Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[CH2:13][C:14]([OH:16])=O>C(Cl)Cl>[Br:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[CH2:13][C:14]([Cl:3])=[O:16]
Reactant: O=C(O)Cc1ccc(F)cc1Br
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)Cc1ccc(F)cc1Br

Procedure:
Add thionyl chloride (1.5 g, 12.6 mmol) to a solution of (2-bromo-4-fluoro-phenyl)-acetic acid (0.3 g, 1.26 mmol) in DCM (3 mL). Reflux the mixture for 2 h. Remove the solvent and excess thionyl chloride under reduced pressure to give the intermediate (2-bromo-4-fluorophenyl)-acetyl chloride. Dissolve the residue in DCM (3 mL) and add to a stirred solution of ethanolamine (0.15 mL, 2.52 mmol) in DCM (3 mL) at 0° C. Stir the mixture overnight. Dilute with DCM and wash with saturated NaHCO3, water, and aqueous saturated sodium chloride. Dry over sodium sulfate. Concentrate the solution in vacuo to give the title compound as a white solid (300 mg, 86%). MS (ES) m/z 276 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])=[CH:12][CH:11]=1)=[O:8].[NH:26]1[CH2:30][CH2:29][C@@H:28]([OH:31])[CH2:27]1>>[Br:1][C:2]1[C:3]([N:26]2[CH2:30][CH2:29][C@@H:28]([OH:31])[CH2:27]2)=[N:4][CH:5]=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(OC(F)(F)C(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Reactant: O[C@@H]1CCNC1
Product: O=C(Nc1ccc(OC(F)(F)C(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described infashion to that described in Stage 33.1 using 5-bromo-6-chloro-N-(4-(perfluoroethoxy)phenyl)nicotinamide (Stage 220.2) and (R)-pyrrolidin-3-ol to afford an off-white crystalline solid. HPLC (Condition 4) tR=6.01 min, UPLC-MS (Condition 3) tR=1.17 min, m/z=496.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:4][CH:3]=1.O[C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[C@H:17]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:16][CH2:15]2.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][O:10][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C@H:17]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:16][CH2:15]3)[CH:5]=[CH:4][CH:3]=1
Reactant: OCCc1cccc(Cl)n1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(O)ccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCc3cccc(Cl)n3)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 29.7 %

Procedure:
To a solution of 2-(6-chloro-2-pyridinyl)ethanol (Example 470, 250 mg, 1.59 mmol) and ethyl [(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]acetate (Example 6, 698 mg, 3.17 mmol) in THF (4 mL) were added PPh3 (832 mg, 3.17 mmol) and DIAD (641 mg, 3.17 mmol). The reaction mixture was vigorously stirred at rt for 24 h, concentrated under reduced pressure, and the residue was purified by silica gel chromatography (6:1 hexanes/EtOAc) to give the product (170 mg, 30%). 1H NMR (400 MHz, CDCl3) δ 1.28 (t, 3H), 1.72-1.77 (m, 1H), 2.34-2.43 (m, 2H), 2.71 (dd, 1H), 2.81-2.89 (m, 2H), 3.21 (t, 2H), 3.51-3.52 (m, 1H), 4.17 (q, 2H), 4.31 (t, 2H), 6.69 (d, 1H), 6.76 (s, 1H), 7.04 (d, 1H), 7.19 (dd, 2H), 7.57 (t, 1H).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[NH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH:36]1[C:41]([NH2:43])=[O:42]>>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:38]4[CH2:39][CH2:40][NH:35][CH:36]([C:41]([NH2:43])=[O:42])[CH2:37]4)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: NC(=O)C1CNCCN1
Product: NC(=O)C1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CCN1

Procedure:
4-[5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]piperazine-2-carboxamide was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and piperazine-2-carboxylic acid amide following General Procedure C.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.CN(C)C=O.[N+:14]([C:17]1[O:21][C:20]([CH:22]=[CH:23][C:24]2[N:33]=[C:32](Cl)[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=2)=[CH:19][CH:18]=1)([O-:16])=[O:15]>O>[N+:14]([C:17]1[O:21][C:20]([CH:22]=[CH:23][C:24]2[N:33]=[C:32]([NH:7][C:6]3[CH:5]=[CH:4][C:3]([OH:8])=[CH:2][CH:1]=3)[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=2)=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: Nc1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(C=Cc2nc(Cl)c3ccccc3n2)o1
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(C=Cc2nc(Nc3ccc(O)cc3)c3ccccc3n2)o1
Reaction time: 72 h
Yield: 64.1 %

Procedure:
A 250 ml Erlenmeyer flask equipped with a magnetic stirrer and oil bath for heating was charged with 8.0 g (0.07 mole) of p-aminophenol and 25 ml of dimethylformamide. After the p-aminophenol was dissolved by stirring, 9.05 g (0.03 mole) of 2-[2-(5-nitro-2-furyl)vinyl]-4-chloroquinazoline (IV) was added. The reaction mixture was then heated at 70°-90°C for 2 hours after which 60 ml of water was added and the solution after cooling was placed in a refrigerator for crystallization. After three days, the brown yellow solid was collected, washed first with water, then methanol and then dried to obtain 7.20 g of product melting at 250°-60°C with decomposition. Recrystallization from a 1:1 dimethylformamidemethanol mixture gave 6.5 g of orange crystals of the purified product which melted at 270°-2°C with decomposition.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]2[C:9]([N:10]=[C:11]3[C:16]=1[CH2:15][CH2:14][CH2:13][CH2:12]3)=[CH:8][CH:7]=[C:6]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:5]=2.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[OH-].[Na+]>C1(O)C=CC=CC=1>[ClH:2].[CH2:27]([NH:34][C:3]1[C:4]2[C:9]([N:10]=[C:11]3[C:16]=1[CH2:15][CH2:14][CH2:13][CH2:12]3)=[CH:8][CH:7]=[C:6]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:5]=2)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NCc1ccccc1
Reactant: CCCCCCCCCCc1ccc2nc3c(c(Cl)c2c1)CCCC3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Oc1ccccc1
Product: CCCCCCCCCCc1ccc2nc3c(c(NCc4ccccc4)c2c1)CCCC3
Yield: 43.9 %

Procedure:
9-Chloro-7-decyl-1,2,3,4-tetrahydroacridine hydrochloride (5.0 g) was dissolved in 50 ml of phenol and heated at 150° C. with 3.50 g of benzylamine. After 2 hours at this temperature the reaction mixture was poured into 10% NaOH and extracted with Et2O. The organic phase was separated, washed with water and treated with 5% HCl. The insoluble hydrochloride was filtered off and recrystallized from MeOH/Et2O to give 2.59 g of product, m.p. 215° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH2:12][OH:13])=[O:9])=[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:5]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])=[C:4]([CH3:29])[N:3]=1.[C:30](Cl)(=[O:32])[CH3:31].O>N1C=CC=CC=1>[CH3:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH2:12][O:13][C:30](=[O:32])[CH3:31])=[O:9])=[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:5]([C:23]([O:25][CH:26]([CH3:27])[CH3:28])=[O:24])=[C:4]([CH3:29])[N:3]=1
Reactant: Cc1nc(C)c(C(=O)OC(C)C)c(-c2cccc([N+](=O)[O-])c2)c1C(=O)OCCO
Reactant: CC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OCCOC(=O)c1c(C)nc(C)c(C(=O)OC(C)C)c1-c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
20.1 g (50 mmols) of 2-hydroxyethyl isopropyl 2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate (Example 1) were dissolved in 75 ml of pyridine. 5.9 g (75 mmoles) of acetyl chloride were added to this. After the exothermic reaction was over, the reaction mixture was stirred at room temperature for 3 hours, poured into water and extracted with CH2Cl2. The organic extracts were washed with dilute hydrochloric acid and, after drying over sodium sulphate, evaporated in vacuo. The resulting oil crystallized completely, it was stirred with petroleum ether, filtered off with suction and dried.
Reaction SMILES: C(N(CC)CC)C.[C:8](#[N:12])[CH2:9][C:10]#[N:11].[Cl-].Cl[C:15]([Cl:21])=[N+:16]([CH2:19][CH3:20])[CH2:17][CH3:18]>ClC1C=CC=CC=1>[Cl:21][C:15]([N:16]([CH2:17][CH3:18])[CH2:19][CH3:20])=[C:9]([C:8]#[N:12])[C:10]#[N:11]
Reactant: N#CCC#N
Reactant: CC[N+](CC)=C(Cl)Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: Clc1ccccc1
Product: CCN(CC)C(Cl)=C(C#N)C#N
Reaction time: 4 h
Yield: 33.7 %

Procedure:
A solution of 12.1 g of triethylamine, 4.0 g of malononitrile, and 20 ml of chlorobenzene was added to a slurry of 11.4 g of N-(dichloromethylene)-N,N-diethylammonium chloride and 50 ml of chlorobenzene, at ambient temperature. The reaction temperature was kept below 50° by controlling the rate of addition (time required for complete addition, 30 minutes). After addition, the reaction mixture was stirred for four hours while it returned to ambient temperature. The reaction mixture was filtered and the filtrate concentrated on the rotary evaporator to give a brownish-red liquid. Vacuum distillation gave 3.7 g of liquid 3-chloro-2-cyano-3-(diethylamino)propenenitrile; b.p. 127°-131°/0.05 mm Hg. The ir and nmr spectra were consistent with the assigned structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[N:15]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=4)[N:13]=[C:12]([C:24]([O:26]C)=O)[C:8]=3[NH:9][C:10]=2[CH:11]=1.[NH3:28]>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[N:15]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=4)[N:13]=[C:12]([C:24]([NH2:28])=[O:26])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: N
Reactant: COC(=O)c1nc(-c2ccc(OC)cc2)nc2c1[nH]c1cc(OC)ccc12
Solvent: CO
Product: COc1ccc(-c2nc(C(N)=O)c3[nH]c4cc(OC)ccc4c3n2)cc1
Temperature: 80 °C

Procedure:
A suspension of methyl 7-methoxy-2-(4-methoxyphenyl)-5H-pyrimido[5,4-b]indole-4-carboxylate (97 mg, 0.27 mmol) in a 7 N solution of ammonia in MeOH (10 mL) in a sealed microwave vial was heated at 80° C. overnight. The solvent was removed and the residue was suspended in EtOAc. Filtration gave 7-methoxy-2-(4-methoxyphenyl)-5H-pyrimido[5,4-b]indole-4-carboxamide (58 mg) as a yellow solid. MS (ESI) m/z 349.0 (M+H). 1H NMR (DMSO-d6) δ ppm 11.68 (1H, br. s.), 8.59-8.73 (3H, m), 8.20 (1H, d, J=8.85 Hz), 8.05 (1H, s), 7.29 (1H, d, J=2.14 Hz), 7.08 (2H, d, J=8.85 Hz), 6.96 (1H, dd, J=8.70, 2.29 Hz), 3.90 (3H, s), 3.87 (3H, s).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[C:9]([O:12]C)[CH:8]=[CH:7][CH:6]=2)[CH3:2].B(Br)(Br)Br.C(Cl)Cl>>[CH2:1]([C:3]1[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[C:9]([OH:12])[CH:8]=[CH:7][CH:6]=2)[CH3:2]
Reactant: CCc1cc2c(OC)cccc2n1Cc1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCc1cc2c(O)cccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 53.7 %

Procedure:
3.1 g (11.7 mmol) of 2-ethyl-4-methoxy-1-(phenylmethyl)-1H-indole is O-demethylated by treating it with 48.6 mL of 1M BBr3/CH2Cl2, then stirred at room temperature for 5 hours and concentrated at reduced pressure. The residue is dissolved in ethyl acetate, then washed with brine and dried. The reaction product is then chromatographed on silica gel (eluted with 20% EtOAc/hexane) to give 1.58 g (54% yield) of 2-ethyl-4-hydroxy-1-(phenylmethyl)-1H-indole, mp, 86-90° C.
Reaction SMILES: [CH:1]1[C:15](=[O:16])[N:14]=[C:13]2[N:3]([C@@H:4]3[O:8][C@H:7]([CH2:9][OH:10])[C@@H:6]([OH:11])[C@@H:5]3[O:12]2)[CH:2]=1.C1C=CN=CC=1.[FH:23].C([O-])([O-])=O.[Ca+2]>O1CCOCC1>[F:23][C@@H:5]1[C@H:6]([OH:11])[C@@H:7]([CH2:9][OH:10])[O:8][C@H:4]1[N:3]1[CH:2]=[CH:1][C:15](=[O:16])[NH:14][C:13]1=[O:12]
Reactant: F
Reactant: O=c1ccn2c(n1)O[C@H]1[C@H](O)[C@@H](CO)O[C@H]12
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2F)c(=O)[nH]1
Temperature: 0 °C
Yield: 79 %

Procedure:
The title compound is prepared via a modification of a literature procedure, J. Fox, et al., J. Org. Chem., Vol. 29, pp. 558-564 (1964). Thus, 2,2′-cyclouridine (5.65 g, 25 mmol) is treated with a solution of 70% hydrogen fluoride/pyridine (65 mL) in anhydrous dioxane (500 mL) at 120° C. in a sealed steel vessel for twenty hours. The reaction mixture is cooled to ice temperature, poured into ice (400 mL), and the pH is adjusted to 7 by addition of solid CaCO3. After the solvent is evaporated in vacuo (1 torr), the residue is dissolved in methanol, adsorbed onto silica gel, and purified by column chromatography using silica and ethyl acetatemethanol (v/v, 20:1) as eluent to give 2′-deoxy-2′-fluoro-uridine as a white solid (4.81 g, 79%). The 5′-DMT and 3′-cyanoethoxy-diisopropyl phosphoramidite derivatized nucleoside are obtained in accordance with the procedures of examples 65 and 66.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([CH2:34][CH:35]1[CH2:37][CH2:36]1)(=[O:33])=[O:32]>>[CH:35]1([CH2:34][S:31]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:6]2[CH:5]=[CH:4][C:3]([C:17]3[CH:22]=[N:21][C:20]([NH2:23])=[N:19][CH:18]=3)=[C:2]([F:1])[CH:7]=2)(=[O:32])=[O:33])[CH2:36][CH2:37]1
Reactant: O=S(=O)(CC1CC1)c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: Nc1ncc(-c2ccc(-c3ccccc3S(=O)(=O)CC3CC3)cc2F)cn1

Procedure:
The title compound was prepared using conditions analogous to those used to make Example 6 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine and 1-bromo-2-((cyclopropylmethyl)sulfonyl)benzene. MS (ESI): mass calcd. for C20H18FN3O2S, 383.11; m/z found, 384.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J=1.5, 2H), 8.11 (dd, J=7.9, 1.2, 1H), 7.80 (m, 1H), 7.72 (m, 1H), 7.62 (m, 1H), 7.46 (dd, J=7.6, 1.1, 1H), 7.37 (dd, J=11.8, 1.7, 1H), 7.28 (dd, J=7.9, 1.7, 1H), 6.93 (s, 2H), 2.91 (d, J=7.2, 2H), 0.78-0.69 (m, 1H), 0.45-0.37 (m, 2H), 0.13-0.05 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:4][C:3]=1[NH:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([P:22](=[O:29])([O:26]CC)[O:23][CH2:24][CH3:25])=[CH:18][CH:17]=1)=[O:15].[OH-].[Na+]>O1CCOCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:4][C:3]=1[NH:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([P:22](=[O:26])([OH:29])[O:23][CH2:24][CH3:25])=[CH:18][CH:17]=1)=[O:15]
Reactant: CCOP(=O)(OCC)c1ccc(C(=O)Nc2cc(-c3cccs3)ccc2N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCOP(=O)(O)c1ccc(C(=O)Nc2cc(-c3cccs3)ccc2N)cc1
Temperature: 80 °C

Procedure:
A suspension of diethyl [4-({[2-amino-5-(2-thienyl)phenyl]amino}carbonyl)phenyl]phosphonate (24.2 mg, 0.0562 mmol) (24.2 mg, 0.0562 mmol), dioxane (140 uL) and 5N aqueous NaOH (140 uL) was heated to 80° C. (oil bath temperature) for 1 h. The reaction was quenched with TFA (˜140 uL) and concentrated. The residue was purified by HPLC (25-80% MeCN in H2O with 0.025% TFA) to afford the requisite product. 1H NMR (DMSO-d6, 600 MHz) δ 9.77 (s, 1H), 8.30 (t, J=8.3 Hz, 2H), 7.69-7.64 (m, 2H), 7.48-7.45 (m, 1H), 7.34-7.31 (m, 1H), 7.26 (dd, J=8.2, 2.0 Hz, 1H), 7.22 (d, J=2.6 Hz, 1H), 7.02 (dd, J=5.0, 3.5 Hz, 1H), 6.79 (d, J=8.5 Hz, 1H), 5.16 (s, 2H), 3.6-3.54 (m, 2H), 1.05 (t, J=7.04 Hz, 3H). MS: cal'd 403 (MH+), exp 403 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])[CH2:18][CH2:17]3)=[C:11](I)[CH:10]=2)[C:5]([Cl:33])=[CH:4][N:3]=1.[CH:34]([C:36]1[CH:37]=[C:38]([NH2:42])[CH:39]=[N:40][CH:41]=1)=[CH2:35]>>[NH2:42][C:38]1[CH:37]=[C:36](/[CH:34]=[CH:35]/[C:11]2[CH:10]=[C:9]([NH:8][C:6]3[C:5]([Cl:33])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:14]=[CH:13][C:12]=2[NH:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH2:18][CH2:17]2)[CH:41]=[N:40][CH:39]=1
Reactant: O=C(OCc1ccccc1)N1CCC(Nc2ccc(Nc3nc(Cl)ncc3Cl)cc2I)CC1
Reactant: C=Cc1cncc(N)c1
Product: Nc1cncc(/C=C/c2cc(Nc3nc(Cl)ncc3Cl)ccc2NC2CCN(C(=O)OCc3ccccc3)CC2)c1
Yield: 75 %

Procedure:
The desired compound was prepared according to the procedure of Example B334, step G, using benzyl 4-({4-[(2,5-dichloropyrimidin-4-yl)amino]-2-iodophenyl}amino)piperidine-1-carboxylate and 5-vinylpyridin-3-amine as the starting materials in 75% yield. LCMS for C30H30Cl2N7O2 (M+H)+: m/z=590.2, 592.1.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7]N.C=O.[ClH:11].[CH3:12][N:13](C=O)C>>[ClH:11].[S:1]1[C:2]2=[CH:6][CH:7]=[CH:12][NH:13][CH:3]2[CH2:4][CH2:5]1
Reactant: NCCc1cccs1
Reactant: CN(C)C=O
Agent: C=O
Agent: Cl
Product: C1=CNC2CCSC2=C1

Procedure:
2-thienylethlamine was reacted with formaldehyde to give the corresponding formimine, which was then added to a solution of hydrochloric acid in DMF, resulting in cyclization to tetrahydrothienopyridine hydrochloride. The DMF used was anhydrous, KF≦0.05%, to avoid formimine hydrolysis.
Reaction SMILES: CO[C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[CH3:22][N:23]([CH3:25])[NH2:24]>>[CH3:22][N:23]([CH3:25])[NH:24][C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4]
Reactant: CCCCc1noc(C)c1COc1cc(C(=O)OC)[nH]n1
Reactant: CN(C)N
Product: CCCCc1noc(C)c1COc1cc(C(=O)NN(C)C)[nH]n1
Yield: 59 %

Procedure:
As described for example 26d, 5-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.34 mmol) was converted, using N,N-dimethylhydrazine instead of 4-aminotetrahydropyran, to the title compound (65 mg, 59%) which was obtained as a colorless oil. MS: m/e=322.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([OH:23])=[C:14]([C:20](O)=[O:21])[N:15]=[C:16]2[Cl:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:25][O:26][C:27](=[O:31])[C@H:28]([CH3:30])[NH2:29]>>[CH3:25][O:26][C:27](=[O:31])[C@@H:28]([NH:29][C:20]([C:14]1[N:15]=[C:16]([Cl:19])[C:17]2[C:12]([C:13]=1[OH:23])=[CH:11][CH:10]=[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:18]=2)=[O:21])[CH3:30]
Reactant: O=C(O)c1nc(Cl)c2cc(OCc3ccccc3)ccc2c1O
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Product: COC(=O)[C@H](C)NC(=O)c1nc(Cl)c2cc(OCc3ccccc3)ccc2c1O

Procedure:
7-Benzyloxy-1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid, 0.33 g, was coupled with L-Alanine methyl ester hydrochloride, 0.150 g, analogously to Example A-1 a). 0.264 G of white solid were obtained: MS-(+)-ion, M+1=415 amu.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:16]3[CH:17]=[C:18]([CH:21]=[C:22]([F:24])[CH:23]=3)[C:19]#[N:20])[CH:8]=2)[NH:3]1.[CH2:25]([O:27][CH:28](OCC)[O:29][CH2:30][CH3:31])[CH3:26]>>[CH2:25]([O:27][CH:28]([O:29][CH2:30][CH3:31])[N:3]1[C:4]2[C:9](=[CH:8][C:7]([C:16]3[CH:17]=[C:18]([CH:21]=[C:22]([F:24])[CH:23]=3)[C:19]#[N:20])=[CH:6][CH:5]=2)[C:10]2([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)[C:2]1=[O:1])[CH3:26]
Reactant: CCOC(OCC)OCC
Reactant: N#Cc1cc(F)cc(-c2ccc3c(c2)C2(CCCCC2)C(=O)N3)c1
Product: CCOC(OCC)N1C(=O)C2(CCCCC2)c2cc(-c3cc(F)cc(C#N)c3)ccc21
Yield: 56.4 %

Procedure:
A solution of 3-(1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-5-fluorobenzonitrile (1.0 eq, 0.27 g, 0.84 mmol) in triethylorthoformate (2 mL, 12 mmol) was heated to 150° C. for 1 h. The reaction mixture was allowed to cool, the excess triethylorthoformate was removed in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with 10% EtOAc/hexane) to give the title compound (0.2 g, 56%) as a white powder, mp 146° C. 1H NMR (DMSO-d6; 400 MHz) δ 1.13 (t, 6H, J=7 Hz), 1.60-1.96 (m, 10H), 3.48 (m, 2H), 3.66 (m, 2H), 6.17 (s, 1H), 7.35 (d, 1H, J=8.3 Hz), 7.68 (dd, 1H, J=2.0, 8.3 Hz), 7.77 (ddd, 1H, J=1.3, 2.4 Hz), 7.89 (d, 1H, J=2.0 Hz), 7.92 (dt, 1H, J=2.4, 10.5 Hz)8.08 (dd, 1H, J=1.3, 2.9 Hz). MS ((+)-EI) m/z 422 [M+]. Anal. Calcd for C25H27FN2O3: C, 71.07; H, 6.44; N, 6.63. Found: C, 70.75; H, 6.48; N, 6.52.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6](=[O:13])[CH:7]([CH3:12])[O:8][C:9]=1[CH2:10]C)(=[O:3])[CH3:2].[C:14](Cl)(=O)C>>[C:1]([O:4][C:5]1[C:6](=[O:13])[CH:7]([CH2:12][CH3:14])[O:8][C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCC1=C(OC(C)=O)C(=O)C(C)O1
Product: CCC1OC(C)=C(OC(C)=O)C1=O

Procedure:
A mixture (1.08 g) of 4-acetoxy-2-ethyl-5-methyl-3(2H)-furanone (major) and 4-acetoxy-5-ethyl-2-methyl-3(2H)-furanone (minor) was obtained by the same method as in Preparation Example 2 except that 0.54 ml of acetyl chloride was used rather than 0.95 ml of pivaloyl chloride.
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@@H:27]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[C@H:26]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@@H:25]([CH2:44][OH:45])[O:24][C@H:11]1[S:12][C:13]1[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=[CH:15][C:14]=1[CH3:23])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:46]1[CH:51]=[CH:50][C:49]([CH2:52]Br)=[CH:48][CH:47]=1.[H-].[Na+]>C1COCC1.CN(C=O)C>[C:1]([O:9][C@@H:10]1[C@@H:27]([O:28][Si:29]([C:32]([CH3:33])([CH3:34])[CH3:35])([CH3:30])[CH3:31])[C@H:26]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@@H:25]([CH2:44][O:45][CH2:52][C:49]2[CH:50]=[CH:51][CH:46]=[CH:47][CH:48]=2)[O:24][C@H:11]1[S:12][C:13]1[CH:18]=[C:17]([C:19]([CH3:20])([CH3:21])[CH3:22])[CH:16]=[CH:15][C:14]=1[CH3:23])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ccccc1
Reactant: Cc1ccc(C(C)(C)C)cc1S[C@@H]1O[C@H](CO)[C@@H](OCc2ccccc2)[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1OC(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1ccc(C(C)(C)C)cc1S[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Yield: 87.8 %

Procedure:
To a solution of crude 28 (approx. 1.23 mmol) in THF/DMF (9:1, 10 ml) at 0° C., BnBr (0.18 ml, 1.50 mmol) and NaH (36 mg, 1.50 mmol) were added. The solution was warmed to room temperature over 2 h, then cooled to 0° C. again and further BnBr (0.18 ml, 1.50 mmol) was added. The reaction was warmed to room temperature over 30 min, cooled to 0° C. and quenched by the addition of water. After dilution with Et2O the phases were separated and the aqueous layer extracted with Et2O. The organic phase was then dried over MgSO4, filtered and concentrated. Column chromatography on silica gel (hexanes/ethyl acetate) afforded 29 (797 mg, 1.08 mmol, 88%). 1H-NMR (400 MHz, CDCl3) δ 8.14-7.00 (m, 18H, Ar—H), 5.31 (dd, 1H, J1=10.1 Hz, J2=8.9 Hz, 2-H), 4.83 (app. d, 1H, J=11.3 Hz, benzyl-Ha), 4.72 (d, 1H, J=10.2 Hz, 1-H), 4.63 (app. d, 1H, J=11.0 Hz, benzyl-Hb), 4.58 (app. d, 2H, J=3.1 Hz, benzyl-H), 3.95 (app. t, 1H, J=8.7 Hz, 3-H), 3.78-3.51 (m, 4H, 4-H, 5-H, 6-H), 2.15 (s, 3H, S—CH3), 1.25 (s, 9H, S-tBu), 0.79 (s, 9H, TBS-tBu), 0.00 (s, 3H, TBS-CH3), −0.16 (s, 3H, TBS-CH3); 13C-NMR (100 MHz, CDCl3) δ 165.6, 149.7, 138.2, 136.5, 133.2, 130.5, 130.1, 129.8, 129.2, 128.5, 128.4, 128.0, 127.72, 127.68, 127.6, 124.7, 88.0 (C-1), 79.5 (C-5), 78.9 (C-4), 77.0 (C-3), 75.1, 73.6 (C-2), 73.5, 69.0 (C-6), 31.4, 25.8, 20.3, −3.9, −4.1; HRMS (ESI): Calcd for C44H56O6SSiNa+ [M+Na]+ 763.3459. found: 763.3500