Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[O:27]1[CH2:32][CH2:31][CH:30]([N:33]2[CH:37]=[C:36](B3OC(C)(C)C(C)(C)O3)[CH:35]=[N:34]2)[CH2:29][CH2:28]1.C(=O)(O)[O-].[Na+].O1CCOCC1>CO.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.O>[CH3:24][N:21]1[CH2:20][CH2:19][N:18]([C:16]2[CH:17]=[C:12]([N:8]3[CH:7]([CH3:26])[CH2:6][C:5]4[C:10](=[CH:11][C:2]([C:36]5[CH:35]=[N:34][N:33]([CH:30]6[CH2:31][CH2:32][O:27][CH2:28][CH2:29]6)[CH:37]=5)=[CH:3][CH:4]=4)[CH2:9]3)[N:13]=[C:14]([NH2:25])[N:15]=2)[CH2:23][CH2:22]1
Reactant: CC1(C)OB(c2cnn(C3CCOCC3)c2)OC1(C)C
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
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: CO
Solvent: O
Solvent: C1COCCO1
Product: CC1Cc2ccc(-c3cnn(C4CCOCC4)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 9.2 %

Procedure:
A mixture of 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (10 mg, 0.02 mmol; Peak 1, Example 49, Step 7), 1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (7.3 mg, 0.026 mmol), tetrakis(triphenylphosphine)palladium(0) (1.4 mg, 0.0012 mmol) and sodium bicarbonate (6.0 mg, 0.072 mmol) in a solution of 1,4-dioxane (0.2 mL) and water (0.1 mL) in a reaction vial was stirred at 90° C. overnight. After cooling, it was diluted with methanol. The solid was filtered off. The filtrate was purified with RP-HPLC (pH=10) to afford 0.9 mg of the desired product. LCMS (M+H)+: m/z=489.4.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:6][CH:7]=1.[NH2:15][NH2:16]>>[NH:15]([C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:6][CH:7]=1)[NH2:16]
Reactant: NN
Reactant: Clc1cccc(-c2ccc(Cl)nn2)c1
Product: NNc1ccc(-c2cccc(Cl)c2)nn1

Procedure:
A slurry of 3-chloro-6-(meta-chlorophenyl)pyridazine (10.25 g.) in anhydrous hydrazine (36 ml) was heated at 82° C. for 3 hours. Upon cooling a solid separated. The solid was isolated by filtration and recrystallized from ethanol to give 3-hydrazino-6-(meta-chlorophenyl)pyridazine, m.p. 173°-174°. When 3-hydrazino-6-(meta-chlorophenyl)-pyridazine was reacted with acrylonitrile using the same procedure described in Example 1, 1-[6'-(meta-chlorophenyl)-pyridazin-3'-yl]-3-aminopyrazol-2-ene was obtained, m.p. 196°-197° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([C:20]([F:23])([F:22])[F:21])=[N:15][C:16]([C:17]([OH:19])=O)=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[N:48]1([C:17]([C:16]2[N:15]=[C:14]([C:20]([F:22])([F:23])[F:21])[N:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][C:10]=23)=[O:19])[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCOCC3)c2C1
Reaction time: 12 h
Yield: 98.9 %

Procedure:
7-Tert-butoxycarbonyl-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-carboxylic acid 20a (330 mg, 1 mmol) was dissolved in 5 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (756 mg, 2 mmol), morpholine (174 mg, 2 mmol) and N,N-diisopropylethylamine (0.5 mL, 3 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure, added with 20 mL of saturated ammonium chloride solution, extracted with dichloromethane (20 mL×3). The organic phase was combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain tert-butyl 1-(morpholine-4-carbonyl)-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylate 20b (400 mg, yield 100.0%) as a yellow solid.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[Cl:9][C:10]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:11]=1[CH:12]=O.CC(O)=O.CNC>CC(O)C>[Cl:9][C:10]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:11]=1[CH:12]=[C:2]([C:3](=[O:4])[CH3:5])[C:1]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)CC(C)=O
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: CNC
Solvent: CC(C)O
Solvent: CC(=O)O
Product: COC(=O)C(=Cc1ccc(Cl)cc1Cl)C(C)=O
Temperature: 40 °C

Procedure:
To a stirred solution of methyl acetoacetate (345 mg, 2.97 mmol) and 2,4-dichlorobenzaldehyde (500 mg, 2.86 mmol) in 2-propanol (5 mL) was added AcOH (7 mg, 0.11 mmol) and dimethylamine (0.06 mL, 2M in THF, 0.11 mmol). The reaction was heated to 40° C. for 4 hrs followed by cooling to ambient temperature for 15 hrs. The reaction was concentrated and purified by flash chromatography (silica gel, 30% EtOAc/hexane) to give methyl 2-(2,4-dichlorobenzylidene)-3-oxobutanoate as a mixture of two isomers (colorless oil, 610 mg, 78%).
Reaction SMILES: B(Br)(Br)Br.[Br:5][C:6]1[C:15]([O:16]C)=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][C:10]([CH2:18][N:19]([CH3:36])[C:20]([C:22]1[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]([CH3:31])[C:23]=1[CH2:32][CH2:33][CH2:34][CH3:35])=[O:21])=[CH:11]2.C(=O)=O.CC(C)=O.O>C(Cl)Cl>[Br:5][C:6]1[C:15]([OH:16])=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][C:10]([CH2:18][N:19]([CH3:36])[C:20]([C:22]1[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]([CH3:31])[C:23]=1[CH2:32][CH2:33][CH2:34][CH3:35])=[O:21])=[CH:11]2
Reactant: CCCCc1c(C(=O)N(C)Cc2ccc3c(Br)c(OC)ccc3c2)c2ccccc2n1C
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: O
Product: CCCCc1c(C(=O)N(C)Cc2ccc3c(Br)c(O)ccc3c2)c2ccccc2n1C
Reaction time: 4 h
Yield: 107.3 %

Procedure:
Boron tribromide (18.78 mL of a 1 M solutioin in methylene chloride; 18.78 mmol) in 20 mL of methylene chloride was added under nitrogen dropwise over fifteen minutes to a solution of 2-butyl-1-methyl-1H-indole-3-carboxylic acid (5-bromo-6-methoxy-naphthalen-2-ylmethyl)-methyl-amide (3.09 g, 6.26 mmol), prepared in the previous step, in 125 mL of methylene chloride at dry ice-acetone temperature. After the addition the dry ice-acetone bath was replaced with an ice bath and the stirring continued for 4 h. Water was added to the reaction at ice bath temperature. The organic layer was separated and the aqueous layer extracted three times with methylene chloride. The combined extracts were dried (MgSO4) and the solvent removed under reduced pressure to give 2-butyl-1-methyl-1H-indole-3-carboxylic acid (5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide (3.22 g, 100%) as a brown solid foam, MS m/z: 479 [M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([NH:13][C@H:14]2[CH2:18][CH2:17][CH2:16][C@@H:15]2[NH2:19])=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[N:22][C:21]=1[C:26]1[C:27]([C:32](O)=[O:33])=[N:28][CH:29]=[CH:30][CH:31]=1.N1C2C(=NC=CC=2)N(O)N=1.C(Cl)CCl.C(N(CC)CC)C>C(Cl)Cl>[Cl:2][C:3]1[C:4]([NH:13][C@H:14]2[CH2:18][CH2:17][CH2:16][C@@H:15]2[NH:19][C:32]([C:27]2[C:26]([C:21]3[N:20]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:31][CH:30]=[CH:29][N:28]=2)=[O:33])=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1Cl
Reactant: O=C(O)c1ncccc1-c1ncccn1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1Cl)c1ncccc1-c1ncccn1

Procedure:
A solution of (1S,2S)-1-N-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 33; 327 mg, 1.03 mmol), 3-(pyrimidin-2-yl)pyridine-2-carboxylic acid (CAS number 1228431-21-7; 250 mg, 1.24 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (211 mg, 1.55 mmol), EDC (297 mg, 1.55 mmol) and triethylamine (0.432 ml, 3.10 mmol) in DCM (4 ml) was stirred at room temperature for 18 hours. The reaction was partitioned between DCM (10 ml) and water (10 ml), filtered through a hydrophobic frit and concentrated in vacuo. The resulting residue was purified by column chromatography (0-100% ethyl acetate/petrol) and was then by reverse phase chromatography (C18 silica, 5-95% water (0.05% ammonia)/acetonitrile) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][C:12]=2[CH3:13])=[N:5][S:4][N:3]=1.[Br:14]N1C(=O)CCC1=O.O.C([O-])([O-])=O.[K+].[K+]>ClC(Cl)(Cl)Cl>[Br:14][CH2:13][C:12]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[C:6]1[C:2]([Cl:1])=[N:3][S:4][N:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccncc1-c1nsnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: Clc1nsnc1-c1cnccc1CBr
Temperature: 75 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)-4-methylpyridine (0.63 g, 3 mmol) in tetrachloromethane (50 ml) was added under nitrogen, N-bromosuccinimide (0.80 g, 4.5 mmol) and α,α-azoisobutyronitril (80 mg, 0.5 mmol). The reaction mixture was stirred at 75° C. overnight. Water (50 ml) was added and after basifying with K2CO3 the reaction mixture was extracted with methylene chloride (3×100 ml). The organic phases were dried (MgSO4) and evaporated. The residue contained a mixture of starting material, the monobromo and the dibromo product. Separation by column chromatography, eluent: ethyl acetate/methylene chloride: 1/10, gave the title compound in 180 mg (20%) yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33]CC4C=CC=CC=4)=[CH:29][CH:28]=3)[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.[H][H]>[Pd].CO>[OH2:33].[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=3)[CH2:23][CH2:24]2)=[CH:4][CH:3]=1.[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=3)[CH2:23][CH2:24]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(Cn2c(NC3CCN(CCc4ccc(OCc5ccccc5)cc4)CC3)nc3ccccc32)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O
Product: Oc1ccc(CCN2CCC(Nc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)cc1
Yield: 88.5 %

Procedure:
A mixture of 7.5 parts of 1-(4-fluorophenylmethyl)-N-[1-{2-[4-(phenylmethoxy)phenyl]ethyl}-4-piperidinyl]-1H-benzimidazol-2-amine and 120 parts of methanol is hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is suspended in 2,2'-oxybispropane. The product is filtered off and dried, yielding 5.5 parts (88.5%) of 4-[2-{4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino]-1-piperidinyl}ethyl]phenol hemihydrate; mp. 111.6° C.
Reaction SMILES: [Cl:1]C1C=C(C=CC=1)[C@H](O)C(O)=O.[Cl:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=1)[C@@H:17]([OH:21])[C:18]([OH:20])=O.Cl.[NH2:26][C@H:27]1[CH2:36][CH2:35][C:34]2[C:29](=[CH:30][C:31]([OH:37])=[CH:32][CH:33]=2)[CH2:28]1>>[ClH:1].[NH2:26][C@@H:27]1[CH2:36][CH2:35][C:34]2[C:29](=[CH:30][C:31]([OH:37])=[CH:32][CH:33]=2)[CH2:28]1.[OH:37][C:31]1[CH:30]=[C:29]2[C:34]([CH2:35][CH2:36][C@H:27]([NH:26][C:18](=[O:20])[C@H:17]([C:16]3[CH:22]=[CH:23][CH:24]=[C:14]([Cl:13])[CH:15]=3)[OH:21])[CH2:28]2)=[CH:33][CH:32]=1
Reactant: O=C(O)[C@@H](O)c1cccc(Cl)c1
Reactant: N[C@H]1CCc2ccc(O)cc2C1
Reactant: O=C(O)[C@H](O)c1cccc(Cl)c1
Agent: Cl
Product: N[C@@H]1CCc2ccc(O)cc2C1
Product: O=C(N[C@H]1CCc2ccc(O)cc2C1)[C@@H](O)c1cccc(Cl)c1

Procedure:
By following the procedure described in PREPARATION IX and substituting the (S)-3-chloromandelic acid for the (R)-3-chloromandelic acid and the (S)-2-amino-7-hydroxytetralin hydrochloride, PREPARATION IV, for the (R)-2-amino-7-hydroxytetralin hydrochloride, the N-[(2S)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(S)-3-chloromandelamide, SR 58574, is obtained; m.p. 145°-146° C.; |alpha|=-34.2° (methanol, c =1%).
Reaction SMILES: [H][H].[N+:3]([C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][C:12](=[O:14])[CH3:13])=[CH:8][CH:7]=1)([O-])=O.[ClH:17]>[Pd].CO>[ClH:17].[NH2:3][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][C:12](=[O:14])[CH3:13])=[CH:8][CH:7]=1
Reactant: CC(=O)COc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(=O)COc1ccc(N)cc1

Procedure:
A stream of hydrogen was passed through a mixture comprising 19.6 g of 1-(4-nitrophenoxy)propan-2-one, 300 ml of methanol, 30 ml of concentrated aqueous hydrochloric acid and 4 g of 10% w/v palladium-on-charcoal at room temperature for 5 hours. At the end of this time, the catalyst was filtered off, and the filtrate was concentrated by evaporation under reduced pressure, to give 20 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=3)[NH2:12])[O:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[O:25]1CC[CH2:27][CH2:26]1.C(Cl)(=O)C>O>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[C:11]([NH:12][C:26](=[O:25])[CH3:27])[CH:13]=[CH:14][CH:15]=3)[O:8][C:4]=2[CH:3]=1
Reactant: C1CCOC1
Reactant: Nc1cccc(-c2nc3ccc(Br)cc3o2)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(=O)Cl
Product: CC(=O)Nc1cccc(-c2nc3ccc(Br)cc3o2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a solution of 3-(6-bromobenzoxazol-2-yl)aniline (Compound of Example 267) (925 mg), triethylamine (390 mg) and tetrahydrofuran (35 ml) was added acetyl chloride (276 mg) at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate-tetrahydrofuran (3:1, v/v). The organic layer was washed with 1 N hydrochloric acid, water, a saturated aqueous solution of sodium bicarbonate and water, successively and dried over MgSO4. The solvent was distilled off under reduced pressure, and the resulting crystals were collected by filtration to obtain N-[3-(6-bromobenzoxazol-2-yl)phenyl]acetamide (923 mg, 87%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[OH:10].Br[CH2:12][CH2:13][CH2:14][Cl:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[O:10][CH2:12][CH2:13][CH2:14][Cl:15]
Reactant: ClCCCBr
Reactant: N#Cc1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCCCCl)c(Br)c1
Temperature: 100 °C
Yield: 75.6 %

Procedure:
A mixture of 2-bromo-4-cyanophenol (3.96 g), 3-bromopropyl chloride (3.46 g), dimethylformamide (20 ml) and anhydrous potassium carbonate (3 g) was heated at 100° C. for 0.5 hour. The inorganic salt was filtered off, and the filtrate was concentrated. The residue was chromatographed on a column of silica gel (90 g), and eluted with a solution of n-hexane-chloroform-acetone (20:10:1) to give 3-(2-bromo-4-cyanophenoxy)propyl chloride as a colorless oil (4.15 g).
Reaction SMILES: C[C@H]1O[C@H]2O[C@H:10]3[C@H:15](O[C@@]2(O)C(=O)C1)[C@@H:14](NC)[C@@H:13](O)[C@@H:12]([NH:20]C)[C@@H:11]3[OH:22].CC1(C)S[C@@H]2[C@H](NC([C@H](N)C3C=CC=CC=3)=O)C(=[O:32])N2[C@H]1C(O)=O.[CH:48]1[C:53]([C@@H](O)[C@H](NC(C(Cl)Cl)=O)CO)=[CH:52][CH:51]=[C:50]([N+:65]([O-])=O)[CH:49]=1.C(O)CCO>>[CH:52]1[CH:51]=[C:50]([NH:65]/[N:20]=[C:12]2\[CH:13]=[CH:14][CH:15]=[CH:10][C:11]\2=[O:22])[C:49]([OH:32])=[CH:48][CH:53]=1
Reactant: CN[C@@H]1[C@H](O)[C@H](NC)[C@H]2O[C@@]3(O)C(=O)C[C@@H](C)O[C@H]3O[C@@H]2[C@H]1O
Reactant: O=C(N[C@H](CO)[C@H](O)c1ccc([N+](=O)[O-])cc1)C(Cl)Cl
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Solvent: OCCCO
Product: O=C1C=CC=C/C1=N\Nc1ccccc1O

Procedure:
coli strain FM5 was transformed with the dha plasmid pDT24 (specR), the btuB plasmids pBtuB1 (ampR) or pBtuB2 (chlR), or the btuBCED plasmid pBCED (chlR). Selection is on LB plates containing 50 mg/L spectinomycin, 50 mg/L ampicillin or 100 mg/L chloramphenicol. Colonies resistant to the appropriate antibiotics were used for 1,3-propanediol production and vitamin or coenzyme B12 uptake.
Reaction SMILES: [N:1]([C@@H:4]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[C@H:8]([NH2:15])[CH2:7][CH2:6][C@H:5]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[F:23])=[N+:2]=[N-:3].[O:24]=[C:25]1[NH:33][C:28]2=[N:29][CH:30]=[CH:31][CH:32]=[C:27]2[C@@:26]21[CH2:44][C:36]1=[N:37][CH:38]=[C:39]([C:41](O)=[O:42])[CH:40]=[C:35]1[CH2:34]2.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>CN(C=O)C>[N:1]([C@@H:4]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[C@H:8]([NH:15][C:41]([C:39]2[CH:40]=[C:35]3[CH2:34][C@@:26]4([C:27]5[C:28](=[N:29][CH:30]=[CH:31][CH:32]=5)[NH:33][C:25]4=[O:24])[CH2:44][C:36]3=[N:37][CH:38]=2)=[O:42])[CH2:7][CH2:6][C@H:5]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[F:23])=[N+:2]=[N-:3]
Reactant: O=C(O)c1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Reactant: [N-]=[N+]=N[C@@H]1c2cccnc2[C@H](N)CC[C@H]1c1cccc(F)c1F
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: CN(C)C=O
Product: [N-]=[N+]=N[C@@H]1c2cccnc2[C@H](NC(=O)c2cnc3c(c2)C[C@@]2(C3)C(=O)Nc3ncccc32)CC[C@H]1c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (5S,6S,9R)-5-azido-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-amine (the mixture of diastereomers described in Intermediate 11) (90 mg, 0.28 mmol), (6S)-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxylic acid (described in Intermediate 4) (85 mg, 0.30 mmol) and HATU (2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (160 mg, 0.43 mmol) in DMF (3.0 mL) was added N,N-diisopropylethylamine (0.15 mL, 0.86 mmol), and the resulting mixture was stirred at ambient temperature for 16 h. The reaction mixture was partially purified by reversed-phase HPLC on a C-18 column, eluting with a gradient of H2O:CH3CN:TFA-100:0:0.1 to 0:100:0.1. Product-containing fractions were combined and neutralized with saturated aqueous sodium carbonate and the acetonitrile was removed by evaporation under reduced pressure. The resulting mixture was extracted with ethyl acetate (50 mL) and dichloromethane (2×50 mL) and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as a mixture of four diastereomers. Separation of the diastereomers was achieved by SFC on a ChiralCel OJ-H column, eluting with CO2:MeOH-80:20, to give four diastereomers in approximately a 2:1:2:5 ratio:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:19])=[C:11]([NH:15][CH2:16][CH2:17][OH:18])[C:12]=3[F:14])[C:7](=[O:20])[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1.[C:26]1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCOCC)C.C(#N)C>C(Cl)(Cl)Cl>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:19])=[C:11]([N:15]4[CH2:16][CH2:17][O:18][CH2:26]4)[C:12]=3[F:14])[C:7](=[O:20])[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(NCCO)c(F)cc2c1=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: CCOCOCC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(N3CCOC3)c(F)cc2c1=O
Reaction time: 3 h

Procedure:
A mixture of 0.70 g of ethyl 1-cyclopropyl-6,8-difluoro-7-(2-hydroxyethylamino)-1,4-dihydro-4-oxoquinoline-3-carboxylate, 0.08 g of p-toluenesulfonic acid, 2.08 g of diethoxymethane and 20 ml of acetonitrile was stirred for 3 hours under reflux. The reaction mixture was allowed to cool down, followed by the addition of 100 ml of chloroform. The resultant mixture was washed successively with 5% aq. sodium carbonate solution and saturated saline, dried over anhydrous magnesium sulfate, and then concentrated.
Reaction SMILES: [H-].[Na+].C[C:4]1([CH3:11])O[C@H:7]([CH2:9]O)[CH2:6][O:5]1.C(Br)C[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].O>C1COCC1>[CH2:6]([O:5][CH2:4][CH2:11][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14])[CH2:7][CH2:9][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14]
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: CC1(C)OC[C@@H](CO)O1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOCCCCCCCCCCCCCCCCCC
Temperature: 80 °C
Reaction time: 8 h
Yield: 60.7 %

Procedure:
To a stirred suspension of NaH (80%; 0.55 g, 17.4 mmol, 2 equiv) in THF (20 ml) was added dropwise a solution of (R)-glycerol acetonide 1 (1.15 g; 1 equiv) in THF (20 ml). After that octadecyl bromide (5.8 g, 17.4 mmol, 2 equiv) dissolved in THF (25 ml) was added dropwise and the mixture obtained was stirred overnight at 80° C. The reaction mixture was cooled to 0° C. and water was added. The resulting mixture was concentrated and the residue was extracted with water and diethyl ether and the combined extracts were dried (MgSO4). The crude product obtained was further purified by flash column chromatography (10% ethyl acetate-n-hexane) to yield the title compound 1b (2.03 g, 5.28 mmol, 61%).
Reaction SMILES: [F:1][C:2]1[C:3]([F:27])=[CH:4][C:5]2[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][NH:18][C@@H:17]([CH2:21][CH2:22][O:23][CH3:24])[CH2:16]3)[C:12]3[CH:11]=[C:10]([CH3:25])[S:9][C:8]=3[NH:7][C:6]=2[CH:26]=1.C=O.[C:30](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:44]CCCl>>[ClH:44].[F:1][C:2]1[C:3]([F:27])=[CH:4][C:5]2[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][N:18]([CH3:30])[C@@H:17]([CH2:21][CH2:22][O:23][CH3:24])[CH2:16]3)[C:12]3[CH:11]=[C:10]([CH3:25])[S:9][C:8]=3[NH:7][C:6]=2[CH:26]=1
Reactant: COCC[C@H]1CN(C2=Nc3cc(F)c(F)cc3Nc3sc(C)cc32)CCN1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: ClCCCl
Agent: C=O
Agent: [Na+]
Product: COCC[C@H]1CN(C2=Nc3cc(F)c(F)cc3Nc3sc(C)cc32)CCN1C
Product: Cl
Temperature: 25 °C
Yield: 96 %

Procedure:
Dissolve (S)-6,7-difluoro-10-[3-(2-methoxy-ethyl)-piperazin-1-yl]-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene (26.1 g, 66.5 mmol) in 1,2-dichloroethane (DCE, 260 mL) with stirring at ambient temperature under nitrogen; cool to 10-15° C. Add aqueous 37% wt. formaldehyde (5.40 g×37%=2.00 g, 66.6 mmol) in one portion. Add powdered sodium triacetoxyborohydride (19.8 g, 93.4 mmol) in a few portions over 10-15 minutes, keeping the temperature below 20° C. Rinse in the residue with DCE (26 mL). Stir the reaction solution at ambient temperature for 1-2 hours. Add aqueous saturated sodium bicarbonate (260 mL) dropwise, and then stir at ambient temperature for 20-30 minutes. Separate the layers, and then extract the aqueous layer with methylene chloride (50 mL). Extract the combined organic layers with water (100 mL) then brine (100 mL). Dry the organic solution over magnesium sulfate with stirring, filter, and then concentrate under reduced pressure to an oily foam residue. Dissolve in methylene chloride and concentrate under reduced pressure to give 26.0 g (96%) of the free base of the title compound as a foam. 1H NMR (400 MHz, DMSO-d6) δ 7.70 (s, 1H), 6.74 (m, 2H), 6.36 (s, 1H), 3.75 (bm, 2H), 3.35 (m, 2H), 3.20 (s, 3H), 2.95 (bt, 1H), 2.75 (m, 2H), 2.30 (s, 3H), 2.22 (s, 3H), 2.15 (bm, 2H), 1.82 (m, 1H), 1.50 (m, 1H). HRMS (ES) exact mass M+H calcd for C20H24F2N4OS 407.1717; found 407.1716.