28][N:29]=4)[C:25]([C:31]4[CH:36]=[CH:35][C:34]([N:37]([C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)[C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)=[CH:33][CH:32]=4)=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.F[C:51]1[CH:52]=[CH:53][C:54]([C:57]#[N:58])=[N:55][CH:56]=1>CN(C)C=O>[C:10]1([N:9]([C:16]2[CH:17]=[CH:18][C:19]([C:22]3[C:30]4[C:26](=[N:27][N:28]([C:51]5[CH:56]=[N:55][C:54]([C:57]#[N:58])=[CH:53][CH:52]=5)[N:29]=4)[C:25]([C:31]4[CH:36]=[CH:35][C:34]([N:37]([C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=5)[C:44]5[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=5)=[CH:33][CH:32]=4)=[CH:24][CH:23]=3)=[CH:20][CH:21]=2)[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N#Cc1ccc(F)cn1
Reactant: c1ccc(N(c2ccccc2)c2ccc(-c3ccc(-c4ccc(N(c5ccccc5)c5ccccc5)cc4)c4n[nH]nc34)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(-n2nc3c(-c4ccc(N(c5ccccc5)c5ccccc5)cc4)ccc(-c4ccc(N(c5ccccc5)c5ccccc5)cc4)c3n2)cn1
Temperature: 80 °C

Procedure:
Sodium hydride (60%, 120 mg, 3 mmol) was added to a solution of Intermediate P (1.21 g, 2.0 mmol) and 5-fluoro-2-pyridinecarbonitrile (0.61 g, 5.0 mmol) in anhydrous dimethylformamide (20 mL), stirred under argon, and the obtained mixture was heated at 80° C. for 16 hours. The reaction mixture was poured into ice/water (200 mL), and extracted with dichloromethane (200 mL). The extract was dried over sodium sulfate, and the solvent was evaporated. The residue was diluted with chlorobenzene (50 mL), and the volatiles were removed under high vacuum. The crude product was purified by chromatography (dichloromethane/hexane 2:1) to give 4,7-bis(4-(N,N-diphenylamino)phenyl)-2-(6-cyanopyridin-3-yl)-2H-benzo[d][1,2,3]triazole, dark-red crystals, 1.20 g (85%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:31](=[O:32])[C:11]3=[CH:12][NH:13][C:14]4[CH2:15][CH2:16][CH:17]([O:20]C(OCC5C=CC=CC=5)=O)[CH2:18][C:19]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1.[H][H]>CN(C=O)C.CCO.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:31](=[O:32])[C:11]3=[CH:12][NH:13][C:14]4[CH2:15][CH2:16][CH:17]([OH:20])[CH2:18][C:19]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)OC1CCc2[nH]cc3c(=O)n(-c4ccc(Cl)cc4)nc-3c2C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CN(C)C=O
Product: O=c1c2c[nH]c3c(c-2nn1-c1ccc(Cl)cc1)CC(O)CC3

Procedure:
2-p-chlorophenyl-8-benzyloxycarbonyloxy-2,3,6,7,8,9-hexahydropyrazolo[4,3-c]quinolin-3(5H)-one (1.60 g) is dissolved in 100 mL of 1:1 mixture of DMF and EtOH and subjected to catalytic hydrogenation with 10% palladium on carbon (0.4 g) for 24 hours under one atmosphere pressure of hydrogen. After the reaction is complete the catalyst is filtered off and the filtrate is evaporated to dryness. The residue is triturated with EtOH to obtain 2-p-chlorophenyl-8-hydroxy-2,3,6,7,8,9-hexahydropyrazolo[4,3-c]quinolin-3(5H)-one.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:64])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47](O)[CH:46]([O:51]S(C3C=CC=CC=3[N+]([O-])=O)(=O)=O)[CH2:45]2)[CH:7]([CH3:65])[CH:6]([O:66][Si](C(C)(C)C)(C)C)[CH2:5][C:4]1=[O:74])[CH3:2].[N-:75]=[N+:76]=[N-:77].[Na+].O>CN(C=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:64])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([N:75]=[N+:76]=[N-:77])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:65])[CH:6]([OH:66])[CH2:5][C:4]1=[O:74])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OS(=O)(=O)c4ccccc4[N+](=O)[O-])C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N=[N+]=[N-])C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Yield: 40.9 %

Procedure:
A solution of 17-ethyl-1,14-dihydroxy-12-[2'-[4"-(2"'-nitrobenzenesulfonyloxy)-3"-hydroxycyclohexyl]-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (105 mg, Example 64, compound A) in dry DMF (1 ml) with sodium azide (22 mg) was heated to 50° C. for 3 h. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and purified by column chromatography on silica gel (2:1 ethyl acetate/hexane) to gave 32 mg of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-azido-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone. This material (30 mg) and triphenylphosphine (15 mg) in 1 ml of wet benzene was refluxed for 6.5 h. The solvent was removed in vacuo and the residue was purified on silica gel (eluted first with 5% MeOH/CH2Cl2, then 1% NH4OH in 5% MeOH/CH2Cl2) to give 12 mg of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[C:28]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:27]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[CH:29]=[C:28]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[N:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: Clc1nc(-c2ccccc2)cc2ccccc12
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CCC12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4nc(-c5ccccc5)cc5ccccc45)cc3CC[C@@H]12
Yield: 41.7 %

Procedure:
A 15 mL round bottom flask was charged with (+)-4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (86 mg, 0.33 mmol), potassium carbonate (158 mg, 1.14 mmol), 1-chloro-3-phenyl- isoquinoline (95 mg, 0.40 mmol) and 1 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80% ethyl acetate/hexanes eluent) to give 64 mg (42%) of the title compound as an off white solid. mp 183°-189°. FDMS: m/e=464. α[D]589 =+54.61 (c=0.53, chloroform).
Reaction SMILES: CCN=C=NCCCN(C)C.[C:12]([O:16][C:17]([N:19]1[CH2:22][CH:21]([NH2:23])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].[F:24][C:25]([F:44])([F:43])[C:26]1[CH:27]=[C:28]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[C:29]([NH:31][CH2:32][C:33](O)=[O:34])=[O:30]>>[C:12]([O:16][C:17]([N:19]1[CH2:22][CH:21]([NH:23][C:33](=[O:34])[CH2:32][NH:31][C:29](=[O:30])[C:28]2[CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=[C:26]([C:25]([F:24])([F:43])[F:44])[CH:27]=2)[CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: O=C(O)CNC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Product: CC(C)(C)OC(=O)N1CC(NC(=O)CNC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1

Procedure:
The title compounds were prepared as white solids from the EDCI coupling between 3-amino-azetidine-1-carboxylic acid tert-butyl ester and (3,5-bistrifluoromethyl-benzoylamino)-acetic acid (analog synthesis by following the procedure on Organic Synthesis XII, 40-2, 1932) using the procedure described in Step F of Example 1.
Reaction SMILES: Br.[CH2:2]([O:4][C:5]([C:7]1[C:8]([CH2:22][CH2:23][CH3:24])=[N:9][S:10][C:11]=1[NH:12][C:13]([O:15]C1C=CC=CC=1)=O)=[O:6])[CH3:3].[CH3:25][NH2:26]>>[CH2:2]([O:4][C:5]([C:7]1[C:8]([CH2:22][CH2:23][CH3:24])=[N:9][S:10][C:11]=1[NH:12][C:13]([NH:26][CH3:25])=[O:15])=[O:6])[CH3:3]
Reactant: CCCc1nsc(NC(=O)Oc2ccccc2)c1C(=O)OCC
Reactant: CN
Agent: Br
Product: CCCc1nsc(NC(=O)NC)c1C(=O)OCC

Procedure:
4-Ethoxycarbonyl-5-phenoxycarbonylamino-3-n-propylisothiazol hydrobromide (41.5 g.) was heated at reflux in ethanolic methylamine (33% w/v; 100 ml.) for 15 minutes. The solution was filtered and on cooling deposited white crystals, which were filtered off and washed with water to give 1-(4-ethoxycarbonyl-3-n-propylisothiazol-5-yl)-3-methylurea (18.5 g.), m.p. 173°-174° C.
Reaction SMILES: ClC1C=CC([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][CH:21]4[CH2:26][CH2:25][CH2:24][N:23]([CH3:27])[CH2:22]4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=C(F)C=1>Cl>[CH3:18][O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:19][CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][N:23]([CH3:27])[CH2:22]1)[N:10]=[CH:9][NH:8][C:7]2=[O:6]
Reactant: COc1cc2c(Oc3ccc(Cl)cc3F)ncnc2cc1OCC1CCCN(C)C1
Agent: Cl
Product: COc1cc2c(=O)[nH]cnc2cc1OCC1CCCN(C)C1
Yield: 66.8 %

Procedure:
4-(4-Chloro-2-fluorophenoxy)-6-methoxy-7-(N-methylpiperidin-3-ylmethoxy)quinazoline (8.7 g, 20 mmol) was dissolved in 2M aqueous hydrochloric acid (150 ml) and the mixture was stirred and heated to reflux for 1.5 hours. The reaction mixture was concentrated by evaporation under vacuum and the residue was basified to pH9 by the addition of saturated aqueous ammonium hydroxide solution. The aqueous layer was extracted with methylene chloride (4×400 ml). The combined organic extracts were filtered through phase-separating paper and evaporated. The solid so obtained was triturated under diethyl ether to give 6-methoxy-7-(N-methylpiperidin-3-ylmethoxy)-3,4-dihydroquinazolin-4-one (4.05 g, 66%) as a white solid; NMR: (DMSOd6) 1.05 (m, 1H), 1.40-1.95 (m, 5H), 2.02 (m, 1H), 2.14 (s, 3H), 2.59 (d, 1H), 2.78 (d, 1H), 3.85 (s, 3H), 3.95 (d, 2H), 7.09 (s, 1H), 7.42 (s, 1H), 7.95 (s, 1H), 12.0 (s, 1H); Mass: M+H+ 304.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][C@H:10]([CH3:13])[CH2:11]Cl.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][C@H:10]([CH3:13])[CH2:11][N:28]1[CH2:29][CH2:30][CH:25]([C:21]2[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=2)[CH2:26][CH2:27]1
Reactant: C[C@H](CCl)COc1ccccc1Cl
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(C[C@@H](C)COc3ccccc3Cl)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-chloro-2-{[(2S)-3-chloro-2-methylpropyl]oxy}benzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 429.1 (M+H)+.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:26])[C@@H:10]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:11]([SH:14])([CH3:13])[CH3:12])C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:12][C:11]1([CH3:13])[S:14][C@H:7]2[CH2:6][CH2:5][CH2:4][N:8]2[C:9](=[O:26])[C@H:10]1[NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(CCCNC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)(C)S)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)S[C@H]2CCCN2C(=O)[C@H]1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 34.9 %

Procedure:
To a round bottom flask was added (R)-benzyl 1-(4,4-diethoxybutylamino)-3-mercapto-3-methyl-1-oxobutan-2-ylcarbamate (6.90 g, 16.2 mmol), DCM (50 mL) and TFA (1.87 mL, 24.3 mmol). The reaction was stirred at rt for 5 hr. The reaction was diluted with DCM (200 mL) and the organics was washed with saturated aqueous NaHCO3 (200 mL), water (200 mL) and saturated aqueous NaCl (200 mL). The organic layer was separated, dried over MgSO4, filtered and concentrated. The residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-100% EtOAc/Hex to give benzyl (3R,8aS)-2,2-dimethyl-4-oxohexahydro-2H-pyrrolo[2,1-b][1,3]thiazin-3-ylcarbamate (1.89 g, 5.65 mmol, 34.9% yield) as a clear oil. Anal. Calcd. for C12H22N2O3S m/z 334.3. found: 335.2 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 7.29-7.44 (m, 5H), 5.92 (d, J=7.15 Hz, 1H), 5.14 (s, 3H), 4.57 (d, J=7.70 Hz, 1H), 3.89-3.68 (m, 1H), 3.60-3.40 (m, 1H), 2.55-2.34 (m, 1H), 2.18-2.00 (m, 1H), 1.99-1.83 (m, 2H), 1.51 (s, 3H), 1.13 (s, 3H); 13C NMR (126 MHz, CDCl3) δ ppm 167.31, 157.00, 136.19, 128.54, 128.20, 128.08, 67.23, 60.46, 55.12, 48.93, 46.26, 33.10, 29.56, 27.70, 23.39.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:29][C:30]([F:45])([C:41]([F:44])([F:43])[F:42])[C:31]([F:40])([F:39])[C:32]([F:38])([F:37])[S:33](F)(=[O:35])=[O:34].O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][S:33]([C:32]([F:37])([F:38])[C:31]([F:39])([F:40])[C:30]([F:29])([F:45])[C:41]([F:44])([F:43])[F:42])(=[O:35])=[O:34])=[CH:17][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-hydroxyphenyl)propanoate (1.257 g, 4.26 mmol), DMAP (26 mg, 0.213 mmol), and triethylamine (0.71 mL, 0.51 g, 5.11 mmol) in anhydrous DCM (15 mL) was cooled to 0° C. Then nonafluorobutanesulfonyl fluoride (0.82 mL, 1.41 g, 4.68 mmol) was added in one portion. The mixture was allowed to warm and stirred at room temperature. After 18 hours, the mixture was poured into water (80 mL) and extracted with DCM (2×100 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure. The resultant residue was chromatographed using a Biotage™ 50 g silica gel cartridge by eluting with 0-10% EtOAc in 1:1 Hexane/DCM over 10 column volumes. The product fractions were combined and concentrated under reduced pressure to give the desired product as a clear, colorless oil. LC-MS: calculated for C19H20F9NO7S 577.08, observed m/e: 478.14 (M+H with loss of BOC)+ (Rt 2.67/4 min).
Reaction SMILES: [Li]CCCC.[Li]N1C(C)(C)CCCC1(C)C.[Br:17][C:18]1[CH:19]=[CH:20][C:21]2[S:25][C:24]([CH3:26])=[N:23][C:22]=2[CH:27]=1.[CH2:28]=[O:29].[NH4+].[Cl-]>C1COCC1>[Br:17][C:18]1[CH:19]=[CH:20][C:21]2[S:25][C:24]([CH2:26][CH2:28][OH:29])=[N:23][C:22]=2[CH:27]=1
Reactant: Cc1nc2cc(Br)ccc2s1
Reactant: C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Li]N1C(C)(C)CCCC1(C)C
Solvent: C1CCOC1
Product: OCCc1nc2cc(Br)ccc2s1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a dry 100 mL flask, 2,2,6′,6′-tetra-methyl piperidine (0.56 g, 4 mmol) and 6 mL of THF was added and cooled to −78° C. Then n-BuLi (1.5 mL, 2.5M) was added rapidly, and the mixture of LiTMP was stirred for 3 hr. 5-Bromo-2-methyl-benzothiazole (0.75 g, 3.3 mmol) was added in solid form in to the reaction at −78° C., and after stirring for 4 hours at −78° C., 6 equivalents of para-formaldehyde was added to the reaction while stirring rapidly. The reaction was worked up by addition of sat. NH4Cl solution, and the reaction was extracted with CH2Cl2 dried, and concentrated in vacuo to give crude product, 1.02 g. The crude product was purified by flash chromatography, eluting with CH2Cl2, then with 20% MeOH/CH2Cl2 to elute the product. 1H NMR (400 MHz, CDCl3) d ppm 3.32 (t, J=5.76 Hz, 2 H) 4.11 (q, J=5.95 Hz, 2 H) 7.48 (dd, J=8.51, 1.92 Hz, 1 H) 7.70 (d, J=8.51 Hz, 1 H) 8.11 (d, J=1.92 Hz, 1 H)