Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][CH:4]([C:13]2[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=2)[CH2:3]1.N1C=CC=CC=1.[CH2:27]([S:29](Cl)(=[O:31])=[O:30])[CH3:28]>ClCCl>[CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][CH:4]([C:13]2[CH:14]=[C:15]([NH:19][S:29]([CH2:27][CH3:28])(=[O:31])=[O:30])[CH:16]=[CH:17][CH:18]=2)[CH2:3]1
Reactant: CCS(=O)(=O)Cl
Reactant: Cc1ccc2c(c1)C(C)(C)CC(c1cccc(N)c1)N2
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1cccc(C2CC(C)(C)c3cc(C)ccc3N2)c1
Yield: 37.4 %

Procedure:
To a stirred mixture of 3-(4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (150 mg, 0.56 mmol) in dichloromethane (3 mL) was added pyridine (79 mg, 1.01 mmol) in dichloromethane (2 mL) and ethanesulfonyl chloride (108 mg, 0.84 mmol) under nitrogen. The resultant mixture was stirred for 18 h. The reaction mixture was diluted with dichloromethane, washed with water (twice), saturated brine, and dried over Magnesium sulfate. Magnesium sulfate was removed by filtration, and after evaporation, the residue was purified on chromatography column (silica gel, petroleum ether: ethyl acetate=10:1) to afford 75 mg of ethanesulfonic acid [3-(4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-amide yellow solid (Yield: 37%). MS (ESI+APCI) M+1=359.2.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:13]=[C:12]2[C:8]([NH:9][CH:10]=[N:11]2)=[C:7]([NH:14][C:15](=[O:17])[CH3:16])[N:6]=1)(=[O:3])[CH3:2].O.[C:19]([C@@:22]1([OH:37])[C@@H:26]([CH2:27][OH:28])[O:25][C:24](Cl)([C:29](=[O:31])[CH3:30])[C@:23]1([C:34](=[O:36])[CH3:35])[OH:33])(=[O:21])[CH3:20]>C1(C)C(C)=CC=CC=1>[C:1]([NH:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[C@:24]2([C:29](=[O:31])[CH3:30])[O:25][C@H:26]([CH2:27][OH:28])[C@@:22]([C:19](=[O:21])[CH3:20])([OH:37])[C@@:23]2([C:34](=[O:36])[CH3:35])[OH:33])=[C:7]([NH:14][C:15](=[O:17])[CH3:16])[N:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)C1(Cl)O[C@H](CO)[C@](O)(C(C)=O)[C@]1(O)C(C)=O
Reactant: CC(=O)Nc1nc(NC(C)=O)c2[nH]cnc2n1
Solvent: Cc1ccccc1C
Solvent: O
Product: CC(=O)Nc1nc(NC(C)=O)c2ncn([C@]3(C(C)=O)O[C@H](CO)[C@](O)(C(C)=O)[C@]3(O)C(C)=O)c2n1
Reaction time: 8 h

Procedure:
The dried chloromercuri derivative (24 g., 0.05 mole) of 2,6-diacetamidopurine was refluxed in xylene using a Dean-Stark water separator. Freshly prepared triacetyl-D ribofuranosyl chloride in xylene was added to the hot chloromercuri derivative and the mixture was refluxed, in an oil bath, with vigorous stirring. After 41/2 hours the reaction mixture was allowed to stand overnight at room temperature and then filtered. The precipitate was extracted (several times) with warm CHCl3. The CHCl3 extract was washed successively with 30% aqueous KI (thrice), water (thrice) dried, charcoaled and filtered. The filtrate was evaporated in vacuo, and the residue on trituration with ether gave 14.3 g. (58%; m.p. 87°-92°) of 2,6-diacetamido-9-triacetyl-β-D-ribofuranosyl purine.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:17](Br)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].[OH-].[K+].[I-].[Na+].Cl>O.C(O)C>[CH2:17]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCBr
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1
Temperature: 100 °C
Yield: 6 %

Procedure:
A mixture of 21.4 g (0.1 mol) of 4'-hydroxybiphenyl-4-carboxylic acid, 33.15 g (0.15 mol) of n-decyl bromide, 13.20 g (0.2 mol) of 85% potassium hydroxide, 1.05 g (7 mmol) of sodium iodide, 500 ml of ethanol and 100 ml of distilled water was heated under reflux at 100° C. for 12 hours. After 40 ml of 25% potassium hydroxide was added, the mixture was further heated under reflux for 2 hours. After allowing the reaction system to cool up to room temperature, the reaction mixture in cold water was acidified with 36% hydrochloric acid. The deposited product was separated by filtration and dissolved in acetone with heating, followed by filtration. The resulting filtrate was concentrated to obtain 1.97 g (6 mmol) of 4'-decyloxybiphenyl-4-carboxylic acid.
Reaction SMILES: CO[C:3](=O)[C@@H:4]1[CH2:8][C:7](=[CH:9][CH3:10])[CH2:6][N:5]1[C:11](OCC1C=CC=CC=1)=O.C[O:23][C:24](=O)[C@@H:25]1CC(=C)CN1C(OCC1C=CC=CC=1)=O>>[CH2:9]([C@@H:7]1[CH2:6][N:5]2[C@H:4]([CH2:3][C:24](=[O:23])[CH2:25][CH2:11]2)[CH2:8]1)[CH3:10]
Reactant: C=C1C[C@@H](C(=O)OC)N(C(=O)OCc2ccccc2)C1
Reactant: CC=C1C[C@@H](C(=O)OC)N(C(=O)OCc2ccccc2)C1
Product: CC[C@H]1C[C@H]2CC(=O)CCN2C1
Yield: 10 %

Procedure:
In a similar manner to the procedures described in. Preparative Examples 8(ii)′, 8(iii)′, 8(iv)′, 8(v)′ and 8(vi)′ above, reactions were conducted in turn, using (S)-1-benzyloxycarbonyl-4-ethylideneproline methyl ester [prepared as described in Preparative Example 24′ above] instead of (S)-1-benzyloxycarbonyl-4-methylideneproline methyl ester, to give the title compound as a brown oil (yield: 10%).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:33]=[CH:32][C:31]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH2:24][C:23]=4[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[NH2:36][CH2:37][C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1.O>O1CCOCC1>[CH:22]1[C:23]2[CH2:24][C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]=2[CH:32]=[CH:33][C:21]=1[C:19]([N:10]1[C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH2:13][N:14]2[C:5]([C:3]([NH:36][CH2:37][C:38]3[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=3)=[O:4])=[CH:6][CH:7]=[C:8]2[CH2:9]1)=[O:20]
Reactant: NCc1cccnc1
Reactant: O=C(c1ccc2c(c1)Cc1ccccc1-2)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Solvent: O
Solvent: C1COCCO1
Product: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc3c(c1)Cc1ccccc1-3)C2
Temperature: 25 °C

Procedure:
A solution of 0.7 g (0.0014 mol) of 2,2,2-trichloro-1-[10-(9H-fluorene-2-carbonyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]-ethanone of Step B and 0.30 g (0.0028 mol) of 3-aminomethylpyridine in 25 mL of 1,4-dioxane was heated under reflux for 1 hour. The reaction mixture was cooled to room temperature and poured into 75 mL of water with stirring. The precipitate was collected, washed with water, and recrystallized from ethanol to provide the title compound, m.p. 116-119° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[N:11]1([CH2:20][C:21]2[N:25]([CH2:26][C:27]([NH:29][CH3:30])=O)[C:24]3[CH:31]=[CH:32][CH:33]=[CH:34][C:23]=3[N:22]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[N:12]1>O1CCCC1>[N:11]1([CH2:20][C:21]2[N:25]([CH2:26][CH2:27][NH:29][CH3:30])[C:24]3[CH:31]=[CH:32][CH:33]=[CH:34][C:23]=3[N:22]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[N:12]1
Reactant: CNC(=O)Cn1c(Cn2nnc3ccccc32)nc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CNCCn1c(Cn2nnc3ccccc32)nc2ccccc21
Reaction time: 3 h
Yield: 29.3 %

Procedure:
In an oven dried round bottom flask, lithium aluminum hydride (26 mg, 0.69 mmol) and aluminum chloride (97 mg, 0.73 mmol) were stirred in 10 mL of anhydrous tetrahydrofuran at 70–80° C. for 1 hour. 2-(2-Benzotriazol-1-ylmethyl-1-H-benzimidazol-1-yl)-N-methyl acetamide (50 mg, 0.156 mmol) was added. After 3 hours, more lithium aluminum hydride (1 M in tetrahydrofuran, 0.312 mL, 0.312 mmol) was added. The reaction mixture was allowed to stirred for 2 additional hours. The solvent was evaporated, and the residue was purified by flash chromatography (CH2Cl2/MeOH=15:1) to give 14 mg (28%) of the title compound as an oil.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][N:5]([CH3:26])[S:6]([N:9]1[CH:13]=[C:12]([CH2:14][C:15]([CH3:19])([CH3:18])[CH2:16][CH3:17])[N:11]=[C:10]1[CH2:20][CH2:21][C:22]([O:24]C)=[O:23])(=[O:8])=[O:7]>O.CO.C1COCC1>[CH3:26][N:5]([CH3:4])[S:6]([N:9]1[CH:13]=[C:12]([CH2:14][C:15]([CH3:19])([CH3:18])[CH2:16][CH3:17])[N:11]=[C:10]1[CH2:20][CH2:21][C:22]([OH:24])=[O:23])(=[O:7])=[O:8]
Reactant: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(CCC(=O)OC)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(CCC(=O)O)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of lithium hydroxide monohydrate (182 mg, 4.3 mmol) in water (1.5 mL) was added to a solution of methyl 3-[1-[(dimethylamino)sulfonyl]-4-(2,2-dimethylbutyl)-1H-imidazol-2-yl]propanoate (for synthesis see intermediate 25) (500 mg, 1.4 mmol) in methanol (1.6 mL) and THF (1.6 mL). After stirring at rt overnight, the reaction mixture was concentrated and 2M hydrochloric acid was added. The resulting reaction mixture was concentrated to dryness to afford the title compound, which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9](O)(=O)[CH2:10][OH:11].O>C1(C)C=C(C)C=C(C)C=1>[OH:11][CH2:10][C:9]1[NH:8][C:7]2[CH:6]=[CH:5][CH:4]=[N:3][C:2]=2[N:1]=1
Reactant: O=C(O)CO
Reactant: Nc1cccnc1N
Solvent: O
Solvent: Cc1cc(C)cc(C)c1
Product: OCc1nc2ncccc2[nH]1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
using a Dan-Stark separator, 2,3-diaminopyridine (54.6 g; 0.5 mol) and glycolic acid (38 g; 0.5 mol) in 700 ml of mesitylene were boiled under reflux until the calculated amount of water had separated off. The mixture was then cooled to room temperature, and the resulting precipitate was filtered off with suction and, with addition of activated carbon, boiled in 800 ml of water for 15 min. The hot suspension was filtered and once more cooled to room temperature, and the colourless crystals that precipitated out were filtered off with suction and dried. Yield: 56.4 g (75%).
Reaction SMILES: C([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:6][C:7]1[CH:57]=[CH:56][C:10]([O:11][CH2:12][C@@H:13]([OH:55])[CH2:14][NH:15][CH2:16][CH2:17][C:18]2[CH:54]=[CH:53][C:21]([NH:22][CH:23]3[CH2:28][CH2:27][N:26]([C:29]([NH:31][CH2:32][CH2:33][C:34]4[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][CH2:43][O:44][C:45]5[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=5)=[CH:36][C:35]=4[O:51][CH3:52])=[O:30])[CH2:25][CH2:24]3)=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[CH3:52][O:51][C:35]1[CH:36]=[C:37]([O:40][CH2:41][CH2:42][CH2:43][O:44][C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:38]=[CH:39][C:34]=1[CH2:33][CH2:32][NH:31][C:29]([N:26]1[CH2:27][CH2:28][CH:23]([NH:22][C:21]2[CH:20]=[CH:19][C:18]([CH2:17][CH2:16][NH:15][CH2:14][C@H:13]([OH:55])[CH2:12][O:11][C:10]3[CH:56]=[CH:57][C:7]([OH:6])=[CH:8][CH:9]=3)=[CH:54][CH:53]=2)[CH2:24][CH2:25]1)=[O:30]
Reactant: COc1cc(OCCCOc2ccccc2)ccc1CCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)cc3)cc2)CC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc(OCCCOc2ccccc2)ccc1CCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 59.2 %

Procedure:
4-[4-(2-{[(2S)-3-(4-{[tert-Butyl (diphenyl)silyl]oxy}phenoxy)-2-hydroxypropyl]-amino}ethyl)anilino]-N-[2-methoxy-4-(3-phenoxypropoxy)phenethyl]-1-piperidinecarboxamide (0.25 g, 0.26 mmol) was reacted according to Procedure H (eluant: 10:1 chloroform-methanol) to give the title compound (0.11 g, 0.154 mmol).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.[OH:9][C:10]([CH3:15])([CH3:14])[C:11](=[O:13])[CH3:12].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(O[Na])(C)(C)C>C1COCC1.[NH4+].[Cl-].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:8][C:4]1[CH:3]=[C:2]([CH2:12][C:11](=[O:13])[C:10]([OH:9])([CH3:15])[CH3:14])[CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)C(C)(C)O
Reactant: Brc1cccc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1CCOC1
Product: CC(C)(O)C(=O)Cc1cccc(Br)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of 1,3-dibromobenzene (1.0 eq.), 3-hydroxy-3-methyl-butan-2-one (1.0 eq.), Pd2(dba)3 (0.02 eq.), xantphos (0.04 eq.) and t-BuONa (1.1 eq.) in THF (0.15M) was stirred at 60° C. for 2 h, poured in saturated aqueous NH4Cl and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. Flash chromatography (Hex:EtOAc; 7:3) afforded the title compound as an oil.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15].[Br:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C(N(CC)CC)C>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[Br:29][C:30]1[CH:35]=[CH:34][C:33]([O:23][C:20]2[CH:21]=[CH:22][C:17]([CH2:16][N:5]([CH2:4][C:3]3[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:2]=3[F:1])[C:6]3[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=3[CH3:15])=[CH:18][CH:19]=2)=[CH:32][CH:31]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: Cc1c(N(Cc2ccc(O)cc2)Cc2ccc(F)cc2F)cccc1[N+](=O)[O-]
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(N(Cc2ccc(Oc3ccc(Br)cc3)cc2)Cc2ccc(F)cc2F)cccc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 62 %

Procedure:
The product from Example 33A (1.0 g, 2.6 mmoles), 4 Å molecular sieves, Cu(OAc)2 (0.71 g, 3.91 mmoles) and 4-bromophenylboronic acid (1.57 g, 7.81 mmoles) in CH2Cl2 (20 mL) was treated with triethylamine (1.81 mL, 13.0 mmoles) and the resulting solution was stirred vigorously overnight. An additional equivalent of Cu(OAc)2, 4-bromophenylboronic acid, and triethylamine were added and the reaction mixture was stirred vigorously for 5 hours. The mixture was filtered through a 1 inch pad of Celite using CH2Cl2 and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 10:1 hexanes:ethyl acetate) to provide the title compound as a yellow oil (0.87 g, 62%).
Reaction SMILES: [OH-].[Na+].[CH3:3][S:4]([N:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18][C:19]1[C:20]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]3[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=3)=[CH:29][C:21]=2[S:22][C:23]=1[C:24]([O:26]CC)=[O:25])S(C)(=O)=O)(=[O:6])=[O:5].C(O)(=O)C>CO.O>[CH3:3][S:4]([NH:7][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18][C:19]1[C:20]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]3[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=3)=[CH:29][C:21]=2[S:22][C:23]=1[C:24]([OH:26])=[O:25])(=[O:5])=[O:6]
Reactant: CCOC(=O)c1sc2cc(OCc3cccnc3)ccc2c1Sc1ccccc1N(S(C)(=O)=O)S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CS(=O)(=O)Nc1ccccc1Sc1c(C(=O)O)sc2cc(OCc3cccnc3)ccc12
Yield: 67.6 %

Procedure:
Sodium hydroxide (1 ml of 1M in water) was added to a solution of ethyl 3-[2-(N,N-dimethylsulfonylamino)phenyl]sulfanyl-6-(3-pyridylmethoxy)benzo[b]thiophene-2-carboxylate (Example 16--185 mg, 0.31 mmol) in methanol (5 ml), and the solution was heated at reflux for 40 minutes. The hot solution was acidified by dropwise addition of acetic acid, diluted with water (5 ml), and cooled. The solid precipitate was isolated by filtration and dried under vacuo to give the title compound as a colourless solid (102 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([OH:9])[CH2:5][C:6]([CH3:8])=[CH2:7].[Br:16][C:17]1[CH:22]=[CH:21][C:20]([C@@H:23]([N:25]=[C:26]=[O:27])[CH3:24])=[CH:19][CH:18]=1.N12CCCN=C1CCCCC2>O1CCCC1>[Br:16][C:17]1[CH:18]=[CH:19][C:20]([C@@H:23]([N:25]2[CH2:2][CH2:3][C@:4]([CH2:5][C:6]([CH3:8])=[CH2:7])([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[O:9][C:26]2=[O:27])[CH3:24])=[CH:21][CH:22]=1
Reactant: C[C@H](N=C=O)c1ccc(Br)cc1
Reactant: C=C(C)CC(O)(CCCl)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: C=C(C)C[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Temperature: 75 °C
Yield: 54.5 %

Procedure:
To a dried 10 L jacketed reactor under a nitrogen atmosphere was charged 1-chloro-5-methyl-3-phenyl-hex-5-en-3-ol (167 g, 81.7 wt %, 610 mmol, 1.00 equiv), 1-bromo-4-((S)-1-isocyanato-ethyl)-benzene (219 g, 93.7 wt %, 911 mmol, 1.50 equiv), anhydrous tetrahydrofuran (3.00 L), and then 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 409 mL, 2.73 mol, 4.50 equiv). The resulting solution was agitated and refluxed (Tint=67-69° C., Text=75° C.) for 19 h, at which point HPLC analysis indicated ˜1A % (220 nm) of the 1-chloro-5-methyl-3-phenyl-hex-5-en-3-ol remained. The dark solution was cooled to Tint=20-25° C. Two liters of tetrahydrofuran were removed by distillation under reduced pressure. The remaining dark solution was diluted with 4.0 L of ethyl acetate and 1.0 L of hexanes. The resulting solution was washed with 4.0 L of a 1.0 M aqueous solution of hydrogen chloride (note: the wash is slightly exothermic). The aqueous solution was cut and the remaining organic solution was dried with anhydrous sodium sulfate, filtered and then concentrated to an oil via reduced pressure. The resulting material was subjected to flash silica chromatography (5-30% ethyl acetate/hexanes, 1.74 kg of silica) to produce 137.8 g of material (59 wt %, 3.1:1 diastereomeric ratio favoring the desired diastereomer
Reaction SMILES: [C:1]([O:5]C(=O)[NH:7][CH:8]1[CH:25]([C:26]([N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:27])[CH2:24][N:11]2[CH2:12][CH2:13][C:14]3[C:19]([CH:10]2[CH2:9]1)=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=3)(C)(C)C.[CH2:34]([Cl:36])[Cl:35].C[OH:38].[NH4+].[OH-]>Cl>[CH2:34]([Cl:36])[Cl:35].[CH3:1][OH:5].[NH4+:7].[OH-:38].[NH2:7][CH:8]1[CH:25]([C:26]([N:28]2[CH2:29][CH2:30][CH2:31][CH2:32]2)=[O:27])[CH2:24][N:11]2[CH2:12][CH2:13][C:14]3[C:19]([CH:10]2[CH2:9]1)=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=3
Reactant: COc1cc2c(cc1OC)C1CC(NC(=O)OC(C)(C)C)C(C(=O)N3CCCC3)CN1CC2
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: COc1cc2c(cc1OC)C1CC(N)C(C(=O)N3CCCC3)CN1CC2
Yield: 74 %

Procedure:
A solution of (RS,RS,RS)-[9,10-dimethoxy-3-(pyrrolidine-1-carbonyl)-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a]isoquinolin-2-yl]-carbamic acid tert-butyl ester (55 mg, 0.12 mmol) in hydrogen chloride solution (4 M in dioxane, 1 mL) was stirred 1 h at r.t., then neutralized with CH2Cl2/MeOH/NH4OH 90:10:0.25 and evaporated. Chromatography of the residue (SiO2, CH2Cl2/MeOH/NH4OH 90:10:0.25) afforded the title compound (32 mg, 74%). Off-white foam, MS (ISP) 359.6 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[N:13][C:12]([O:17][CH3:18])=[CH:11][CH:10]=2)=[O:5])[CH3:2].C(N(CC)CC)C.C(OCC)(=O)C>[Pd].C(O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[N:13][C:12]([O:17][CH3:18])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2ccc(OC)nc2c1Cl
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc2ccc(OC)nc2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 82.3 %

Procedure:
A mixture of 4-chloro-6-methoxy-[1,5]naphthyridine-3-carboxylic acid ethyl ester (75 g, 241.86 mmol, 1.0 eq), triethylamine (75 mL, 538.08 mmol, 2.22 eq), and 10% palladium on activated carbon (8.2 g) in ethanol (1350 mL) is stirred under hydrogen flow at room temperature for 6 hours. The catalyst is then removed by filtration and the solution is evaporated to dryness to give a yellow solid as crude product, which is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 5:1, v/v) to afford 6-methoxy-[1,5]naphthyridine-3-carboxylic acid ethyl ester as a light yellow powder (46.2 g, 77% yield).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1.CS(O)(=O)=O.[N-:18]=[N+]=[N-].[Na+].[OH-].[Na+]>C(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:12])[NH:18][CH2:7][CH2:8][O:9][C:10]=2[CH:11]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CCOc2cc(Br)ccc21
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O=C1NCCOc2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 4 h
Yield: 101.9 %

Procedure:
A solution of 7-bromochroman-4-one (340 mg, 1.5 mmol) and methanesulfonic acid (3 mL, 23.0 mmol) in DCM was cooled to 0° C. and treated with NaN3 (146 mg, 2.25 mmol) portionwise, while maintaining the internal temperature below 5° C. The reaction was then stirred at 0° C. for 4 h. At completion, the reaction was slowly neutralized with 8 N aq. NaOH, then diluted with DCM (20 mL) and water (20 mL). The layers were separated and the organics were dried over MgSO4, filtered and evaporated to afford 8-bromo-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one (370 mg, 100% yield). MS (EI) m/z=242.1 [M+1]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10]2[NH:14][N:13]=[C:12]([CH:15]3[CH2:17][CH2:16]3)[CH:11]=2)[N:3]=1.[OH:18][C@@H:19]1[CH2:23][NH:22][C@H:21]([C:24]([NH:26][C:27]2[S:28][C:29]([CH3:32])=[CH:30][N:31]=2)=[O:25])[CH2:20]1.ClC1N=C(NC2NN=C(C3CC3)C=2)N=C(N2CCC[C@@]2(C)C(NC2C=NC(F)=CC=2)=O)N=1>>[Cl:8][C:6]1[N:5]=[C:4]([NH:9][C:10]2[CH:11]=[C:12]([CH:15]3[CH2:17][CH2:16]3)[NH:13][N:14]=2)[N:3]=[C:2]([N:22]2[CH2:23][C@@H:19]([OH:18])[CH2:20][C@H:21]2[C:24]([NH:26][C:27]2[S:28][C:29]([CH3:32])=[CH:30][N:31]=2)=[O:25])[N:7]=1
Reactant: Cc1cnc(NC(=O)[C@@H]2C[C@H](O)CN2)s1
Reactant: Clc1nc(Cl)nc(Nc2cc(C3CC3)n[nH]2)n1
Agent: C[C@@]1(C(=O)Nc2ccc(F)nc2)CCCN1c1nc(Cl)nc(Nc2cc(C3CC3)n[nH]2)n1
Product: Cc1cnc(NC(=O)[C@@H]2C[C@H](O)CN2c2nc(Cl)nc(Nc3cc(C4CC4)[nH]n3)n2)s1

Procedure:
96C was prepared from 1A and 96B as described for 1C. LC/MS [M+H]+: 462; Ret time (Method F): 2.53 min.
Reaction SMILES: [CH3:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].Br[C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=1>>[CH3:1][CH2:2][C:3]([N:5]([C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4]
Reactant: CCC(=O)Nc1ccccc1
Reactant: Cc1cccnc1Br
Product: CCC(=O)N(c1ccccc1)c1ncccc1C
Yield: 99.8 %

Procedure:
Using 2-methylacetanilide (4.48 g) and 2-bromo-3-methylpyridine (10.3 g), a reaction was made in the same manner as in 1) of Production Example 14. The subsequent purification by silica gel column chromatography (developing solvent, ethyl acetate: hexane=1:3) produced 2-methyl-N-(3-methyl-2-pyridyl)acetanilide (7.2 g, crude product) as a pale brown oil.
Reaction SMILES: Br[CH2:2][B-:3]([F:6])([F:5])[F:4].[K+:7].[C:8]([N:15]1[CH2:20][CH2:19][NH:18][C@H:17]([CH3:21])[CH2:16]1)([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[C:11]([O:10][C:8]([N:15]1[CH2:20][CH2:19][N:18]([CH2:2][B-:3]([F:6])([F:5])[F:4])[C@H:17]([CH3:21])[CH2:16]1)=[O:9])([CH3:14])([CH3:12])[CH3:13].[K+:7]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: F[B-](F)(F)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C[B-](F)(F)F
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
A mixture of potassium (bromomethyl)trifluoroborate (1.20 g, 5.38 mmol) and (R)-4-N-Boc-2-methyl-piperazine (1.166 g, 5.65 mmol) in THF (7.00 mL) was heated at 80° C. under nitrogen for 24 h. After cooling, the mixture was concentrated, re-dissolved in acetone (125 mL) and treated with K2CO3 (1 eq). The suspension was stirred for 30 min and filtered through a short plug of Celite® (diatomaceous earth), washing with additional acetone and the combined organic phases were concentrated to give potassium (R)-((4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)methyl)trifluoroborate as a pale yellow foam (1.627 g, 94%). 19F-NMR (377 MHz, d6-acetone) δ −141.36.