Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[N:11]1[N:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[O:13][C:12]1=[O:20]>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N:11]2[N:15]=[C:14]([C:16]([CH3:17])([CH3:19])[CH3:18])[O:13][C:12]2=[O:20])[CH:4]=1
Reactant: CC(C)(C)c1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(=O)o1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1nn(-c2cc(N)ccc2Cl)c(=O)o1
Temperature: 80 °C
Yield: 90.2 %

Procedure:
Electrolytic iron powder (93.5 g) was suspended in 5% acetic acid (187.2 ml), and the suspension was heated to 80° C. A solution of 3-(2-chloro-5-nitrophenyl)-5-(1,1-dimethylethyl)-1,3,4-oxadiazol-2(3H)-one (47.21 g) in acetic acid (167.5 ml) and ethyl acetate (167.5 ml) was added thereto. The resultant mixture was heated at a temperature of 70° C. for 3 hours. The reaction mixture was subjected to filtration on celite while hot. The filtrate was extracted with ethyl acetate, and the extract was washed with water and sodium bicarbonate solution and dried. Removal of the solvent under reduced pressure gave 3-(5-amino-2-chlorophenyl)-5-(1,1-dimethylethyl)-1,3,4-oxadiazol-2(3H)-one (38.28 g). m.p., 126.0° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](Cl)=[O:13])([CH3:4])([CH3:3])[CH3:2].[NH2:16][NH2:17].C(N(CC)CC)C>C1COCC1>[C:1]([O:5][C:6](=[O:15])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:13])[NH:16][NH2:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)Cl
Reactant: NN
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)NN
Temperature: 0 °C
Reaction time: 8 h
Yield: 54.5 %

Procedure:
A solution of carbamoyl chloride 1 (1.00 g; from above) in dry THF (3.5 ml) was added over 10 minutes to an ice-cold solution of anhydrous hydrazine (0.269 g; 0.310 ml; 8.40 mmol) and triethylamine (0.708 g; 0.975 ml; 7.00 mmol) in dry THF (4 ml). Stirring was continued overnight at room temperature. The mixture was filtered and evaporated to a light yellow solid. Recrystallization from hexanes-ethyl/acetate gave pure carbazide 3 (0.533 g; 2.33 mmol; 52%) as a white solid, mp 83°-84° C. TLC (silica gel; CH2Cl2 --CH3OH, 10:1)Rf=0.25-0.35. MS m/e 173 (M+ -56). Analysis: Calculated for C10H19N3O3 : C, 52.39; H, 8.35; N, 18.33. Found: C, 52.08; H, 8.58; N, 18.01; NMR (CDCl3); δ1.43 (9H.S); 2.0-2.3 (4H,m); 3.1-3.4(2H,m); 3.8(2H,bs): 4.3-4.6(1H,m); 6.2(1H,bs); IR(CHCl3 ): 3500-3300, 1730, 1660, 1640 cm-1. [α]D =-46.5±0.5°.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].Br[C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([N:28]5[CH2:29][CH2:30][O:31][CH2:32][CH2:33]5)[CH:23]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: Brc1cccc(N2CCOCC2)c1
Reactant: CS(=O)(=O)c1cccc(-c2cccn3nc(N)nc23)c1
Product: CS(=O)(=O)c1cccc(-c2cccn3nc(Nc4cccc(N5CCOCC5)c4)nc23)c1

Procedure:
[8-(3-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(3-morpholin-4-yl-phenyl)-amine was prepared from 8-(3-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (100.0 mg, 0.3468 mmol) and 4-(3-bromo-phenyl)-morpholine (126.0 mg, 0.5204 mmol) in a manner analogous to Step 2d and was isolated as a tan foam (0.018 g, 12%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.60-8.58 (m, 1H), 8.48 (dd, J=6.7, 1.1 Hz, 1H), 8.46-8.42 (m, 1H), 8.02-7.98 (m, 1H), 7.72 (t, J=7.8 Hz, 1H), 7.68 (dd, J=7.5, 1.1 Hz, 1H), 7.33-7.30 (m, 1H), 7.25 (t, J=8.0 Hz, 1H), 7.06 (dd, J=7.8, 1.5 Hz, 1H), 7.01 (dd, J=7.2, 7.2 Hz, 1H), 6.85 (s, 1H), 6.58 (dd, J=8.4, 2.1 Hz, 1H), 3.91-3.86 (m, 4H), 3.25-3.20 (m, 4H), 3.13 (s, 3H). MS=450 (MH)+.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][CH2:5][CH2:6][NH:7][CH2:8][C:9](=[O:34])[CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([O:18][C:19](=[O:33])[NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:14][CH2:13]1.[OH-].[Na+].Cl>C1COCC1>[C:22]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[NH:20][C:19]([O:18][CH:15]1[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][C:9]([CH2:8][NH:7][CH2:6][CH2:5][CH2:4][C:3]([OH:35])=[O:2])=[O:34])[CH2:17][CH2:16]1)=[O:33]
Reactant: COC(=O)CCCNCC(=O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CCCNCC(=O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-({3-[4-(biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]-propionyl}methylamino)butyric acid methyl ester (1.00 g, 2.08 mmol) in THF (10 mL) was added dropwise aqueous sodium hydroxide (1.0 M, 10.4 mL, 10.4 mmol) and the reaction mixture was stirred overnight at room temperature. LC-MS (Method 10-90) showed product was present (Rt 3.34 min; in/z 468.2 [M+H]+). The pH of the mixture was adjusted to pH 5 with aqueous hydrochloric acid (6 M) and the mixture was concentrated under reduced pressure. Aqueous ammonium chloride solution was added to the residue and this mixture was washed with EtOAc. The pH of the aqueous layer was adjusted to pH 4 with phosphate buffer solution and the aqueous layer was then extracted with a 1:3 mixture of isopropyl acetate/chloroform (4×). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a colorless oil, which was used without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]3[CH2:12][CH:11]3[CH:13]=O)[CH:8]=2)[CH:3]=[CH:2]1.[CH3:15][NH:16][CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]3[CH2:12][CH:11]3[CH2:13][N:16]([CH3:17])[CH3:15])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=CC1CC1c1ccc2cc[nH]c2c1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: CN(C)CC1CC1c1ccc2cc[nH]c2c1

Procedure:
The crude 2-(1H-indol-6-yl)-cyclopropanecarbaldehyde was dissolved in methanol at room temperature with stirring. Dimethylamine (1M solution in THF, 20.00 mL, 20.00 mmol) was added followed by sodium triacetoxyborohydride (4.24 g, 20.00 mmol) After 15 h of stirring at room temperature, the solution was concentrated to dryness in vacuo. The residue was then partitioned between methylene chloride and 1 N NaOH solution. The layers were separated, and the organic layer dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude amine was purified by flash chromatography (50% MeOH/EtOAc) to give [2-(1H-indol-6-yl)-cyclopropylmethyl]-dimethyl-amine as a yellow solid (0.62 g, 74% for the two reactions). 1H NMR (CDCl3): δ8.61 (bs, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.08 (t, J=2.7 Hz, 1H), 7.06 (s, 1H), 6.86 (dd, J=11.4, 1.8 Hz, 1H), 6.47 (m, 1H), 2.51 (m, 1H), 2.35 (s, 7H), 1.85 (m, 1H), 0.99 (m, 1H), and 0.85 (m, 1H); LCMS: MH+: 215.16, 78% AP.
Reaction SMILES: [Cl:1][C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:5]2=[C:4]([C:18]([N:20]2C=CN=C2)=[O:19])[C:3]=1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[N:32])[CH:26]=1.N.O>CN(C)C=O>[C:18]([C:4]1[C:3]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[N:32])[CH:26]=2)=[C:2]([Cl:1])[N:6]2[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:5]=12)(=[O:19])[NH2:20]
Reactant: CC(C)(C)OC(=O)N1CCn2c(Cl)c(-c3cccc(C#N)c3)c(C(=O)n3ccnc3)c2C1
Agent: N
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCn2c(Cl)c(-c3cccc(C#N)c3)c(C(N)=O)c2C1
Temperature: 110 °C
Reaction time: 3 h
Yield: 99.6 %

Procedure:
To a solution of 3.28 g (7.26 mmol) of tert-butyl 6-chloro-7-(3-cyanophenyl)-8-(1H-imidazol-1-ylcarbonyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate in 4 ml of dimethylformamide in an autoclave are added 6 ml of 33% aqueous ammonia. The mixture is stirred for 3 hours at 110° C. and, after cooling, is then poured into 80 ml of water and the solid is separated out by filtration. The solid is taken up in dichloromethane, the solution is then dried over sodium sulfate and the solvent is evaporated off under reduced pressure to give 2.9 g of tert-butyl 8-carbamoyl-6-chloro-7-(3-cyanophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate after drying.
Reaction SMILES: [C:1]([C:3]1[C:7](I)=[CH:6][N:5]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[N:4]=1)#[N:2].C([Li])CCC.[F:26][C:27]([F:39])([F:38])[C:28]([F:37])([F:36])[C:29]([F:35])([F:34])[C:30](OC)=[O:31].O>O1CCCC1>[C:1]([C:3]1[C:7]([C:30](=[O:31])[C:29]([F:34])([F:35])[C:28]([F:36])([F:37])[C:27]([F:39])([F:38])[F:26])=[CH:6][N:5]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[N:4]=1)#[N:2]
Reactant: COC(=O)C(F)(F)C(F)(F)C(F)(F)F
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1I
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C(=O)C(F)(F)C(F)(F)C(F)(F)F
Temperature: -73 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (3.0 g) in tetrahydrofuran (80 ml) at -80° C. under an atmosphere of nitrogen was added, at such a rate that the temperature of the reaction mixture did not exceed -73° C., n-butyllithium (2.78 ml of a 2.5M solution in hexanes). The mixture was stirred at -73° C. for 10 minutes and then a solution of methyl heptafluorobutyrate (1.07 ml) in tetrahydrofuran (5 ml) was then added at such a rate that the temperature of the reaction mixture did not exceed -75° C. Upon completion of the addition the mixture allowed to warm to room temperature over a period of 1.5 hours. Water (100 ml) was added and the mixture extracted twice with ethyl acetate (50 ml). The combined organic layers were dried (Na2SO4) and evaporated to give a pale yellow solid which was purified by column chromatography on silica gel (150 g) eluted with ether:hexane (3:2). Combination and evaporation of suitable fractions gave a yellow oil which was further purified by column chromatography on silica gel (150 g) eluted initially with hexane:ether (19:1), then hexane:ether (9:1) and finally hexane:ether (1:1). Combination and evaporation of suitable fractions gave the title compound as a pale yellow solid, m.p. 102-103° C.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([N:15]1[CH2:19][C@H:18]([OH:20])[CH2:17][C@H:16]1[C:21](=[O:24])[NH:22][CH3:23])=[O:14])([CH3:11])([CH3:10])[CH3:9].[CH3:25][S:26](Cl)(=[O:28])=[O:27].[Cl-].[Na+]>O1CCCC1>[C:8]([O:12][C:13]([N:15]1[CH2:19][C@H:18]([O:20][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:17][C@H:16]1[C:21](=[O:24])[NH:22][CH3:23])=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CS(=O)(=O)Cl
Reactant: CNC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
7.11 ml of triethylamine were added, whilst ice-cooling, to a solution of 11.29 g of (2S, 4R)-1-(t-butoxycarbonyl)-2-methylcarbamoyl-4-hydroxypyrrolidine [prepared as described in step (1) above] dissolved in 120 ml of dry tetrahydrofuran, and then 3.93 ml of methanesulfonyl chloride were added to the resulting mixture, and the mixture was stirred at 0° to 5° C. for 30 minutes and then at 15° C. for 30 minutes. It was then poured into an aqueous solution of sodium chloride and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, giving 11.58 g of the title compound as colorless crystals.
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([O:16][CH3:17])[CH2:11][NH:10][C@H:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)=[CH:3][CH:2]=1.[C:24]([O:28][C:29]([NH:31][C@@H:32]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH:41]=[CH2:42])[C:33](O)=[O:34])=[O:30])([CH3:27])([CH3:26])[CH3:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:2]=[CH:3][C:4]([C:7]2([O:16][CH3:17])[CH2:11][N:10]([C:33](=[O:34])[C@@H:32]([NH:31][C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH:41]=[CH2:42])[CH:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)=[CH:5][CH:6]=1
Reactant: C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@@H]1C[C@@](OC)(c2ccc(-c3ccccc3)cc2)CN1
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=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC(OC)(c2ccc(-c3ccccc3)cc2)CC1C(=O)OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.4 %

Procedure:
To a solution of (2S,4R)-methyl 4-(biphenyl-4-yl)-4-methoxypyrrolidine-2-carboxylate (150 mg, 0.482 mmol), (S)-2-(tert-butoxycarbonylamino)non-8-enoic acid (144 mg, 0.530 mmol), and HATU (260 mg, 0.723 mmol) in DCM (5 ml) was added N,N-diisopropylethylamine (0.252 ml, 1.445 mmol) at 0° C. The reaction mixture was allowed to warm to rt and was stirred for 18 h. It was then diluted with DCM, washed with 5% citric acid, and brine, dried(MgSO4), filtered, and concentrated in vacuo. The residue was purified by prep-HPLC to yield 2S,4R)-methyl 4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)non-8-enoyl)-4-methoxypyrrolidine-2-carboxylate (140 mg, 51.5% yield) as white foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:21](O)=[O:22])[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:25][CH2:26][C:27]([CH3:31])([CH3:30])[CH2:28][OH:29]>>[OH:29][CH2:28][C:27]([CH3:31])([CH3:30])[CH2:26][NH:25][C:21]([C:17]1[N:18]([CH3:20])[N:19]=[C:15]([O:14][CH2:13][C:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9][O:10][C:11]=2[CH3:24])[CH:16]=1)=[O:22]
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)O)n(C)n1
Reactant: CC(C)(CN)CO
Product: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)NCC(C)(C)CO)n(C)n1
Yield: 70 %

Procedure:
As described for example 55, 5-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid (100 mg, 0.3 mmol) was converted, using 3-amino-2,2-dimethyl-1-propanol instead of 2-amino-2-methyl-1-propanol, to the title compound (88 mg, 70%) which was obtained as a white solid. MS: m/e=417.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]([O:17][CH3:18])[C:13]([NH:15][CH3:16])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]([O:17][CH3:18])[C:13]([NH:15][CH3:16])=[S:33]
Reactant: CNC(=O)C(OC)c1ccccc1COc1cc(C)ccc1C
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CNC(=S)C(OC)c1ccccc1COc1cc(C)ccc1C
Temperature: 80 °C
Reaction time: 2 h
Yield: 112.7 %

Procedure:
A solution of 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxy-N-methylacetamide (0.12 g, 0.38 mmol) and Lawesson's reagent (0.14 g, 0.35 mmol) in toluene (5 ml) was heated with stirring at 80° C. for 2 hours. The mixture was cooled to room temperature, and purified by column chromatography on silica gel (n-hexane/ethyl acetate=4/1) to give the desired compound 2-[2-(2,5-dimethylphenoxymethyl)-phenyl]-2-methoxy-N-methylthioacetamide (0.13 g, 100%) as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH:5]([O:25][CH:26]([CH3:28])[CH3:27])[CH2:6][C:7]1[CH:15]=[C:14]([CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:10]2[O:11][CH:12]=[CH:13][C:9]=2[CH:8]=1)[CH3:2]>C(O)C.[H][H].[C].[Pd]>[CH2:1]([O:3][C:4](=[O:29])[CH:5]([O:25][CH:26]([CH3:28])[CH3:27])[CH2:6][C:7]1[CH:15]=[C:14]([CH2:16][NH:17][C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[C:10]2[O:11][CH2:12][CH2:13][C:9]=2[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1cc(CNC(=O)OC(C)(C)C)c2occc2c1)OC(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(Cc1cc2c(c(CNC(=O)OC(C)(C)C)c1)OCC2)OC(C)C
Yield: 92.6 %

Procedure:
29 mg of 3-(7-[(t-butoxycarbonyl)amino]methylbenzo[b]furan-5-yl)-2-isopropoxypropionic acid ethyl ester was dissolved in ethanol, and 30 mg of 10% palladium carbon was added, followed by stirring for 3 days at room temperature in hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated, to give 27 mg of 3-(7-[(t-butoxycarbonyl)amino]methyl-2,3-dihydrobenzo[b]furan-5-yl)-2-isopropoxypropionic acid ethyl ester was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[S:10][C:9](S(C)(=O)=O)=[N:8][C:6]=2[N:7]=1.[BH4-].[Na+]>CO.O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[C:5]2[S:10][CH:9]=[N:8][C:6]=2[N:7]=1
Reactant: CS(=O)(=O)c1nc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Clc1nc(N2CCOCC2)c2scnc2n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
5-Chloro-2-(methylsulfonyl)-7-morpholinothiazolo[4,5-d]pyrimidine was slurried in dry methanol/tetrahydrofuran (1:10). The solution was cooled to 0° C. under nitrogen and sodium borohydride (1.1 eq) was added in four portions. The solution was stirred at 0° C. for 30 min. An additional 0.1 eq sodium borohydride was added if necessary. The solvent was removed under vacuum and the resulting residue was purified by silica gel chromatography isocratic 1:1 methylene chloride:ethylacetate. The resulting white solid of 4-(5-chlorothiazolo[4,5-d]pyrimidin-7-yl)morpholine 16 was isolated.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][O:21][CH2:22][CH3:23].[CH:24]([N:27]=[C:28]=[O:29])([CH3:26])[CH3:25]>C(Cl)Cl.CN(C)C=O>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][O:21][CH2:22][CH3:23])[N:6]([NH:5][CH2:4][CH2:3][CH2:2][NH:1][C:28]([NH:27][CH:24]([CH3:26])[CH3:25])=[O:29])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CC(C)N=C=O
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1NCCCN
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOCc1nc2c(N)nc3ccccc3c2n1NCCCNC(=O)NC(C)C
Reaction time: 15 h
Yield: 45.6 %

Procedure:
A solution of N1-(3-aminopropyl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline-1,4-diamine (1.04 g, 3.31 mmol) in 30 mL of CH2Cl2 and 5 mL of N,N-dimethylformamide was placed under an atmosphere of nitrogen and slowly treated with isopropyl isocyanate (0.320 mL, 3.31 mmol). After 15 h, the reaction mixture was concentrated under reduced pressure to yield a yellow/orange foam. The foam was purified by chromatography (SiO2, 30% (80:18:2 CHCl3:MeOH: conc. ammonium hydroxide (NH4OH)) in CHCl3) to give an off-white solid. The solid was triturated with diethyl ether (Et2O) and collected by vacuum filtration to yield 1-(3-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]amino}propyl)-3-isopropylurea (0.603 g) as an off-white solid. mp 174–177° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.45 (d, J=8.1 Hz, 1H), 7.58 (d, J=8.2 Hz, 1H), 7.46–7.41 (m, 1H), 7.26–7.22 (m, 1H), 6.96 (t, J=5.5 Hz, 1H), 6.60 (s, 2H), 5.72 (t, J=5.5 Hz, 1H), 5.59 (d, J=7.7 Hz, 1H), 4.75 (s, 2H), 3.70–3.58 (m, 3H), 3.19–3.08 (m, 4H), 1.72–1.63 (m, 2H), 1.17 (t, J=7.0 Hz, 3H), 0.99 (d, J=6.5 Hz, 6H); 13C NMR (75 MHz, DMSO-d6) δ 157.8, 152.3, 149.5, 145.3, 132.4, 127.4, 126.1, 124.2, 121.2, 114.7, 65.9, 63.1, 50.2, 41.2, 37.4, 28.9, 23.6, 15.4; MS (APCI) m/z 400 (M+H)+; Anal. Calcd for C20H29N7O2: C, 60.13; H, 7.32; N, 24.54; Found: C, 59.94; H, 7.58; N, 24.45.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][S:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][CH:10]=[CH:9]2>Cl.CC(C)=O>[N:12]1[C:13]2[C:8](=[CH:7][C:6]([S:5][CH2:4][CH:3]=[O:2])=[CH:15][CH:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: COC(CSc1ccc2ncccc2c1)OC
Agent: Cl
Solvent: CC(C)=O
Product: O=CCSc1ccc2ncccc2c1

Procedure:
6-[(2,2-Dimethoxyethyl)thio]quinoline (1.0 g) was dissolved in aqueous 1N hydrochloric acid (6 mL) and acetone (3 mL). The reaction mixture was refluxed for 3 h. Acetone was removed under reduced pressure. The aqueous layer was neutralized with saturated sodium bicarbonate and extracted with ethyl acetate. The organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel with 20% ethyl acetate in hexanes to afford the desired product. LCMS: (M+H)=204.0; (M+H2O)=221.9; (M+MeOH)=236.0.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[S:10][CH:9]=2)=[CH:3][CH:2]=1.[H-].[Na+].S(OC)(O[CH3:23])(=O)=O>CN(C)C=O>[CH3:23][N:7]([C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)[C:8]1[C:16]2[C:11](=[N:12][CH:13]=[CH:14][CH:15]=2)[S:10][CH:9]=1
Reactant: COS(=O)(=O)OC
Reactant: c1cnc2scc(Nc3ccncc3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(c1ccncc1)c1csc2ncccc12
Temperature: 0 °C
Yield: 70.6 %

Procedure:
A solution of 3-(4-pyridinylamino)thieno[2,3-b]pyridine (4 g) in 25 mL of dimethylformamide was added to an ice-cooled suspension of sodium hydride (60% oil dispersion, 0.85 g, washed with heptane) in 5 mL of dimethylformamide. After anion formation was completed a solution of dimethyl sulfate (2.4 g) in 5 mL of dimethylformamide was added. After one hour the reaction mixture was poured into ice-water and extracted with ethyl acetate. The organic extract was washed with water and saturated sodium chloride, and then was dried (anhydrous magnesium sulfate), filtered and evaporated to 4 g of a solid. Elution through silica with 10% methanol in ethyl acetate via flash column chromatography afforded 3 g of a solid, m.p. 143°-145° C. Recrystallization from acetonitrile afforded 2.1 g of crystals, m.p. 150°-152° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[C:16]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)=[C:15]([C@H:24]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:14]([CH3:35])=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[CH3:36][N:37]1[C:41]([CH3:42])=[C:40](B(O)O)[CH:39]=[N:38]1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:31]([O:30][C@@H:24]([C:15]1[C:14]([CH3:35])=[CH:13][C:11]2[N:12]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:40]4[CH:39]=[N:38][N:37]([CH3:36])[C:41]=4[CH3:42])=[CH:3][CH:4]=3)[S:9][C:10]=2[C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[C:25]([O:27][CH2:28][CH3:29])=[O:26])([CH3:34])([CH3:33])[CH3:32]
Reactant: Cc1c(B(O)O)cnn1C
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc(Br)cc3)sc2c1-c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc(-c4cnn(C)c4C)cc3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 2.5 h

Procedure:
(S)-ethyl 2-(2-(4-bromophenyl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (50.0 mg, 0.087 mmol), 1,5-Dimethyl-1H-pyrazole-4-boronic acid, pinacol ester (24.7 mg, 0.105 mmol), tetrakis(triphenylphosphine)palladium(0) (15.1 mg, 0.013 mmol), and K2CO3 (36.2 mg, 0.262 mmol) were taken in a microwave vial, and the vial was vacuum pumped and flushed with argon three times. To this mixture was added degassed 1,4-dioxane (0.8 mL) and degassed water (0.2 mL). The reaction mixture was stirred at 100° C. for 2.5 h, filtered through Celite (ethyl acetate eluent), and concentrated. Purification by flash column chromatography on silica gel (hexanes/ethyl acetate eluent) provided the product. LCMS-ESI+ calc'd for C33H35ClN3O3S (M+H+): 588.2; Found: 588.3 (M+H+).