Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:21]([O:22][CH3:23])[CH2:20][C@@:19]2([CH3:24])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C:17](=[O:25])[CH2:16][C@@:15]2([CH3:26])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[BrH:27].BrBr.O>CO.C(O)(=O)C>[Br:27][CH2:13][C:12](=[O:14])[C@@H:11]1[C@:15]2([CH3:26])[C@H:8]([C@H:7]3[C@H:18]([C:17](=[O:25])[CH2:16]2)[C@:19]2([CH3:24])[C@H:4]([CH2:3][C@H:2]([OH:1])[C@@H:21]([O:22][CH3:23])[CH2:20]2)[CH2:5][CH2:6]3)[CH2:9][CH2:10]1
Reactant: CO[C@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(C)=O)[C@@]4(C)CC(=O)[C@@H]32)C[C@@H]1O
Reactant: Br
Agent: BrBr
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CO[C@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(=O)CBr)[C@@]4(C)CC(=O)[C@@H]32)C[C@@H]1O
Temperature: 25 °C

Procedure:
A solution of 3α-hydroxy-2β-methoxy-5α-pregnane-11,20-dione (2 g.) in methanol (15 ml.) was treated with hydrobromic acid in glacial acetic acid (3 drops). The mixture was stirred at room temperature and bromine (530 mg.) in methanol (1.45 ml.) was added dropwise over a period of 30 minutes. The mixture was stirred for a further 30 minutes and poured into water, stirred, filtered, washed with water and dried. Purification by preparative t.l.c., followed by crystallisation from ethyl acetate and petrol gave title compound (250 mg.) as colourless plates; m.p. 185°-188°; [α]D + 104°.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[Br:20][C:21]1[CH:26]=[CH:25][C:24]([SH:27])=[CH:23][C:22]=1[CH3:28]>>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([S:27][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=3[CH:19]=2)=[CH:23][C:22]=1[CH3:28]
Reactant: Cc1cc(S)ccc1Br
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCl)cc21
Product: Cc1cc(SCCCCOc2ccc3c(c2)C(C)(C)OC(=O)N3)ccc1Br

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-bromo-3-methyl-thiophenol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)=[CH:17][C:9]1=2.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:29])([F:30])[F:31])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([C:21]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[O:23])[CH:24]=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: C1COCCN1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1)N1CCOCC1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with morpholine as in General Procedure 10 to give the title compound. LCMS: m/z=516.96 (M+H+); retention time=0.76 minutes.
Reaction SMILES: [Li].[F:2][CH:3]([F:21])[O:4][C:5]1[CH:6]=[C:7]([C:11]([O-])=[CH:12][C:13](=O)[C:14]([O:16]CC)=[O:15])[CH:8]=[N:9][CH:10]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Cl.[Cl:45][C:46]1[CH:47]=[C:48]([NH:53][NH2:54])[CH:49]=[CH:50][C:51]=1[F:52]>>[Cl:45][C:46]1[CH:47]=[C:48]([N:53]2[C:11]([C:7]3[CH:8]=[N:9][CH:10]=[C:5]([O:4][CH:3]([F:2])[F:21])[CH:6]=3)=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[N:54]2)[CH:49]=[CH:50][C:51]=1[F:52]
Reactant: CCOC(=O)C(=O)C=C([O-])c1cncc(OC(F)F)c1
Reactant: NNc1ccc(F)c(Cl)c1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: O=C(O)c1cc(-c2cncc(OC(F)F)c2)n(-c2ccc(F)c(Cl)c2)n1

Procedure:
220 mg (0.64 mmol) of the compound of Example 17A is reacted analogously to the synthesis of the compound of Example 20A with 188 mg (0.96 mmol) of 3-chloro-4-fluorophenylhydrazine hydrochloride. After hydrolysis, 120 mg (49% of theory) of the title compound is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=2)=O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C(OP([CH2:31][C:32]#[N:33])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O1C2C=CC(C(C3C=C(OC)C=C(OC)C=3)=CC#N)=CC=2OCC1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=2)=[CH:31][C:32]#[N:33])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(OC)cc(C(=O)c2cc(OC)cc(OC)c2)c1
Reactant: CCOP(=O)(CC#N)OCC
Agent: COc1cc(OC)cc(C(=CC#N)c2ccc3c(c2)OCCO3)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C(=CC#N)c2cc(OC)cc(OC)c2)c1
Yield: 76.3 %

Procedure:
Bis-(3,5-dimethoxyphenyl)methanone (1.29 g, 4.27 mmol), cyanomethylphosphonic acid diethyl ester (1.34 ml, 8.53 mmol) in anhydrous THF (10 ml), and lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 8.53 ml, 8.53 mmol) were treated in the same manner as described above for the synthesis of 3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxyphenyl)acrylonitrile. The crude material was purified via flash column chromatography (5% EtOAc in hexane gradient to 40% EtOAc in hexane in about 45 min.) to give 3,3-bis-(3,5-dimethoxy-phenyl)-acrylonitrile as an off-white solid (1.06 g, 76%): mp, 149-151° C.; 1HNMR (DMSO-d6) δ 6.66-6.62 (m, 2H, Ar), 6.50-6.47 (m, 4H, Ar), 6.39 (s, 1H, double bond proton), 3.76 (s, 6H, 2OCH3), 3.74 (s, 6H, 2OCH3); 13C NMR (CDCl3) δ 163.0, 160.9, 160.8, 140.8, 138.7, 117.7, 107.8, 106.9, 102.4, 102.2, 95.5, 55.6; Anal. Calcd. For C19H19NO4: C, 70.14; H, 5.89; N, 4.30. Found: C, 69.93; H, 5.96; N, 4.18.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]4[C:19]=3[CH:18]=[CH:17][CH:16]=[N:15]4)[CH:8]=[CH:7][N:6]=2)[CH2:3][CH2:2]1.[H-].[Na+].[CH3:22]I>CN(C=O)C>[CH:1]1([N:4]([CH3:22])[C:5]2[N:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]4[C:19]=3[CH:18]=[CH:17][CH:16]=[N:15]4)[CH:8]=[CH:7][N:6]=2)[CH2:2][CH2:3]1
Reactant: CI
Reactant: c1cnn2ncc(-c3ccnc(NC4CC4)n3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(c1nccc(-c2cnn3ncccc23)n1)C1CC1
Reaction time: 1 h
Yield: 75.1 %

Procedure:
To a solution of N-cyclopropyl-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine (25 mg, 0.1 mmol) in DMF (2 mL) was added sodium hydride (6 mg, 0.25 mmol) and methyl iodide (0.013 mL, 0.15 mmol). The reaction was allowed to stir for about 1 hour. The reaction was concentrated in vacuo. Water (10 mL) was added and the aqueous layer was extracted with EtOAc (2×30 mL). The combined organic layers were dried (MgSO4) filtered and concentrated in vacuo. The residue was triturated with diethylether to give the title compound as light orange solid (20 mg, 80%). 1H-NMR (400 MHz, CDCl3) δ 9.07 (d, 1H, J=8.8 Hz), 8.46 (s, 1H), 8.35 (m, 2H) 7.12 (dd, 1H, J=8.8, 4.4 Hz), 6.89 (d, 1H, J=5.6 Hz), 3.23 (s, 3H), 2.85 (m, 1H), 0.94 (m, 2H), 0.73 (m, 2H); MS (ESI) (M+H)+ 267.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH3:18][C@H:19]1[NH:24][C@@H:23]([CH3:25])[CH2:22][N:21]([C:26]([C:28]2[C:29]([CH3:35])=[C:30]([CH:33]=O)[NH:31][CH:32]=2)=[O:27])[CH2:20]1>C(O)C.N1CCCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[CH:33][C:30]2[NH:31][CH:32]=[C:28]([C:26]([N:21]4[CH2:20][C@H:19]([CH3:18])[NH:24][C@H:23]([CH3:25])[CH2:22]4)=[O:27])[C:29]=2[CH3:35])[C:11](=[O:17])[NH:12]3)=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c[nH]c1C=O
Reactant: O=C1Cc2c(cccc2-c2ccc(Br)cc2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c[nH]c1C=C1C(=O)Nc2cccc(-c3ccc(Br)cc3)c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 60.8 %

Procedure:
To a solution of 4-(4-bromo-phenyl)-1,3-dihydro-indol-2-one (72.0 mg, 0.25 mmol) and 4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 4-(4-bromo-phenyl)-3-[4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (79 mg, 61%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10]Br)[CH:5]=1.C([O-])([O-])=O.[K+].[K+].[Br:19][C:20]1[C:21]([OH:31])=[C:22]([O:28][CH2:29][CH3:30])[CH:23]=[C:24]([CH:27]=1)[CH:25]=[O:26].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:31][C:21]2[C:22]([O:28][CH2:29][CH3:30])=[CH:23][C:24]([CH:25]=[O:26])=[CH:27][C:20]=2[Br:19])[CH:5]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: CCOc1cc(C=O)cc(Br)c1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(C=O)cc(Br)c1OCc1cccc(C(=O)OC)c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
3-Bromomethylbenzoic acid methyl ester (0.77 g), K2CO3 (1.0 g) and a catalytic amount of n-Bu4NI were added to a solution of 5-bromo-3-ethoxy-4-hydroxybenzaldehyde (0.75 g) in 10 mL DMF and the reaction mixture was stirred at 70° C. for 1 h. A solution of 3% citric acid in water was added and the reaction mixture was extracted with ethyl acetate. The organic phases were washed with water and brine, dried over MgSO4 and concentrated. The title compound was obtained after flash column chromatography (silica gel, heptane/ethyl acetate (1/4, v/v), Rf=0.25).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.Cl.[NH2:50][C@@H:51]([CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[CH2:52][N:53]1[C:61](=[O:62])[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[C:54]1=[O:63]>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:50][C@@H:51]([CH2:64][C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[CH2:52][N:53]2[C:61](=[O:62])[C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[C:54]2=[O:63])=[O:9])=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1
Reactant: Cn1nccc1-c1cc(C(=O)O)sc1Cl
Reactant: N[C@@H](Cc1ccccc1)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1nccc1-c1cc(C(=O)N[C@@H](Cc2ccccc2)CN2C(=O)c3ccccc3C2=O)sc1Cl
Reaction time: 16 h
Yield: 45.5 %

Procedure:
To a solution of 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (0.21 g, 0.87 mmol), PyBrOP (610 mg, 1.3 mmol) and diisopropylethyl amine (0.76 mL, 4.35 mmol) in DCM (20 mL) at 25° C. was added 2-[(2S)-2-amino-3-phenylpropyl]-1H-isoindole-1,3(2H)-dione HCl (380 mg, 0.96 mmol)[prepared according to Preparation 5]. After 16 h, the solution was partitioned between H2O and washed with DCM. The combined organic fractions were dried (Na2SO4), concentrated and purified via column chromatography (silica) affording the title compound (200 mg, 46%) as a white solid: LC-MS (ES) m/z=505 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[CH3:15][N:16]([CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[C:17]([N:19]1[CH:23]=[C:22]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[N:21]=[CH:20]1)=[O:18].C(N(CC)CC)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>ClCCl.CN(C1C=CN=CC=1)C>[CH3:15][N:16]([CH:30]1[CH2:35][CH2:34][N:33]([S:44]([CH3:43])(=[O:46])=[O:45])[CH2:32][CH2:31]1)[C:17]([N:19]1[CH:23]=[C:22]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[N:21]=[CH:20]1)=[O:18]
Reactant: CN(C(=O)n1cnc(-c2cccnc2)c1)C1CCNCC1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)n1cnc(-c2cccnc2)c1)C1CCN(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
To an ice-water cooled suspension of N-methyl-N-(piperidin-4-yl)-4-(pyridin-3-yl)-1H-imidazole-1-carboxamide bis(2,2,2-trifluoroacetate) (300 mg, 0.584 mmol) in dichloromethane (10 mL) was added DMAP (35.7 mg, 0.292 mmol), followed by the dropwise addition of triethylamine (0.326 mL, 2.337 mmol), followed in turn by addition of methanesulfonyl chloride (0.072 mL, 0.934 mmol). The solution was allowed to stir at room temperature overnight, whereupon it was quenched by the addition of methanol and allowed to stir at room temperature. The white precipitate was collected by filtration, washed with methanol and ether, then dried to give the product as a white solid, (158 mg, 74%).
Reaction SMILES: [O:1]([CH2:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Ca+2].[NH2:17][C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([S:25]([CH2:28][N+:29]([O-:31])=[O:30])(=[O:27])=[O:26])=[C:20]([CH3:32])[CH:19]=1.C(=O)=O.Cl>O1CCCC1.C(OCC)(=O)C.O>[CH3:24][C:22]1[CH:23]=[C:18]([NH:17][C:9](=[O:10])[CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:19]=[C:20]([CH3:32])[C:21]=1[S:25]([CH2:28][N+:29]([O-:31])=[O:30])(=[O:27])=[O:26]
Reactant: O=C(Cl)COc1ccccc1
Reactant: Cc1cc(N)cc(C)c1S(=O)(=O)C[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(NC(=O)COc2ccccc2)cc(C)c1S(=O)(=O)C[N+](=O)[O-]
Yield: 67 %

Procedure:
Phenoxyacetyl chloride (427 mg, 2.5 mM) was added to a stirred suspension of calcium carbonate (300 mg, 3 mM) and (4-amino-2,6-dimethylphenylsulfonyl)nitromethane (488 mg, 2 mM) in dry tetrahydrofuran (THF; 2.5 mL). The mixture was stirred for 30 minutes during which time carbon dioxide was released. Water (10 mL) and ethyl acetate (30 mL) were then added and the mixture acidified with 2M hydrochloric acid to pH 3. The organic phase was separated and washed with saturated sodium chloride solution (2×10 mL) and then dried (MgSO4). The solvent was evaporated and the residue recrystallised from ethyl acetate. The solid obtained was washed with ether and air dried to give (2,6-dimethyl-4-[2-phenoxyacetamido]phenylsulfonyl)nitromethane as white crystals, having m.p. 166°-167° C. and in 67% yield after recrystallisation from ethyl acetate/hexane; microanalysis, found: C, 54.1; H, 5.1; N, 7.3%; C17H18N2O6S requires: C, 54.0: H, 4.8; N, 7.4%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13](N)[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.C(Cl)(Cl)[Cl:21].N(OC(C)(C)C)=O.C([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C>[Cl:21][C:13]1[N:14]=[CH:15][C:16]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[CH3:19])[CH:17]=2
Reactant: Cc1ccc(F)cc1-c1ccc2cc(N)ncc2c1
Reactant: ClC(Cl)Cl
Agent: CC(C)(C)ON=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1ccc(F)cc1-c1ccc2cc(Cl)ncc2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 36.3 %

Procedure:
To a solution of 7-(5-fluoro-2-methylphenyl)isoquinolin-3-amine (0.5177 g, 2.052 mmol) in chloroform (10 mL, 100 mmol) was added cuprous monochloride (0.3159 g, 3.191 mmol) and tert-butyl nitrite (0.50 mL, 3.8 mmol). The reaction mixture was stirred at room temperature in a flask shielded from the light with foil for 20 hours. To the reaction mixture was added 2M aqueous Na2CO3 and ethyl acetate, and the resulting mixture was filtered through celite. The organic layer was then dried over MgSO4, filtered, and evaporated in vacuo. The resulting residue was purified via flash chromatography on silica gel (40 g silica, solvent gradient: 0-50% ethyl acetate in heptanes) to yield 202.6 mg (36%) of 3-chloro-7-(5-fluoro-2-methylphenyl)isoquinoline. LCMS (ESI): M+H=272.2; 1H NMR (400 MHz, DMSO-d6) δ 9.26 (s, 1H), 8.19 (s, 1H), 8.11 (s, 1H), 8.05 (d, J=8.5 Hz, 1H), 7.87 (d, J=8.5 Hz, 1H), 7.45-7.36 (m, 1H), 7.19 (t, J=7.9 Hz, 2H), 2.24 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[C:14]2[N:19]=[CH:18][C:17](Br)=[CH:16][N:15]=2)[CH2:10][C@H:9]1[CH2:36][O:37][CH3:38])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:39][N:40]1[CH:44]=[CH:43][C:42](B2OC(C)(C)C(C)(C)O2)=[N:41]1.C(=O)([O-])O.[Na+].O>COCCOC.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:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[C:14]2[N:19]=[CH:18][C:17]([C:43]3[CH:42]=[N:41][N:40]([CH3:39])[CH:44]=3)=[CH:16][N:15]=2)[CH2:10][C@H:9]1[CH2:36][O:37][CH3:38])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)n1
Reactant: COC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(Br)cn2)CN1C(=O)OC(C)(C)C
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)CN1C(=O)OC(C)(C)C
Temperature: 95 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
A mixture of ((2S,4S)-4-(5-bromo-pyrimidin-2-ylamino)-2-methoxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (2.84 mmol; 1.1 g), 3,5-bis(trifluoromethyl)benzyl bromide (4.3 mmol; 0.78 mL) and sodium hydride (60% dispersion in mineral oil, 4.3 mmol; 0.17 g) in DMF (9 mL) is stirred for 1 hour at room temperature under nitrogen. The reaction mixture is quenched with water then saturated ammonium chloride solution. The product is extracted twice with EtOAc. The combined organic layer is washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue is passed though silica pad (eluent: n-hexane/EtOAc) to give (2S,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-2-methoxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester. To a mixture of (2S,4S)-4-[(3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-2-methoxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester, 1-methylpyrazol-3-yl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (7.1 mmol, 1.48 g), tetrakis(triphenylphosphine)palladium(0) (0.43 mmol, 490 mg) and 2M aqueous sodium hydrogen carbonate (3.6 mL) in 1,2-dimethoxy-ethane (4 mL) is allowed to warm to 95° C. and stirred for 3 hours. The mixture is cooled to room temperature and then added water. The mixture is extracted with CH2Cl2, and the combined organic layer is dried over Na2SO4, filtrated, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent: n-hexane/EtOAc) to give (2S,4S)-4-{(3,5-bis-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-methoxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.3 g, 74% overall yield for 2 steps); ESI-MS m/z: 615 [M+1]+, Retention time 2.12 min (condition A).
Reaction SMILES: O=C(CCCCCC)CCCCCCCCCCC(O)=O.ClCl.[C:24]([N:28]=[N:29][C:30](Cl)([CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42])([CH3:27])([CH3:26])[CH3:25].[C-:51]#[N:52].[Na+]>CCCCC.CO.O>[C:24]([N:28]=[N:29][C:30]([C:51]#[N:52])([CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42])([CH3:27])([CH3:26])[CH3:25]
Reactant: [C-]#N
Reactant: CCCCCCC(Cl)(CCCCCCCCCCC(=O)O)N=NC(C)(C)C
Agent: CCCCCCC(=O)CCCCCCCCCCC(=O)O
Agent: ClCl
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCCCC
Product: CCCCCCC(C#N)(CCCCCCCCCCC(=O)O)N=NC(C)(C)C
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 75.8 %

Procedure:
To a solution of 21.0 grams (0.0568 moles) of the t-butylhydrazone of 12-ketostearic acid in 50 ml of pentane, cooled to -20°C, was passed 2.02 grams (0.0285 moles) of chlorine over a 10 minute period. The reaction was stirred an additional 15 minutes at -20°C, the white solid that formed, filtered off, and the pentane filtrate, which should contain approximately 0.0285 moles of 12-t-butylazo-12-chlorostearic acid added to a solution of 1.5 grams (0.03 moles) of sodium cyanide in 20 mls of 75% aqueous methanol. The reaction was stirred for 1 hour at 20°C, poured into 100 ml of water, the pentane layer separated, washed with 5% HCl and then with water until neutral. The pentane solution was dried over anhydrous sodium sulfate, filtered and the pentane evaporated under reduced pressure to leave 8.5 grams (76% yield) of the desired acid.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][C:7]([C:10]([OH:12])=[O:11])=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[CH3:13][Si](C=[N+]=[N-])(C)C>CO.CCOCC>[NH:1]1[C:5]2=[N:6][C:7]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1ccc2cc[nH]c2n1
Solvent: CCOCC
Solvent: CO
Product: COC(=O)c1ccc2cc[nH]c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1H-pyrrolo[2,3-b]pyridine-6-carboxylic acid [898746-35-5] (500 mg, 3.08 mmol) in MeOH was added a 2M solution of trimethylsilyldiazomethane in Et2O at 0° C., and the reaction mixture was stirred at RT for 30 min. The reaction mixture was concentrated in vacuo to give the title compound. MS (LC/MS): 177 [M+H]+, 375 [2M+H]+; tR (HPLC conditions k): 2.71
Reaction SMILES: CCN(CC)CC.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.C(OC([N:26]1[CH2:29][CH2:28][C@H:27]1[CH2:30][O:31][C:32]1[CH:33]=[C:34]([C@H:38]2[CH2:40][C@@H:39]2[CH2:41][CH2:42][OH:43])[CH:35]=[N:36][CH:37]=1)=O)(C)(C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14]([O:43][CH2:42][CH2:41][C@H:39]2[CH2:40][C@@H:38]2[C:34]2[CH:35]=[N:36][CH:37]=[C:32]([O:31][CH2:30][C@@H:27]3[CH2:28][CH2:29][NH:26]3)[CH:33]=2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc([C@H]2C[C@@H]2CCO)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC[C@H]2C[C@@H]2c2cncc(OC[C@@H]3CCN3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
4-(Dimethylamino)pyridine (DMAP; 14 mg, 0.11 mmol, 0.02 equiv.), Et3N (0.24 mL, 1.7 mmol, 3.0 equiv.), and p-toluenesulfonyl chloride (164 mg, 0.86 mmol, 1.5 equiv.) were added to a stirred solution of 2-[(1R,2S)-2-[5-[[1-(tert-butoxycarbonyl)-(2S)-azetidinyl]methoxy]-3-pyridyl]cyclopropyl]ethanol (200 mg, 574 μmol) in dry CH2Cl2 (5 mL) at 0° C. The reaction mixture was stirred at room temperature overnight, then diluted with CH2Cl2 (50 mL). The organic phase was washed with aqueous NaHCO3 and brine, dried over Na2SO4, and concentrated in vacuo. 2-[(1R,2S)-2-[5-[(2(S)-Azetidinyl)methoxy]-3-pyridyl]cyclopropyl]ethyl p-toluenesulfonate (Rf=0.4, 50% EtOAc in petroleum ether) was obtained by CC (237 mg, 82%) and was directly used for the next reaction.