Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:12])=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5](O)=[O:6].O1CCCC1.B(F)(F)F.O1CCCC1.O>C(Cl)Cl>[NH2:1][C:2]1[C:3]([Cl:12])=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[CH2:5][OH:6]
Reactant: Nc1cc(Cl)cc(C(=O)O)c1Cl
Agent: FB(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: Nc1cc(Cl)cc(CO)c1Cl
Temperature: 8 °C
Reaction time: 1 h
Yield: 11.5 %

Procedure:
Into a 1 liter three-neck flask was introduced 40 g (0.19 mole) of 3-amino-2,5-dichlorobenzoic acid and 150 ml of tetrahydrofuran. The solution was cooled to 8°-10° C. in an ice bath. A borontrifluoride-tetrahydrofuran (1M) solution (280 ml) was added dropwise over a period of 1 hr. After being stirred at 8° C. for an additional 1 hr. the solution was allowed to warm up slowly to room temperature. The reaction flask was then cooled again in an ice bath and 50 ml of water was added through a dropping funnel. The mixture was taken into 1 liter of methylene chloride and washed once with NaHCO3 and twice with water, then dried over calcium sulfate. The methylene chloride solution afforded 19.2 g of crude solid product, mp 111-121. Five grams of the crude solid was recrystallized from acetonitrile to yield 4.2 g of 3-amino-2,5-dichlorobenzyl alcohol; mp 121-127; nmr (DMSO-d6) δ 4.50 (D, 2H), 5.34 (t, 1H), 5.52 (S, 2H), 6.73 (S, 2H); ir (CHCl3) 3490, 3380, 3240, 1630 and 1598 Cm-1.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[CH2:26]([C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)[CH3:27]>C(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][C:28]([CH2:26][CH3:27])=[CH:29][CH:30]=2)[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Reactant: CCc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1ccc(C(=O)N[C@@H]2CCc3cccc(N4CCN(C)CC4)c3C2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (110 mg, 0.46 mmol) and triethylamine (95 μL, 0.68 mmol) in methylene chloride (20 mL) was added dropwise 4-ethylbenzoyl chloride (81 mg, 0.48 mmol) in methylene chloride (5 mL). After the addition the reaction was allowed to stir at ambient temperature for 15 min and then washed with water. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:4) as the eluent. Yield: 120 mg (66%) of the title compound as white crystals: mp 177-178° C.; [α]21D -43° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 377 (27, M+).
Reaction SMILES: C[O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=O.[NH2:12][C:13]1[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:14]=1[C:15]#[N:16].[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33]C[C@H:31]([NH2:35])[CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[Br:21][C:19]1[CH:20]=[C:13]2[C:14]([C:15]([NH:35][C@H:31]3[CH2:33][CH2:34][N:29]([C:27]([O:26][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:28])[CH2:30]3)=[N:16][C:5]([C:4]3[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=3[OH:2])=[N:12]2)=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Reactant: N#Cc1ccc(Br)cc1N
Reactant: COc1ccccc1C(=O)Cl
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3ccccc3O)nc3cc(Br)ccc23)C1

Procedure:
The title compound was prepared from 2-methoxybenzoyl chloride, 2-amino-4-bromobenzonitrile and (S)-3-amino-piperidine-1-carboxylic acid tert-butyl ester using methods analogous to those described in Synthesis 1, steps 1-A, 2-B and 1-D.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([NH2:23])[CH:17]=3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[C:31](Cl)(Cl)=[O:32]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]4[O:22][C:31](=[O:32])[NH:23][C:18]=4[CH:17]=3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C(Cl)Cl
Reactant: COc1ccc(-c2nc(-c3ccc(O)c(N)c3)cs2)cc1OC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(-c2nc(-c3ccc4oc(=O)[nH]c4c3)cs2)cc1OC
Reaction time: 0.5 h
Yield: 15.4 %

Procedure:
In 20 ml of tetrahydrofuran was dissolved 300 mg of 2-(3,4-dimethoxyphenyl)-4-(3-amino-4-hydroxyphenyl)thiazole. Thereto was added 0.46 ml of triethylamine at room temperature. The mixture was stirred at the same temperature for 30 minutes. 100 mg of phosgene was blown thereinto, and the resulting mixture was stirred for 2 hours. The solvent was distilled off. The residue was washed with diethyl ether, followed by filtration to collect crystals. The crystals were recrystallized from methanol to obtain 50 mg of 2-(3,4-dimethoxyphenyl)-4-(benzoxazol-2-on-5-yl)thiazole as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]([CH2:17][C:18](O)=[O:19])[C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])=[O:7])=[CH:4][CH:3]=1.[NH:23]1[CH2:32][CH2:31][CH2:30][C@H:24]1[C:25]([O:27][CH2:28][CH3:29])=[O:26]>>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]([CH2:17][C:18]([N:23]2[CH2:32][CH2:31][CH2:30][C@H:24]2[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:19])[C:9]2[C:10]([CH3:16])=[CH:11][CH:12]=[CH:13][C:14]=2[CH3:15])=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@@H]1CCCN1
Reactant: Cc1cccc(C)c1N(CC(=O)O)C(=O)c1ccc(Cl)cc1
Product: CCOC(=O)[C@@H]1CCCN1C(=O)CN(C(=O)c1ccc(Cl)cc1)c1c(C)cccc1C

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl)-2-(2,6-dimethylanilino)acetic acid and ethyl L-prolinate and suitable processing produces ethyl N-[N-(p-chlorobenzoyl)-2-(2,6-dimethylanilino)acetyl]-L-prolinate (oil), saponification of which and processing of the reaction product yields N-[N-(p-chlorobenzoyl)-2-(2,6-dimethylanilino)acetyl]-L-proline (M.P. 199°).
Reaction SMILES: [C:1](=[O:8])([O:5][CH2:6][CH3:7])OCC.[H-].[Na+].[C:11]1(=[O:21])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1.C(O)(=O)C>C1(C)C=CC=CC=1>[O:21]=[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH:12]1[C:1]([O:5][CH2:6][CH3:7])=[O:8]
Reactant: CCOC(=O)OCC
Reactant: O=C1CCCc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C1CCc2ccccc2C1=O
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
To a solution of diethyl carbonate (200 g) in toluene (800 ml) was added 60% sodium hydride (27.4 g), and the mixture was stirred at 50° C. for 30 minutes, and thereto was added dropwise a solution of 3,4-dihydro-1(2H)-napthalenone (50 g) in toluene (200 ml). The mixture was refluxed for one hour, and poured into ice-water, and the mixture was neutralized with acetic acid. The toluene layer was collected, washed successively with an aqueous potassium carbonate solution and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by distillation under reduced pressure to give ethyl 1,2,3,4-tetrahydro-1-oxo-2-naphthalenecarboxylate (47 g) as an oily product, b.p. 135°-145° C./2 mmHg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([CH3:28])=[C:15]([CH2:17][N:18]3[CH:22]=[C:21]([C:23]([O:25]CC)=[O:24])[CH:20]=[N:19]3)[N:16]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[OH-].[Na+].O>C(O)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([CH3:28])=[C:15]([CH2:17][N:18]3[CH:22]=[C:21]([C:23]([OH:25])=[O:24])[CH:20]=[N:19]3)[N:16]=2)[CH:5]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:7]=1
Reactant: CCOC(=O)c1cnn(Cc2nc(-c3cc(Cl)cc(C(F)(F)F)c3)sc2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Cc1sc(-c2cc(Cl)cc(C(F)(F)F)c2)nc1Cn1cc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
To a solution of the compound (230 mg, 0.54 mmol) obtained in Example 83a in ethanol/tetrahydrofuran (v/v=1/1, 4 mL) was added 2N aqueous sodium hydroxide solution (1.1 mL, 2.2 mmol), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the aqueous layer was washed with diethyl ether, neutralized with 1N aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was recrystallized (ethyl acetate-hexane) to give the title compound (150 mg, 70%) as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](Cl)=[O:4].[NH2:8][C:9]1[CH:34]=[CH:33][C:12]([CH2:13][N:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[CH:17]([CH2:30][CH3:31])[S:16][C:15]2=[O:32])=[CH:11][CH:10]=1>ClCCl.C(N(CC)CC)C>[F:1][C:2]([F:7])([F:6])[C:3]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[CH:17]([CH2:30][CH3:31])[S:16][C:15]2=[O:32])=[CH:33][CH:34]=1)=[O:4]
Reactant: O=C(Cl)C(F)(F)F
Reactant: CCC1SC(=O)N(Cc2ccc(N)cc2)N=C1c1ccc(OC)c(OC)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC1SC(=O)N(Cc2ccc(NC(=O)C(F)(F)F)cc2)N=C1c1ccc(OC)c(OC)c1

Procedure:
0.8 ml of trifluoroacetyl chloride is added with stirring and ice cooling to a solution of 1.4 g of 3-(4-amino-benzyl)-5-(3,4-dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one ("D") in 60 ml of dichloromethane and 1 ml of triethylamine, and the mixture is subsequently stirred for 3 hours. The solvent is removed and the residue is worked up in the conventional manner. Recrystallization from isopropanol/petroleum ether gives 1.9 g of 3-(4-trifluoroacetamidobenzyl)-5(3,4-dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one, m.p. 124°.
Reaction SMILES: [OH:1][CH:2]1[C:27]2[C:19](=[CH:20][C:21]3[O:25][CH2:24][O:23][C:22]=3[CH:26]=2)[C:4]2([C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:5]2=[O:18])[CH2:3]1.[H-].[Na+].I[CH3:31].O>C1COCC1>[CH3:31][O:1][CH:2]1[C:27]2[C:19](=[CH:20][C:21]3[O:25][CH2:24][O:23][C:22]=3[CH:26]=2)[C:4]2([C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:5]2=[O:18])[CH2:3]1
Reactant: CCCCCN1C(=O)C2(CC(O)c3cc4c(cc32)OCO4)c2ccccc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCN1C(=O)C2(CC(OC)c3cc4c(cc32)OCO4)c2ccccc21
Yield: 57 %

Procedure:
To a solution of 7-hydroxy-1′-pentyl-6,7-dihydrospiro[indeno[5,6-d][1,3]dioxole-5,3′-indol]-2′(1′H)-one (0.05 g, 0.14 mmol) in THF (10.0 mL) was added sodium hydride (0.01 mg, 0.21 mmol) at 0° C. The reaction mixture was stirred for half an hour followed by the addition of iodomethane (0.50 mL). The mixture was stirred at ambient temperature for two hours, then poured into water (100 mL), and extracted with ethyl acetate (100 mL). The organic layer was washed with water, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to flash column chromatography to afford the title compound (0.03 g, 57%) as an oil: 1H NMR (300 MHz, CDCl3) δ 7.26-7.18 (m, 1H), 6.98-6.82 (m, 4H), 6.10 (s, 1H), 5.88 (s, 2H), 5.26 t, 1H), 3.88-3.63 (m, 2H), 3.45 (s, 3H), 2.71-2.54 (m, 2H), 1.80-1.65 (m, 2H), 1.45-1.29 (m, 4H), 0.90 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 178.3, 148.9, 148.4, 142.4, 136.8, 136.6, 135.1, 128.1, 123.1, 122.6, 108.5, 105.0, 103.2, 101.5, 82.7, 57.9, 55.6, 43.4, 40.3, 29.1, 27.2, 22.4, 14.0: MS (ES+) m/z 402.4 (M+23).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@:4]1([CH2:17][OH:18])[CH2:8][C@H:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:5]1.[Br:19]N1C(=O)CCC1=O.O>CCOC(C)=O>[Br:19][C@@H:6]1[C@H:5]2[O:1][CH2:2][CH2:3][C@@:4]2([CH2:17][OH:18])[CH2:8][C@@H:7]1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C=C[C@@](CO)(CCO)C1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@]2(CO)CCO[C@@H]2[C@H]1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a chilled solution of the product of Step F (343.60 g) in EtOAc (4 L) was added N-bromosuccinimide (237.60 g) followed by stirring at rt for 18 h. To the mixture was added water (5 mL) and the reaction heated to 60° C. for 30 min. The reaction was filtered, the filtrate was washed with aqueous sodium thiosulfate until the organic layer was negative for peroxides. The organic layer was washed with aqueous Na2CO3 (10%), dried (Na2SO4) and the reaction was concentrated under reduced pressure. Near the end of the concentration, heptane (1.2 L) was added, and the product was collected by filtration to provide the product of Step G. 1H NMR (400 MHz, CHLOROFORM-d) δ=4.78-4.91 (m, 1H), 4.41 (br. s., 1H), 4.31 (s, 2H), 3.88-3.98 (m, 1H), 3.61-3.77 (m, 3H), 2.08-2.24 (m, 1H), 1.82 (m, 2H), 1.60-1.70 (t, 1H), 1.45 (s, 9H)
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][CH2:6][C@H:5]([O:9][C:10]2[C:15]([NH:16][C:17]3[C:18]4[C:25]([CH3:26])=[C:24]([C:27](O)=[O:28])[S:23][C:19]=4[N:20]=[CH:21][N:22]=3)=[CH:14][CH:13]=[CH:12][N:11]=2)[CH2:4]1.N.C[N:32](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][CH2:6][C@H:5]([O:9][C:10]2[C:15]([NH:16][C:17]3[C:18]4[C:25]([CH3:26])=[C:24]([C:27]([NH2:32])=[O:28])[S:23][C:19]=4[N:20]=[CH:21][N:22]=3)=[CH:14][CH:13]=[CH:12][N:11]=2)[CH2:4]1
Reactant: CO[C@H]1CCC[C@H](Oc2ncccc2Nc2ncnc3sc(C(=O)O)c(C)c23)C1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: CN(C)C=O
Product: CO[C@H]1CCC[C@H](Oc2ncccc2Nc2ncnc3sc(C(N)=O)c(C)c23)C1

Procedure:
Prepared analogously to example 1.4 from 0.11 g racemic 4-[2-((trans)-3-Methoxycyclohexyloxy)-pyridin-3-ylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid and ammonia (7 M in methanol) using TBTU instead of HATU in DMF as solvent.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[F:18])=[O:10].N([O-])=O.[Na+].C(OC(C)C)(=O)C.[I-:30].[K+]>O.C(O)(=O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([I:30])=[C:3]([C:9]([C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[F:18])=[O:10])[CH:4]=1
Reactant: [I-]
Reactant: Nc1ccc(Cl)cc1C(=O)c1c(F)cccc1F
Agent: O=N[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CC(=O)OC(C)C
Product: O=C(c1cc(Cl)ccc1I)c1c(F)cccc1F
Temperature: 2.5 °C
Yield: 79.7 %

Procedure:
Into a reactor at room temperature was added (2-amino-5-chlorophenyl)(2,6-difluorophenyl)methanone (1, 60.0 kg, 224 mol) and acetic acid (427 L). The mixture was stirred until all solids fully dissolved, filtered and washed with acetic acid (9.47 L). Concentrated HCl (156 L) was added over a minimum of 30 minutes at 20 to 25° C. and the resulting mixture was cooled to 0 to 5° C. A solution of sodium nitrite (18.6 kg, 269 mol) in water (88.0 L) was added while maintaining the reaction temperature between 0 and 5° C. The mixture was stirred for 1 h at 0 to 5° C. Water (270 L) and isopropyl acetate (717 L) were then added at 0 to 5° C. A solution of potassium iodide (50.2 kg, 303 mol) in water (133 L) was added over 1 h at 0 to 5° C. The reaction mixture was stirred for 30 min and warmed to 20 to 25° C. over 1.5 h. The layers were separated and the organic phase was washed with a dilute brine solution (22 kg NaCl in 200 L water) and a sodium carbonate solution (175 kg Na2CO3 in 523 L water). The resulting organic layer was washed twice with a sodium ascorbate solution (15.8 kg in 188 L water for each wash) followed by water (200 L). The organic phase was concentrated using a maximum 50° C. jacket temperature until 430 L of solvent was removed. Heptane (400 L) was added and the mixture was concentrated using a 50° C. jacket temperature until 395 L of solvent were removed. 2-Butanol (398 L) was added and the mixture was concentrated using a maximum 60° C. jacket temperature until 322 L of solvent were removed. An additional portion of 2-butanol (398 L) was added and the mixture was concentrated using a 70° C. jacket temperature until 390 L of solvent were removed. The reaction mixture was cooled to −5 to −8° C., stirred for 2 h, filtered and washed with 2-butanol (2×84.2 L) at −5 to 0° C. The resulting wet cake was dried at 40 to 50° C. under vacuum to provide 67.6 kg (80% yield) of 2. 1H NMR (300 MHz, CDCl3) δ 7.89 (d, J=8.2 Hz, 1H), 7.51 (m, 1H), 7.44 (d, J=2.3 Hz, 1H), 7.18 (dd, J=2.3, 8.2 Hz, 1H), 7.00 (m, 2H); Elemental Anal. Calcd. for C13H6ClF2IO: C, 41.25; H, 1.60; Cl, 9.37; F, 10.04; I, 33.52; O, 4.23. Found: C, 41.36; H, 1.65; Cl, 9.51; F, 10.03; I, 33.41; O, 4.04.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([Cl:16])[N:3]=1.[CH3:17][NH:18][CH2:19][CH2:20][C:21]#[N:22].CN(C)C=O>C(O)(C)C>[ClH:16].[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:18]([CH2:19][CH2:20][C:21]#[N:22])[CH3:17])[N:3]=1
Reactant: CNCCC#N
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: COc1cc2nc(N(C)CCC#N)nc(N)c2cc1OC
Product: Cl
Temperature: 100 °C
Reaction time: 6 h
Yield: 74.2 %

Procedure:
50 gms, 0.208 moles of 4-amino-2-chloro-6,7-dimethoxyquinazoline and 21.2 gms, 0.252 moles of 3-methylaminopropionitrile were charged in a round bottom flask containing 350 ml dimethylformamide. The reaction mass was stirred at about 100° C. for 6 hours, cooled to 25° C. and charged with 250 ml isopropanol. The reaction mass was further stirred for 15 minutes, filtered and washed with 50 ml isopropanol and subjected to drying at 50° C. for 7-8 hours to yield N-(4-amino-6,7-dimethoxyquinazol-2-yl)-N-methyl-2-cyanoethylamine hydrochloride (50 gms).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[N:11]=[CH:10][N:9]([CH2:12][C:13]3[CH:29]=[CH:28][C:16]4[N:17]=[C:18]([NH:20][C@@H:21]5[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]5[OH:27])[S:19][C:15]=4[CH:14]=3)[C:6]2=[N:7][CH:8]=1)=[CH2:2]>[Ni].CO.C1COCC1>[CH2:1]([C:3]1[CH:4]=[C:5]2[N:11]=[CH:10][N:9]([CH2:12][C:13]3[CH:29]=[CH:28][C:16]4[N:17]=[C:18]([NH:20][C@@H:21]5[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]5[OH:27])[S:19][C:15]=4[CH:14]=3)[C:6]2=[N:7][CH:8]=1)[CH3:2]
Reactant: C=Cc1cnc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1cnc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 30 %

Procedure:
To a stirred solution of (1R,2R)-2-((6-((6-vinyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (20 mg, 0.049 mmol) from Example 98 in 1:1 MeOH/THF (2 mL) was added Raney Ni (10 mg). The resulting mixture was stirred under a H2 balloon at rt for 4 h. LCMS analysis showed that the reaction was complete. The reaction mixture was filtered through a Celite plug and the filtrate was purified with preparative TLC to give (1R,2R)-2-((6-((6-ethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (6 mg, 30%). 1H NMR (300 MHz, DMSO-d6) δ 8.53 (br s, 1H), 8.26 (br s, 1H), 7.95 (d, J=12.4 Hz, 2H), 7.66 (br s, 1H), 7.25-7.42 (m, 1H), 7.06-7.25 (m, 1H), 5.45 (br s, 2H), 4.74 (d, J=4.5 Hz, 1H), 3.51 (br s, 1H), 2.73 (d, J=7.2 Hz, 2H), 2.04 (br s, 1H), 1.86 (br s, 1H), 1.62 (br s, 2H), 1.23 (t, J=6.8 Hz, 7H). LCMS (ESI) m/z 408 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH2:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([S:19][CH3:20])[N:14]=2)=[CH:4][CH:3]=1.[OH-:30].[NH4+]>O.C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH2:21][CH2:22][CH2:23][N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([S:19]([CH3:20])=[O:30])[N:14]=2)=[CH:6][CH:7]=1
Reactant: CSc1nccc(-c2c(-c3ccc(F)cc3)ncn2CCCN2CCOCC2)n1
Reactant: [OH-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: CS(=O)c1nccc(-c2c(-c3ccc(F)cc3)ncn2CCCN2CCOCC2)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 73 %

Procedure:
A solution of K2S2O8 (0.20 g, 0.73 mmol) in water (5 mL) was added to 4-(4-fluorophenyl)-5-[2-(methylthio)-4-pyrimidinyl]-1-[3-(4-morpholinyl)propyl]imidazole (0.20 g, 0.48 mmol) in glacial acetic acid (10 mL). After stirring at ambient temperature for 72 h, the reaction mixture was poured into water, neutralized with concentrated aqueous ammonium hydroxide and extracted four times with dichloromethane. The organic phases were combined and evaporated. The residue was purified by flash chromatography eluting successively with 1%, 2%, 4% and 10% methanol in dichloromethane to afford the title compound as a clear oil (0.15 g, 73%). 1H NMR (CDCl3) δ8.57(d, J=7 Hz, 1H), 7.77(s, 1H), 7.47 (dd, 2H), 7.18(d, J=5 Hz, 1H)7.09(t, J=9 Hz, 2H), 4.56(m, 2H), 3.72(t, J=5 Hz, 4H), 3.00(s, 3H), 2.40(brd. s, 4H), 2.33(t, J=8 Hz, 2H), 1.94(m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[CH2:20]([NH:22][CH2:23][CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)[CH3:21]>N1C=CC=C(C)C=1>[ClH:1].[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([N:26]4[CH2:27][CH2:28][CH:24]([CH2:23][NH:22][CH2:20][CH3:21])[CH2:25]4)[CH:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Reactant: CCNCC1CCNC1
Solvent: Cc1cccnc1
Product: CCNCC1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C1
Product: Cl
Temperature: 25 °C
Yield: 51.2 %

Procedure:
A solution of 0.57 g (2.0 mmol) of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.58 ml (4.0 mmol) of 3-[(ethylamino)methyl]pyrrolidine and 10 ml of 3-picoline was heated under reflux for 17 hours. After cooling to room temperature the mixture was filtered and the solid washed with hot methanol to give 0.42 g of the title compound, mp >300° C.