Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH:5]1[CH2:7][CH:6]1[N:8]1[CH:15]=[CH:14][C:12](=O)[NH:11][C:9]1=[O:10])[CH2:3][OH:4].C[Si](C)(C)[NH:18][Si](C)(C)C.C(N)=O>CO>[OH:1][CH:2]([CH:5]1[CH2:7][CH:6]1[N:8]1[CH:15]=[CH:14][C:12]([NH2:18])=[N:11][C:9]1=[O:10])[CH2:3][OH:4]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: O=c1ccn(C2CC2C(O)CO)c(=O)[nH]1
Solvent: NC=O
Solvent: CO
Product: Nc1ccn(C2CC2C(O)CO)c(=O)n1
Temperature: 140 °C
Reaction time: 85 h

Procedure:
To 85.8 mg (0.42 mmol) of 1-(2'-(1",2"-dihydroxyethyl) cyclopropyl)uracil, the product of Step B of Example 9, is added 0.44 mL (2.1 mmol) of hexamethyldisilazane and 0.034 mL (0.82 mmol) of formamide and the resultant mixture is heated with stirring in a sealed tube at 140° C. After 85 h, 10 mL of methanol is added to the cooled reaction mixture, the tube resealed and heated to 65° C. After 3 h at 65° C., the cooled reaction mixture is concentrated under reduced pressure. The residue is dissolved in 10 mL of water and the resultant aqueous solution treated with 50 mg of Darco G-60 charcoal, filtered and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel eluted with a gradient of methanol in methylene chloride from 100% methylene chloride to 30% methanol affords the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2Cl)[C:9]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:8]([CH2:23][O:24][CH2:25][CH:26]=O)[NH:7][C:6]=1[CH3:28])=[O:4].[ClH:29].[OH:30][NH3+:31].C(N(CC)CC)C>CO>[CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:29])[C:9]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:8]([CH2:23][O:24][CH2:25][CH:26]=[N:31][OH:30])[NH:7][C:6]=1[CH3:28])=[O:4]
Reactant: CCOC(=O)C1=C(COCC=O)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Reactant: Cl
Reactant: [NH3+]O
Solvent: CCN(CC)CC
Solvent: CO
Product: CCOC(=O)C1=C(COCC=NO)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 4-(2-chlorophenyl)-2-methyl-6-(2-oxo-ethoxymethyl)-1,4-dihydro-3,5-pyridinedicarboxylic acid 5-ethyl 3-methyl ester (ID, 6.2 g), hydroxylammonium hydrochloride (1.27 g) and triethylamine (1.85 g) in methanol (100 mL) was stirred at room temperature for 6 h. Methanol was removed under reduced pressure and the residue was dissolved in ethyl acetate (200 mL) and water (200 mL). With vigorous stirring, the pH of the mixture was adjusted to 10 with aqueous 1N sodium hydroxide solution. After stirring for a further 15 min, the organic layer was collected, dried (sodium sulfate), filtered and concentrated in vacuo. The residue was recristallized from ether and hexane to give the title compound IB (6.1 g). HRMS: calc. for C20 H23CIN2O6 422.1245 found 422.1248; m.p. 161.4°-162.2° C.; IR (KBr, cm-1): 3446, 3379, 1698, 1671, 1601.
Reaction SMILES: Br[C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:17]([CH3:19])[CH3:18])[NH:9][C:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=[O:11])=[O:7].C([O-])([O-])=O.[Na+].[Na+].[F:31][C:32]([F:44])([F:43])[O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1B(O)O>COCCOC>[F:24][C:22]1[CH:21]=[CH:20][C:3]([O:4][CH2:5][C:6]([N:8]([CH:17]([CH3:19])[CH3:18])[NH:9][C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[O:11])=[O:7])=[C:2]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[O:33][C:32]([F:31])([F:44])[F:43])[CH:23]=1
Reactant: CC(C)N(NC(=O)c1cccs1)C(=O)COc1ccc(F)cc1Br
Reactant: OB(O)c1ccccc1OC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)c1cccs1)C(=O)COc1ccc(F)cc1-c1ccccc1OC(F)(F)F
Yield: 56.3 %

Procedure:
A solution of thiophene-2-carboxylic acid N′-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N′-isopropyl-hydrazide (263 mg, 0.63 mmol) in DME (5 ml)/2M Na2CO3 (1.10 ml, 2.22 mmol) was with 2-trifluoromethoxyphenylboronic acid (196 mg, 0.95 mmol) and Pd[PPh3]4 (146 mg, 0.13 mmol) in a microwave oven at 150° C. for 10 min. The reaction mixture was partitioned between water and DCM. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was adsorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate/hexane gradient to afford the product as a solid (176 mg, 56%). MS m/e 497.41 (M+H+)
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[CH2:13]1[CH2:23][CH2:22]N2[C:16](=NCCC2)[CH2:15][CH2:14]1.C1(Br)CCCCC1>CN(C=O)C>[CH:13]1([O:1][N:2]2[C:3](=[O:12])[C:4]3[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:7])[CH2:14][CH2:15][CH2:16][CH2:22][CH2:23]1
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CN(C)C=O
Solvent: BrC1CCCCC1
Product: O=C1c2ccccc2C(=O)N1OC1CCCCC1
Temperature: 55 °C
Reaction time: 15 h

Procedure:
N-hydroxylphthalimide (61.3 mmol, 10.0 g) was dissolved in anhydrous DMF (60 mL) under nitrogen. To the stirring solution, DBU (92.0 mmol, 13.75 mL) was injected followed by cyclohexyl bromide (76.6 irmol, 9.43 mL) and the reaction was warmed to 55° C. After stirring for 15 hours, the reaction was warmed to 80° C. for 5 hours, then cooled to room temperature and concentrated to a red oil. The reaction was partitioned between ethyl acetate and 1N HCl. The organic layer was washed with 1N NaOH, brine and dried over magnesium sulfate. The solvent was removed under vacuum and the crude product was triturated with hexanes providing 2.89 g (19%) of a yellow solid. Rf: 0.7 (2:1 hexanes/ethyl acetate); H1-NMR (CDCl3): δ 7.80 (2H,m), 7.73 (2H,m), 4.21 (1H,m), 2.02-1.98 (2H,m), 1.87-1.82 (2H,m), 1.59-1.53 (4H,m), 1.30-1.24 (2H,m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([Cl:11])=[O:10].[S:12](=[O:15])(=[O:14])=[O:13].C(Cl)(Cl)Cl>ClCCl.ClC(Cl)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([S:12]([OH:15])(=[O:14])=[O:13])[C:9]([Cl:11])=[O:10]
Reactant: O=C(Cl)Cc1ccccc1Cl
Reactant: O=S(=O)=O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: O=C(Cl)C(c1ccccc1Cl)S(=O)(=O)O
Temperature: 25 °C

Procedure:
A solution of 2-(2-chlorophenyl)acetyl chloride (1.89 g, 10 mmole) in dichloromethane (20 ml) was treated with a suspension of sulphur trioxide--dioxane complex (15 mmole) in dichloroethane at 0° C. The mixture was stirred at room temperature for eighteen hours and evaporated to afford a yellow gum. νmax. (CHCl3) 1800 cm-1.
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].CC1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][N+:10]=1[O-].C(O)C.C(=O)(O)[O-].[Na+]>CS(C)=O>[C:13]([C:12]1[CH:15]=[CH:16][C:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])=[N:10][CH:11]=1)#[N:14]
Reactant: Cc1ccc(C#N)c[n+]1[O-]
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCO
Product: CC(=O)OCc1ccc(C#N)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Acetic anhydride (3.2 g, 31.31 mmol) is heated to 115° C. under an argon atmosphere. The compound of Example 30A (700 mg, 5.22 mmol) is added and the solution is stirred at reflux for one hour. Ethanol (3 ml, 51.12 mmol) is added dropwise to the mixture and refluxing is continued for 10 minutes. The mixture is cooled to room temperature, poured into ice water and neutralised with saturated sodium bicarbonate solution. The aqueous phase is extracted with diethyl ether. The organic phase is washed with brine, dried with magnesium sulphate, filtered and concentrated in vacuo to afford a black oil. The oil is dissolved in dimethylsulfoxide (8 ml) and purified by preparative HPLC.
Reaction SMILES: [F:1][C:2]1([F:36])[CH2:5][CH:4]([CH2:6][O:7][CH2:8][C:9]2[CH:14]=[C:13]([C:15]([O:17]CC)=[CH2:16])[N:12]=[C:11]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[C:31]([CH3:33])[N:30]=[N:29][CH:28]=4)=[C:23]([O:34][CH3:35])[CH:22]=3)[N:10]=2)[CH2:3]1.O.Cl>O1CCOCC1>[F:36][C:2]1([F:1])[CH2:5][CH:4]([CH2:6][O:7][CH2:8][C:9]2[N:10]=[C:11]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[C:31]([CH3:33])[N:30]=[N:29][CH:28]=4)=[C:23]([O:34][CH3:35])[CH:22]=3)[N:12]=[C:13]([C:15](=[O:17])[CH3:16])[CH:14]=2)[CH2:3]1
Reactant: C=C(OCC)c1cc(COCC2CC(F)(F)C2)nc(Nc2ccc(-c3cnnc(C)c3)c(OC)c2)n1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(Nc2nc(COCC3CC(F)(F)C3)cc(C(C)=O)n2)ccc1-c1cnnc(C)c1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 95.3 %

Procedure:
To a solution of 4-(((3,3-difluorocyclobutyl)methoxy)methyl)-6-(1-ethoxyvinyl)-N-(3-methoxy-4-(6-methylpyridazin-4-yl)phenyl)pyrimidin-2-amine (104 mg, 0.21 mmol) in dioxane (15 mL) were added water (1 mL) and HCl (conc. 0.052 mL, 0.63 mmol). The mixture was stirred at 50° C. for 20 minutes. The solvent was evaporate and 50% saturated aqueous sodium bicarbonate solution was added. The mixture was extracted with DCM. The organic phase was separated on phase separator and evaporated to give the title compound (94 mg, 95%).
Reaction SMILES: [P:1]([O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1CCCCCCCCC)([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1CCCCCCCCC)[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1CCCCCCCCC.P(OC1C=CC(C(C)(C)C)=CC=1C(C)(C)C)(OC1C=CC(C(C)(C)C)=CC=1C(C)(C)C)OC1C=CC(C(C)(C)C)=CC=1C(C)(C)C.P(OCC)(OC1C(C)=CC(C(C)(C)C)=CC=1C(C)(C)C)OC1C(C)=CC(C(C)(C)C)=CC=1C(C)(C)C>>[P:1]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[O:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCCCCCCCCc1ccccc1OP(Oc1ccccc1CCCCCCCCC)Oc1ccccc1CCCCCCCCC
Agent: CC(C)(C)c1ccc(OP(Oc2ccc(C(C)(C)C)cc2C(C)(C)C)Oc2ccc(C(C)(C)C)cc2C(C)(C)C)c(C(C)(C)C)c1
Agent: CCOP(Oc1c(C)cc(C(C)(C)C)cc1C(C)(C)C)Oc1c(C)cc(C(C)(C)C)cc1C(C)(C)C
Product: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1

Procedure:
diphenyl alkyl phosphites; phenyl dialkyl phosphites; tris(nonylphenyl) phosphite [WESTON 399, available from GE Specialty Chemicals]; tris(2,4-di-tert-butylphenyl) phosphite [IRGAFOS 168, available from Ciba Specialty Chemicals Corp.]; and bis(2,4-di-tert-butyl-6-methylphenyl) ethyl phosphite [IRGAFOS 38, available from Ciba Specialty Chemicals Corp.]; and 2,2′,2″-nitrilo[triethyltris(3,3′5,5′-tetra-tert-butyl-1,1′-biphenyl-2,2′-diyl) phosphite [IRGAFOS 12, available from Ciba Specialty Chemicals Corp.].
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:14])[C:6]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]([OH:13])[CH:7]=1)[CH:2]=[CH2:3].[Br:15]C1C(O)=CC(C(O)=O)=CC=1O>>[CH2:1]([O:4][C:5](=[O:14])[C:6]1[CH:11]=[C:10]([OH:12])[C:9]([Br:15])=[C:8]([OH:13])[CH:7]=1)[CH:2]=[CH2:3]
Reactant: O=C(O)c1cc(O)c(Br)c(O)c1
Reactant: C=CCOC(=O)c1cc(O)cc(O)c1
Product: C=CCOC(=O)c1cc(O)c(Br)c(O)c1

Procedure:
This compound was prepared analogously to 3,5-Dihydroxy-benzoic acid allyl ester [Example 1(a)], however 4-bromo-3,5-dihydroxybenzoic acid was used instead of 3,5-dihydroxybenzoic acid. 1H NMR (DMSO-d6, 350 MHz): δ=7.04 (s, 2H, aromatic); 5.97-6.06 (m, 1H); 5.25-5.40 (m, 2H); 4.73-4.75(dd, 2H).
Reaction SMILES: C[Si](C1([B:10]([Cl:12])[Cl:11])C=CC=C1)(C)C.[CH3:13][Si:14]([C:17]1[CH:18]([Si](C)(C)C)[C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH3:16])[CH3:15].C(=O)=O.B(Cl)(Cl)Cl>>[CH3:13][Si:14]([C:17]1[CH:18]([B:10]([Cl:12])[Cl:11])[C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH3:16])[CH3:15]
Reactant: C[Si](C)(C)C1=Cc2ccccc2C1[Si](C)(C)C
Reactant: C[Si](C)(C)C1(B(Cl)Cl)C=CC=C1
Agent: ClB(Cl)Cl
Agent: O=C=O
Product: C[Si](C)(C)C1=Cc2ccccc2C1B(Cl)Cl
Temperature: -30 °C
Reaction time: 3 h

Procedure:
In a manner similar to the preparation of compound 2, 12.3 g (0.047 mol) of compound 13 were introduced into a round-bottomed flask which was cooled to -30° C. and had a reflux condenser cooled with dry ice. 5.6 g (0.046 mol) of BCl3 were added to this. When the addition was complete, the cooling bath was removed and the reaction mixture warmed to room temperature and was stirred for 3 hours. The temperature was then raised to 55° C. for 6 hours. After cooling and removal of the volatile contents in vacuo, the crude product was obtained. Distillation under a high vacuum gave the purified product, the main isomer of which was identified as follows:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([OH:24])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(N(C)C)=C(C)C.[NH2:33][C:34]1[CH:35]=[N:36][C:37]2[C:42]([C:43]=1[N:44]1[CH2:49][CH2:48][CH2:47][C@H:46]([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])[CH2:45]1)=[CH:41][CH:40]=[CH:39][CH:38]=2.N1C=CC=CC=1>C1COCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[S:13][C:12]([C:14]2[C:15]([F:21])=[CH:16][CH:17]=[CH:18][C:19]=2[F:20])=[N:11][C:10]=1[C:22]([NH:33][C:34]1[CH:35]=[N:36][C:37]2[C:42]([C:43]=1[N:44]1[CH2:49][CH2:48][CH2:47][C@H:46]([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:55])([CH3:54])[CH3:56])[CH2:45]1)=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:24])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(N)cnc3ccccc23)C1
Agent: CC(C)=C(Cl)N(C)C
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnc2ccccc2c1N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.5 %

Procedure:
To a solution of 5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (81.1 mg, 0.228 mmol) in THF (0.5 mL), a solution of 1-chloro-N,N,2-trimethylpropenylamine (Aldrich, 80.5 mg, 0.602 mmol) in THF (1.0 mL) was added. The mixture was stirred at room temperature for 5 h. To the above mixture was added a solution of tert-butyl [(3S)-1-(3-aminoquinolin-4-yl)piperidin-3-yl]carbamate (63.8 mg, 0.186 mmol) in THF (2.0 mL) followed by pyridine (146.4 mg, 1.851 mmol). The mixture was stirred at room temperature for 2 h, and then concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel (0-100% EtOAc in hexanes) to afford the sub-title compound as a yellow solid (115.8 mg, 91%). LCMS calc. for C34H39F2N6O5S (M+H)+: m/z=681.3. found 681.3.
Reaction SMILES: [ClH:1].Cl.[NH2:3]/[C:4](=[N:25]\[OH:26])/[C:5]1[CH:24]=[CH:23][C:8]2[CH:9]=[C:10]([C:12]([NH:14][C@@H:15]3[CH:20]4[CH2:21][CH2:22][N:17]([CH2:18][CH2:19]4)[CH2:16]3)=[O:13])[S:11][C:7]=2[CH:6]=1.[H-].[Na+].[C:29]1([CH2:35][C:36](OC)=O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>CN(C=O)C.C1COCC1>[ClH:1].[N:17]12[CH2:18][CH2:19][CH:20]([CH2:21][CH2:22]1)[C@@H:15]([NH:14][C:12]([C:10]1[S:11][C:7]3[CH:6]=[C:5]([C:4]4[N:3]=[C:36]([CH2:35][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[O:26][N:25]=4)[CH:24]=[CH:23][C:8]=3[CH:9]=1)=[O:13])[CH2:16]2
Reactant: N/C(=N\O)c1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reactant: COC(=O)Cc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2ccc(-c3noc(Cc4ccccc4)n3)cc2s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
110 mg (0.26 mmol) of 6-[amino(hydroxyimino)methyl]-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride (Example 27A) are dissolved in 2 ml of DMF and 0.75 ml of THF. 250 mg of 4 Å molecular sieves are added, and the mixture is stirred at room temperature for 30 min. Addition of 31.2 mg (0.79 mmol) of sodium hydride (60% suspension in mineral oil) is followed by heating at 60° C. for 20 min and then cooling to room temperature. A solution of 110 μl (0.79 mmol) of methyl phenylacetate in 1 ml of THF is added, and the mixture is heated at 80° C. for 14 h. Addition of a further 20.8 mg (0.52 mmol) of sodium hydride (60% suspension in mineral oil) and 1.14 ml (7.91 mmol) of methyl phenylacetate in 1 ml of THF is followed by heating at 70° C. for a further 24 h. The reaction is stopped by adding water. Purification takes place by preparative HPLC. The product fractions are concentrated and, after addition of a 5:1 mixture of methanol and 4N hydrogen chloride in dioxane, again concentrated. Drying under high vacuum results in 4.1 mg (3% of theory) of the title compound.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:41])[C@@H:6]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:7][C:8]1[CH:32]=[CH:31][C:11]([O:12][C:13]([NH:15][CH2:16][CH2:17][CH2:18][C@@H:19]([C:28](O)=[O:29])[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:14])=[CH:10][CH:9]=1)[CH:2]=[CH2:3].[C:42]([S:61][CH2:62][C@@H:63]([C:65]([NH2:67])=[O:66])[NH2:64])([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH2:1]([O:4][C:5](=[O:41])[C@@H:6]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]([NH:15][CH2:16][CH2:17][CH2:18][C@@H:19]([C:28]([NH:64][C@H:63]([C:65]([NH2:67])=[O:66])[CH2:62][S:61][C:42]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)([C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[O:29])[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:14])=[CH:31][CH:32]=1)[CH:2]=[CH2:3]
Reactant: NC(=O)[C@@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1)NC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(N)=O)cc1)NC(=O)OC(C)(C)C
Temperature: 60 °C

Procedure:
1.20 g (2.07 mmol) of the compound from example 9A was dissolved in 48 ml dichloromethane. 0.750 g (2.07 mmol) S-Trityl-L-cysteinamide, 0.36 ml (2.07 mmol) N,N-diisopropylethylamine and 0.787 g (2.07 mmol) HATU were added. The reaction mixture was split into 3 portions. The portions were heated for 30 min in a sealed tube at 60° C. in a microwave synthesizer. From the combined reaction mixture the solvent was removed by rotary evaporation (approx. 40° C., approx. 200 mbar, approx. 30 min.). The raw product was dissolved in dichloromethane and chromatographed over approx. 400 ml silica gel. Solvents used were dichloromethane/ethyl acetate 2/1, dichloromethane/ethyl acetate 1/1. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 1.30 g (1.5 mmol, 56% of theory, 82% purity) of the desired product.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3]C.[H-].[Na+].[CH3:8][C:9]1[C:14]([C:15]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([O:24][CH3:25])=[C:19]([O:26][CH3:27])[C:18]=2[O:28][CH3:29])=[O:16])=[C:13]([O:30][CH3:31])[CH:12]=[CH:11][CH:10]=1.C(COC)OC>C(OCC)(=O)C.O>[CH3:8][C:9]1[C:14]([C:15]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([O:24][CH3:25])=[C:19]([O:26][CH3:27])[C:18]=2[O:28][CH2:29][CH2:1][CH2:2][CH3:3])=[O:16])=[C:13]([O:30][CH3:31])[CH:12]=[CH:11][CH:10]=1
Reactant: CCCCO
Reactant: COc1cc(C)c(C(=O)c2c(C)cccc2OC)c(OC)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: CCCCOc1c(OC)c(OC)cc(C)c1C(=O)c1c(C)cccc1OC

Procedure:
A mixture of n-butanol (5 ml) and sodium hydride (60% in oil, 10 mmol) is stirred until the formation of H2 gas ceases. A mixture of 1C (0.7 g, 2,2 mmol) and dimethoxyethane (15 ml) is added to the resulting reaction mixture. Subsequently, the reaction mixture is heated under reflux with stirring for 24 hours. A mixture of water and ethyl acetate (1:1 v/v; 100 ml) is then slowly added at room temperature. The organic phase is separated, concentrated and the residue is purified by column chromatography (petrol ether: ethyl acetate, 95:5 v/v) yielding the pure product as a yellow oil, 0.2 g, (24.4%).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]([NH:9][C@@H:10]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:11][CH2:12][OH:13])[C:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]([OH:28])=[O:27])=[CH:21][C:20]=2[O:29][CH3:30])=[C:5]([CH3:31])[N:4]=1.[C:32]([O-])(O)=O.[Na+]>CO>[NH2:2][C:3]1[N:8]=[C:7]([NH:9][C@@H:10]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:11][CH2:12][OH:13])[C:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]([O:28][CH3:32])=[O:27])=[CH:21][C:20]=2[O:29][CH3:30])=[C:5]([CH3:31])[N:4]=1
Reactant: CCCC[C@@H](CCO)Nc1nc(N)nc(C)c1Cc1ccc(CC(=O)O)cc1OC
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCC[C@@H](CCO)Nc1nc(N)nc(C)c1Cc1ccc(CC(=O)OC)cc1OC
Temperature: 70 °C

Procedure:
Concentrated HCl (1 mL) was added to a solution of the product from step (i) (0.1 g) in MeOH (2 mL). The mixture was heated at 70° C. for 2 h, poured into saturated aqueous NaHCO3 solution (10 mL) and the aqueous was adjusted to pH 7 by adding NaHCO3. The aqueous was extracted with EtOAc and the combined organic phase was dried, filtered and evaporated. The crude product was purified by RPHPLC to give the title compound, 0.018 g.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[C:16]([CH2:21][C:22]#[N:23])[CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC([OH:28])(C)C.[OH-].[K+]>C(OCC)(=O)C>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[C:16]([CH2:21][C:22]([NH2:23])=[O:28])[CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCCn1ccc2c(CC#N)cccc21
Reactant: CC(C)(C)O
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCCn1ccc2c(CC(N)=O)cccc21
Yield: 77 %

Procedure:
Add {1-[3-(tert-Butyldimethylsilyloxy)propyl]-1H-indol-4-yl}acetonitrile (1.9 g, 11.0 mmol) to 2-methyl-2-propanol (20 mL). Heat to reflux under nitrogen and add potassium hydroxide pellets (7.4 g, 132 mmol). Stir and reflux under nitrogen for 30 minutes. Pour solution off of the excess potassium hydroxide and dilute with ethyl acetate. Wash with a 1:1 mixture of aqueous saturated sodium chloride, aqueous saturated sodium hydrogen carbonate. Dry the organic phase over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Rinse the solid with cold diethyl ether and dry under vacuum to obtain 1.62 g (77%) of the title compound as an off-white solid. ESMS (M++1): 347.2.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N(CC)C(C)C)(C)C.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.ClCCl>O1CCOCC1>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][NH:24][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:7]
Reactant: NCc1ccccc1
Reactant: CCOC(=O)CBr
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CNCc1ccccc1
Temperature: 90 °C
Yield: 75 %

Procedure:
To a solution of ethyl bromoacetate (2.22 mL, 20.0 mmol) in 1,4-dioxane (40 mL) is added N,N-diisopropylethylamine (7.0 mL, 40.0 mol) and benzylamine (3.3 mL, 30.0 mmol), and the mixture is heated at 90° C. for 3 h. The reaction mixture is cooled to RT, dichloromethane is added, and the solution is washed with water, brine, then dried (MgSO4), and filtered. The filtrate is evaporated, and the residue is residue purified by chromatography on silica gel; elution with EtOAc:MeOH:heptane (35:5:60) gives 2.9 g of the product 421. 1H NMR (CDCl3) δ 7.4-7.3 (m, 6 H), 4.19 (q, 2 H), 3.80 (s, 2 H), 3.40 (s, 2 H), 1.25 (t, 3 H); MS: m/z 194 (M++1).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:12][CH3:13])=[CH:7][CH:8]=2)[N:3]=1.[O:14]1[CH2:19][CH2:18][N:17]([S:20]([C:23]2[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:16][CH2:15]1>CC(O)C>[CH3:13][O:12][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[N:11][C:2]([NH:27][C:26]3[CH:28]=[CH:29][C:23]([S:20]([N:17]4[CH2:18][CH2:19][O:14][CH2:15][CH2:16]4)(=[O:22])=[O:21])=[CH:24][CH:25]=3)=[N:3]2)=[CH:8][CH:7]=1
Reactant: COc1ccc2cnc(Cl)nc2c1
Reactant: Nc1ccc(S(=O)(=O)N2CCOCC2)cc1
Solvent: CC(C)O
Product: COc1ccc2cnc(Nc3ccc(S(=O)(=O)N4CCOCC4)cc3)nc2c1
Temperature: 80 °C
Yield: 99 %

Procedure:
A mixture of 2-chloro-7-methoxyquinazoline (1 eq) and 4-(Morpholinosulfonyl) Aniline (1 eq) in 2-propanol was heated at 80° C. overnight. Product was precipitated in the reaction mixture. The precipitate was filtered, washed and dried under vacuum to provide 7-methoxy-N-(4-(morpholinosulfonyl)phenyl)quinazolin-2-amine as a yellow solid in 99% yield. ES/MS m/z 401.0 (MH+).