Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([OH:11])=[N:5][NH:6]2.O.Cl[C:14]([O:16][CH2:17][CH3:18])=[O:15]>N1C=CC=CC=1>[CH2:17]([O:16][C:14]([N:6]1[C:7]2[C:3](=[C:2]([Br:1])[CH:10]=[CH:9][CH:8]=2)[C:4]([OH:11])=[N:5]1)=[O:15])[CH3:18]
Reactant: Oc1n[nH]c2cccc(Br)c12
Reactant: CCOC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)n1nc(O)c2c(Br)cccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a room temperature suspension of 4-Bromo-1H-indazol-3-ol CLXXXIII (3.19 g, 15.0 mmol) in pyridine (13 ml) and H2O (20 ml) was dropwise added ethyl chloroformate (1.43 ml, 15.0 mmol). After stirring 18 hours at room temperature, the mixture was cooled to 0° C., and the precipitate was filtered and washed with cold AcOH (10 ml in 5 ml of H2O). The solid was dried in vacuo affording 4-Bromo-3-hydroxy-indazole-1-carboxylic acid ethyl ester CLXXXIV as a yellow powder (2.97 g, 69% yield).
Reaction SMILES: CO.[NH2:3][CH2:4][CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1)[OH:6]>CC(C)CC(=O)C>[NH2:3][CH2:4][C@@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1)[OH:6]
Reactant: NCC(O)c1cccc(Cl)c1
Solvent: CO
Solvent: CC(=O)CC(C)C
Product: NC[C@H](O)c1cccc(Cl)c1
Temperature: 25 °C
Yield: 35.1 %

Procedure:
To 20 ml of methanol were added 1.70 g of the concentrate obtained in the same manner as in Example 295, containing 1.29 g (7.50 mmol) of 2-amino-1-(3-chlorophenyl)ethanol, and 2.88 g (7.50 mmol) of L-di-p-toluoyltartaric acid (hereinafter abbreviated as L-PTTA), and the resultant mixture was heated for dissolution and added with 20 ml of 4-methyl-2-pentanone. The mixture was cooled to room temperature and left over night to give crystals. The crystals precipitated was isolated by filtration to afford 1.69 g (2.63 mmol) of (R)-2-amino-1-(3-chlorophenyl)ethanol.L-PTTA salt. The yield of the compound relative to (R)-2-amino-1-(3-chlorophenyl)ethanol in the concentrate was 70.1%.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:8]=2)[CH:6]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[C:30]=1[OH:37].B(O)O>O1CCOCC1.CC(N(C)C)=O>[CH3:36][O:35][C:31]1[CH:32]=[C:33]([C:6]2[N:5]([C:7]3[CH:12]=[CH:11][N:10]=[C:9]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)[N:8]=3)[CH:4]=[N:3][CH:2]=2)[CH:34]=[C:29]([O:28][CH3:27])[C:30]=1[OH:37]
Reactant: Brc1cn(-c2ccnc(N3CCOCC3)n2)cn1
Reactant: COc1cccc(OC)c1O
Agent: O=P([O-])([O-])[O-]
Agent: OBO
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: C1COCCO1
Product: COc1cc(-c2cncn2-c2ccnc(N3CCOCC3)n2)cc(OC)c1O
Temperature: 170 °C
Yield: 96.3 %

Procedure:
To a solution of 4-[4-(4-Bromo-imidazol-1-yl)-pyrimidin-2-yl]-morpholine (0.20 g, 0.65 mmol) in anhydrous dioxane (6 ml) and anhydrous DMA (0.6 m) was added tripotassium phosphate (0.28 g, 1.3 mmol) and 2,6-dimethoxy-phenol-boronic acid (0.18 g, 0.91 mmol). The resultant mixture was degassed with sonication for 10 minutes before the addition of bis(tri-butylphospine)palladium (0.017 g, 0.033 mmol) and degassing for a further 5 minutes. The reaction vessel was sealed and heated under the influence of microwave radiation (170° C., 11 min, low absorption setting). Upon completion, the reaction was filtered through a thin silica plug which was then washed with 10% methanol/CH2Cl2. The filtrate was concentrated in vacuo and the crude residue purified by flash chromatography (SiO2) (1:1—EtOAc:Hexanes) to give the desired product (0.24 g, 96%) as a white crystalline solid in analytically pure form. m/z (LC-MSW, ESP):384.4 [M+H]+, R/T=2.72 mins.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C@@H:9]2[CH2:13][N:12]([C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[C:11](=O)[CH2:10]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>>[CH2:1]([O:3][C:4]([C:6]1([C@H:9]2[CH2:13][N:12]([C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[C:11](=[S:32])[CH2:10]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)C1([C@H]2CC(=O)N([C@@H](C)c3ccccc3)C2)CC1
Product: CCOC(=O)C1([C@@H]2CC(=S)N([C@@H](C)c3ccccc3)C2)CC1

Procedure:
The thus separated (4R)-4-(1-ethoxycarbonylcyclopropyl)-1-[(S)-1-phenylethyl]-2-pyrrolidone is allowed to react with Lawesson reagent to give (4S)-4-(1-ethoxycarbonylcyclopropyl)-1-[(S)-1-phenylethyl]-2-pyrrolidinethione. This reaction can also be effected using phosphorus pentasulfide.
Reaction SMILES: CC(C)([O-:4])C.[K+].[Br:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=O.[CH2:16]1[CH2:20][O:19][CH2:18][CH2:17]1>CS(C)=O>[Br:7][C:8]1[CH:9]=[C:10](/[CH:11]=[CH:20]/[CH2:16][CH2:17][C:18]([OH:4])=[O:19])[CH:13]=[CH:14][CH:15]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: C1CCOC1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(O)CC/C=C/c1cccc(Br)c1
Reaction time: 18 h
Yield: 82 %

Procedure:
A 1M solution of potassium tert-butoxide in THF (80 mL) was added dropwise to (3-carboxypropyl)triphenylphosphoium bromide (17 g, 40 mmol) in anhydrous DMSO (20 mL) under nitrogen at 24° C., and the solution was stirred 30 min before addition of 3-bromobenzaldehyde (4.7 mL, 40 mmol). After several minutes a precipitate was observed and an additional 20 mL of DMSO was added to aid salvation, and the reaction was stirred 18 hours. The solution was poured onto water (120 mL) and washed with chloroform. The aqueous layer was acidified with conc. HCl and extracted with chloroform (3×250 mL). The organic phase was concentrated and applied to a 65 (M) Biotage® silica gel column; Gradient elution from 15-65% B (A=Hexanes; B=EtOAc) over 2 L to give Example 1, (E)-5-(3-bromophenyl)pent-4-enoic acid 8.2 g (82%). 1H NMR (300 MHz, CDCl3) δ 7.45 (t, J=1.5 Hz, 1H), 7.30 (dt, J=7.7, 1.5 Hz, 1H), 7.2-7.16 (m, 1H), 7.12 (t, J=7.7 Hz, 1H), 6.40-6.32 (m, 1H), 6.23-6.14 (m, 1H), 2.52 (s, 4H). RT=2.0 minutes (condition 1); LRMS: Anal. Calcd. for C11H11BrO2: 252.97. found: 252.98 (M−H).
Reaction SMILES: [Br:1][CH:2]1[C:10](=O)[C:6]2=[N:7][O:8][N:9]=[C:5]2[CH2:4][CH2:3]1.[NH2:12][C:13]([NH2:15])=[S:14]>C(O)C>[BrH:1].[N:7]1[O:8][N:9]=[C:5]2[CH2:4][CH2:3][C:2]3[S:14][C:13]([NH2:15])=[N:12][C:10]=3[C:6]=12
Reactant: O=C1c2nonc2CCC1Br
Reactant: NC(N)=S
Solvent: CCO
Product: Br
Product: Nc1nc2c(s1)CCc1nonc1-2
Temperature: 60 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of commercially available 5-bromo-6,7-dihydro-5H-benzo[1,2,5]oxadiazol-4-one (1.1 g, 5.1 mmol) in absolute ethanol (60 mL) was added thiourea. The reaction mixture was stirred at 60° C. for overnight and then concentrated. The residue was triturated in hexanes to afford 1.3 g (90%) of the title compound. MS (ESI+) m/z 195 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([NH:21][C:22](=[O:33])[C@H:23]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH3:24])[C@@H:18]([OH:34])[C@H:17]3[OH:35])=[C:9]([NH:36][CH2:37][CH:38]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:8]=2)[CH2:3]1.C1([O:57][C:58](=O)[NH:59][C:60]2[CH:61]=[N:62][CH:63]=[CH:64][CH:65]=2)C=CC=CC=1>CN1C(=O)CCC1>[CH2:26]([O:25][C@H:23]([CH3:24])[C:22]([NH:21][C@H:19]1[CH2:20][C@@H:16]([N:13]2[CH:12]=[N:11][C:10]3[C:14]2=[N:15][C:7]([N:4]2[CH2:5][CH2:6][C@@H:2]([NH:1][C:58]([NH:59][C:60]4[CH:61]=[N:62][CH:63]=[CH:64][CH:65]=4)=[O:57])[CH2:3]2)=[N:8][C:9]=3[NH:36][CH2:37][CH:38]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[C@H:17]([OH:35])[C@@H:18]1[OH:34])=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Reactant: C[C@@H](OCc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](N)C4)nc32)[C@H](O)[C@@H]1O
Solvent: CN1CCCC1=O
Product: C[C@@H](OCc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)Nc5cccnc5)C4)nc32)[C@H](O)[C@@H]1O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A solution comprising (R)-N-{(1S,2R,3S,4R)-4-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-benzyloxy-propionamide (1 equivalent) and pyridin-3-yl-carbamic acid phenyl ester (Intermediate ZB) (1 equivalent) in NMP is stirred at 100° C. for 1 hour. The solvent is removed in vacuo and the title compound is obtained after purification by column chromatography/crystallisation.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.N(C1C=C(S(N)(=O)=O)C=CC=1)=[C:13]=[O:14]>>[N:1]([C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:9])=[O:10])=[CH:4][CH:3]=1)=[C:13]=[O:14]
Reactant: NS(=O)(=O)c1cccc(N=C=O)c1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Product: NS(=O)(=O)c1ccc(N=C=O)cc1

Procedure:
This compound is prepared from 4-aminobenzenesulphonamide using a procedure analogous to that of 3-isocyanato-benzenesulfonamide (Intermediate 5) by replacing 3-aminobenzenesulphonamide with 4-aminobenzenesulphonamide.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4].[NH2:8][C:9]1[CH:18]=[CH:17][C:16]2[NH:15][C:14](=[O:19])[N:13]3[CH2:20][CH2:21][N:22]=[C:12]3[C:11]=2[CH:10]=1>N1C=CC=CC=1.CCOCC>[C:1]([NH:8][C:9]1[CH:18]=[CH:17][C:16]2[NH:15][C:14](=[O:19])[N:13]3[CH2:20][CH2:21][N:22]=[C:12]3[C:11]=2[CH:10]=1)(=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)CC(=O)Cl
Reactant: Nc1ccc2c(c1)C1=NCCN1C(=O)N2
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)CC(=O)Nc1ccc2c(c1)C1=NCCN1C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.5 g (0.02 mol) of isovaleric acid chloride were added to 2.02 g (0.01 mol) of 9-amino-5-oxo-2,3,5,6-tetrahydroimidazo-[1,2-c]-quinazoline in 30 ml of absolute pyridine, and the mixture was stirred for 8 hours at room temperature. The mixture was then diluted with ether, and the precipitated crystals were separated off. The crystals were dissolved in water, the aqueous solution was purified with active charcoal and the free base was then precipitated by the addition of ammonia. It was filtered off under suction and dried.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH:4]=[CH2:5].CCN(C(C)C)C(C)C.Cl[C:17](Cl)([O:19]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:28][C@@H:29]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH:40]=[CH2:41])[C:30]([O:32][CH2:33][CH3:34])=[O:31].[OH-].[Na+]>O1CCOCC1>[CH2:1]([O:6][C:17]([NH:28][C@@H:29]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH:40]=[CH2:41])[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:19])[CH2:2][CH2:3][CH:4]=[CH2:5]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C=CCCCCC[C@H](N)C(=O)OCC
Reactant: C=CCCCO
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCCCC[C@H](NC(=O)OCCCC=C)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 122.3 %

Procedure:
To a stirred solution of pent-4-en-1-ol (0.62 g, 7.21 mmol) and DIPEA (1.26 mL, 7.21 mmol) in anhydrous 1,4-dioxane (20 ml), at 10° C. and under nitrogen, was slowly added a solution of triphosgene (0.75 g, 2.52 mmol) in anhydrous 1,4-dioxane (20 mL). The reaction mixture was stirred at RT for 1 hour, and ethyl (2S)-2-aminonon-8-enoate*HCl (0.85 g, 3.61 mmol) and 1 M aqueous NaOH (7.21 ml, 7.21 mmol) added, and the reaction mixture was heated to 50° C. for 15 hours. After cooling to RT, the reaction mixture was basified to pH 8 with 1M aqueous NaOH and extracted with ether (3×200 ml). The combined organic phases were washed with water (100 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel (5 to 75% EtOAc in hexane) to give the title compound (0.96 g). LRMS (ESI) m/z 312.5 [(M+H)+; calcd for C17H30NO4: 312.2].
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].C(=O)([O-])[O-].[Na+].[Na+].[CH3:20][NH:21][CH3:22]>O1CCOCC1.O1CCCC1>[CH3:20][N:21]([CH3:22])[S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11]
Reactant: CNC
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reaction time: 4 h
Yield: 94 %

Procedure:
To a solution of 2-nitro-benzenesulfonyl chloride (15 g, 0.068 mol) in 1,4-dioxane (100 mL) was added sodium carbonate (10.76 g, 0.1015 mol) and 2.000 M of dimethylamine in tetrahydrofuran (40.61 mL) at room temperature and the reaction mixture was stirred for 4 hours. The reaction mixture was partitioned between water and dichloromethane, and the aqueous layer was extracted once with dichloromethane. The combined organic extracts were dried (MgSO4), concentrated, and the solid residue was recrystallized from MeOH to afford N,N-dimethyl-2-nitro-benzenesulfonamide (14.7 g, 94%) as a white solid. LC/MS (ESI+): 230.92 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[C:10](O)(=[O:13])[CH2:11][CH3:12].FC(F)(F)S(O)(=O)=O>>[CH3:1][C:2]1[CH:7]=[C:6]([C:10](=[O:13])[CH2:11][CH3:12])[CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9]
Reactant: CCC(=O)O
Reactant: Cc1cccc(C)c1O
Agent: O=S(=O)(O)C(F)(F)F
Product: CCC(=O)c1cc(C)c(O)c(C)c1
Temperature: 80 °C

Procedure:
A mixture of 2,6-dimethylphenol (10.5 g, 85.95 mmol), propionic acid (4.64 mL, 86.81 mmol), and trifluoromethanesulfonic acid (59 g) was heated to 80° C. for 48 h, then poured onto ice. The mixture was extracted with chloroform and this organic phase was washed with aqueous bicarbonate and brine. The organic layer was dried and concentrated to a dark orange oily solid. The residue was kugelrohr distilled at 1.5 mm Hg and the following fractions were collected: 23-105° C. (pot temperature), discarded forerun; 105-135° C., 11.2 g (73%) of 2,6-dimethyl-4-propionylphenol as a yellow-white solid which had NMR identical to that of preparation 15.
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].[C:9]1([CH2:15][O:16][C:17]([NH:19][C@H:20]([C:24]([OH:26])=[O:25])[CH2:21][CH2:22][OH:23])=[O:18])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N1C=CN=C1.CO>CN(C)C=O>[C:9]1([CH2:15][O:16][C:17]([NH:19][C@H:20]([C:24]([OH:26])=[O:25])[CH2:21][CH2:22][O:23][Si:5]([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:7])[CH3:6])=[O:18])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(N[C@@H](CCO)C(=O)O)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 22 h

Procedure:
[(1,1-Dimethylethyl)dimethylsilyl]chloride (37.5 g., 249 mmol.) was added to a solution of N-[(phenylmethoxy)carbonyl]-L-homoserine [prepared as described in Example 6(a), 41.56 mmol.] in dimethylformamide (125 ml.), followed by imidazole (33.95 g., 498 mmol.). The resulting light yellow solution was stirred at room temperature for 22 hours. Methanol (500 ml.) was added, the reaction mixture was stirred for an additional 6 hours, and then the methanol and most of the dimethylformamide were removed in vacuo. The remaining residue was taken up into ethyl acetate (800 ml.), washed with 10% citric acid (2×300 ml.), and the combined aqueous phase was extracted with ethyl acetate (300 ml.). The combined ethyl acetate phase was washed with water and brine, dried (sodium sulfate), concentrated, and the residue was evaporated with hexane to form a white powder. This powder was dried in vacuo to give 12.942 g. of title product.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C:16]1[N:21]=[N:20][C:19]([N:22]([CH3:33])[CH:23]2[CH2:28][C:27]([CH3:30])([CH3:29])[NH:26][C:25]([CH3:32])([CH3:31])[CH2:24]2)=[CH:18][CH:17]=1)C1C=CC=CC=1.CCOC(C)=O>CO.C(Cl)Cl.[Pd]>[F:15][C:13]1[CH:12]=[CH:11][C:10]([C:16]2[N:21]=[N:20][C:19]([N:22]([CH3:33])[CH:23]3[CH2:28][C:27]([CH3:29])([CH3:30])[NH:26][C:25]([CH3:32])([CH3:31])[CH2:24]3)=[CH:18][CH:17]=2)=[C:9]([OH:8])[CH:14]=1
Reactant: CN(c1ccc(-c2ccc(F)cc2OCc2ccccc2)nn1)C1CC(C)(C)NC(C)(C)C1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(c1ccc(-c2ccc(F)cc2O)nn1)C1CC(C)(C)NC(C)(C)C1
Reaction time: 4 h
Yield: 81.6 %

Procedure:
Following GENERAL METHOD 4-1, Pd/C (10% wt, 47.0 mg, 0.044 mmol) was added to a solution of 6-(2-(benzyloxy)-4-fluorophenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (198 mg, 0.441 mmol) in MeOH (2 mL)/EtOAc (2 mL) at RT. The reaction mixture was evacuated and filled with H2 (2×), then stirred under H2 atmosphere for 4 h and filtered through celite using MeOH. The filtrate was concentrated in vacuo affording a yellow oil, which was redissolved in DCM and concentrated in vacuo affording the title compound as a yellow solid (129 mg, 82% yield). LCMS Rt=0.49 min (LCMS method Q); MS (M+1)=359.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 14.10 (br. s, 1H), 8.11 (d, J=9.60 Hz, 1H), 7.83-7.92 (m, 1H), 7.32 (d, J=10.11 Hz, 1H), 6.67-6.77 (m, 2H), 4.83-4.98 (m, 1H), 2.95 (s, 3H), 1.54 (dd, J=12.13, 3.54 Hz, 2H), 1.43 (t, J=12.13 Hz, 2H), 1.25 (s, 6H), 1.09 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[N:10][C:11]([S:14][CH3:15])=[N:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:24]N(C)C=O.CI.O>[Cl-].[Na+].O.C(Cl)Cl>[C:1]([O:5][C:6](=[O:23])[N:7]([CH3:24])[C:8]1[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[N:10][C:11]([S:14][CH3:15])=[N:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CSc1ncc(NC(=O)OC(C)(C)C)c(-c2ccccc2C)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CI
Product: CSc1ncc(N(C)C(=O)OC(C)(C)C)c(-c2ccccc2C)n1
Reaction time: 1 h
Yield: 98.5 %

Procedure:
To a solution of 1.9 g (5.73 mmol) (2-methylsulfanyl-4-o-tolyl-pyrimidin-5-yl)-carbamic acid tert.-butyl ester in 15 ml N,N-dimethylformamide 0.29 g (7.45 mmol) sodiumhydride (60% dispersion in mineraloil) was added and the reaction mixture stirred for 1 hr. After the addition of 0.57ml (9.17 mmol) methyl iodide at 0°, the reaction mixture was stirred for 3 hrs. The reaction mixture was distributed between 75 ml H2O, 75 ml brine and 75 ml CH2Cl2. The phases were separated, the aqueous layer washed twice with 75 ml CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/ethyl acetate 15:1) to give 1.95 g (98%) methyl-(2-methylsulfanyl-4-o-tolyl-pyrimidin-5-yl)-carbamic acid tert.-butyl ester as a colorless oil. MS (TSP): 345 (M+).
Reaction SMILES: [S:1]1[C:5]([C:6](O)=[O:7])=[CH:4][C:3]2[CH2:9][CH2:10][CH2:11][CH2:12][C:2]1=2.C(Cl)(=O)C([Cl:16])=O>ClCCl.CN(C)C=O>[S:1]1[C:5]([C:6]([Cl:16])=[O:7])=[CH:4][C:3]2[CH2:9][CH2:10][CH2:11][CH2:12][C:2]1=2
Reactant: O=C(O)c1cc2c(s1)CCCC2
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc2c(s1)CCCC2
Temperature: 0 °C

Procedure:
4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carboxylic acid (1.0 g, 5.50 mmol) is dissolved in dichloromethane [DCM] (25 mL) that contains 5 drops of N,N-dimethylformamide [DMF] under nitrogen and cooled to 0° C. Oxalyl chloride (13.7 mL of a 2.0M solution in DCM) is added via syringe and allowed to warm to RT over 1 hour. All solvent is then removed under reduced pressure, and the resultant oil is reduced from toluene (3×20 mL) to remove residual oxalyl chloride. The residue is then dissolved in ethyl acetate and washed with saturated sodium bicarbonate (1×100 mL), then washed with saturated sodium chloride (1×100 mL) and dried over sodium sulfate. The solution is then filtered and concentrated under reduced pressure to give 4,5,6,7-tetrahydro-benzo[b]thiophene-2-carbonyl chloride (1) as an off-white solid (1.03 g).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7]1.[Br:16]Br>C(Cl)(Cl)Cl.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>[Br:16][C:5]1[S:1][C:2]([C:6]2([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7][CH2:8]2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)C1(c2nccs2)CC1
Reactant: BrBr
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)C1(c2ncc(Br)s2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 46.9 %

Procedure:
The product from Step 2 (860 mg, 3.82 mmol) was taken up in CHCl3 (19 mL) and placed in a cool water bath. NaHCO3 (353 mg, 4.20 mmol) was added, followed by bromine (1.22 g, 7.63 mmol). After stirring for 90 min at room temperature, the reaction was diluted with 10% Na2S2O3 and saturated NaHCO3 and extracted with CH2Cl2 (2×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated. Flash chromatography (0-10% ether in hexanes) afforded tert-butyl 1-(5-bromo-1,3-thiazol-2-yl)cyclopropanecarboxylate (545 mg, 47%) as a colorless oil. MS ESI: [M-t-Bu]+ m/z 247.9/249.9.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[C:18](=[O:32])[N:19]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH:20]=[C:21]([NH2:23])[CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:33]([N:40]1[CH:44]=[C:43]([C:45](O)=[O:46])[CH:42]=[N:41]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[C:18](=[O:32])[N:19]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:30])[CH3:31])[CH:20]=[C:21]([NH:23][C:45]([C:43]2[CH:42]=[N:41][N:40]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:44]=2)=[O:46])[CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(N)cn(COCC[Si](C)(C)C)c2=O)cc2ccccc21
Reactant: O=C(O)c1cnn(Cc2ccccc2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2cc(NC(=O)c3cnn(Cc4ccccc4)c3)cn(COCC[Si](C)(C)C)c2=O)cc2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (6c), 2-[5-amino-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylic acid tert-butyl ester (0.3 g, 0.659 mmol) in acetonitrile (10 mL) was added 1-benzyl-1H-pyrazole-4-carboxylic acid (0.111 g, 0.549 mmol) and triethylamine (0.133 g, 0.184 mL, 1.32 mmol). O-benzotriazole-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (0.312 g, 0.823 mmol) was added last and the reaction mixture was stirred at ambient temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate (25 mL) and aqueous saturated sodium hydrogen carbonate solution (20 mL). The organic layer was separated and the aqueous was extracted with a further portion of ethyl acetate (25 mL). The combined ethyl acetate layers were washed with brine, dried (Na2SO4) and concentrated in vacuo. The resultant crude product was purified by flash chromatography on SiO2 eluting with hexane—35% ethyl acetate/hexane—50% ethyl acetate/hexane (gradient) to afford the desired title compound as a light brown solid, 0.246 g, 70%.