Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]#[N:7])=[N:2]1.C[O-].[Na+].[Cl-:11].[NH4+:12]>>[ClH:11].[NH:1]1[CH:5]=[N:4][C:3]([C:6](=[NH:12])[NH2:7])=[N:2]1
Reactant: N#Cc1nc[nH]n1
Reactant: [Cl-]
Reactant: [NH4+]
Agent: C[O-]
Agent: [Na+]
Product: Cl
Product: N=C(N)c1nc[nH]n1

Procedure:
1H-1,2,4-triazole-3-carbonitrile (0.94 g, 10 mmol) was reacted with sodium methoxide (0.81 g, 15 mmol) and ammonium chloride (0.96 g, 18 mmol) according to the procedure as described in Example 61, Step B to give the title compound as an offwhite solid (0.59 g, 40%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](S)=[N:7][C:6]=2[CH:11]=1.[CH3:12][N:13]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([N:16]3[CH2:17][CH2:18][CH2:19][N:13]([CH3:12])[CH2:14][CH2:15]3)=[N:7][C:6]=2[CH:11]=1
Reactant: CN1CCCNCC1
Reactant: Cc1ccc2oc(S)nc2c1
Solvent: ClC(Cl)Cl
Product: Cc1ccc2oc(N3CCCN(C)CC3)nc2c1

Procedure:
5-Methyl-2-mercaptobenzoxazole (200 mg) was dissolved in chloroform (20 ml), N-methylhomopiperazine (1.24 ml) was added dropwise to the solution and then the mixture was stirred with heating for 2 days. After evaporation of the solvent, the thus obtained mixture was purified by a silica gel column chromatography (methylene chloride:methanol=10:1) to obtain the title compound 5-methyl-2-(4-methyl-1-homopiperazinyl)benzoxazole (124 mg).
Reaction SMILES: [Cl-].[NH4+].O.[CH2:4]([N:6]([CH2:27][CH3:28])[C:7](=[O:26])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[C:10]=1[N+:23]([O-])=O)[CH3:5].C(OCC)(=O)C>C(O)C.[Fe]>[CH2:27]([N:6]([CH2:4][CH3:5])[C:7](=[O:26])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[C:10]=1[NH2:23])[CH3:28]
Reactant: CCN(CC)C(=O)Cc1cccc(Oc2ccccc2F)c1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)Cc1cccc(Oc2ccccc2F)c1N
Yield: 98.7 %

Procedure:
A mixture of iron powder (5 g.), ammonium chloride (0.5 g.), ethanol (40 ml.) and water (20 ml.) and a solution of N,N-diethyl-2-[2-nitro-3-(2-fluorophenoxy)phenyl]acetamide (5.1 g.) in ethanol (5 ml.) were treated in a similar manner to that of Example 1-(1) [extraction solvent: ethyl acetate] to give oily N,N-diethyl-2-[2-amino-3-(2-fluorophenoxy)phenyl]acetamide (4.6 g.). This substance was dissolved in a mixture of methanol and hydrochloric acid. The solution was evaporated and the residue was pulverized with ethyl acetate. The resultant product (4.15 g.). was recrystallized from a mixture of ethanol and ethyl acetate to give white needles of the captioned compound (2.95 g.). mp 159° to 160° C.
Reaction SMILES: CON(C)[C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH:21]([CH3:23])[CH3:22])=[O:5].[CH3:25][Mg]Br>O1CCCC1>[CH:21]([C:7]1[N:8]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:18])([F:20])[F:19])=[CH:15][CH:16]=2)[S:10][C:6]=1[C:4](=[O:5])[CH3:25])([CH3:22])[CH3:23]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C(C)C
Solvent: C1CCOC1
Product: CC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C(C)C
Temperature: 0 °C
Yield: 81.7 %

Procedure:
4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid methoxy-methyl-amide (7.56 g, 21.09 mmol) is suspended in anhydrous tetrahydrofuran (100 mL), and cooled to 0° C. with stirring under nitrogen. Methyl magnesium bromide (28 mL, 3.0M in diethyl ether, 84.36 mmol) is slowly added to the reaction over 1 h. The reaction is allowed to warm slowly to room temperature and monitored by TLC. Upon complete consumption of starting material, the reaction is carefully neutralized with 1N hydrochloric acid, extracted with diethyl ether, washed, dried, and concentrated. The 1-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanone (5.4 g, 17.23 mmol) 82% yield, is used without further purification.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=1.[Na].[C:12]([O:20][C:21]1[CH:26]=[C:25]([CH2:27]Br)[CH:24]=[C:23]([O:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:22]=1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:30]([O:29][C:23]1[CH:24]=[C:25]([CH2:27][S:1][C:2]2[NH:10][C:5]3[CH:6]=[N:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[CH:26]=[C:21]([O:20][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:22]=1)(=[O:37])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Sc1nc2cnccc2[nH]1
Reactant: O=C(Oc1cc(CBr)cc(OC(=O)c2ccccc2)c1)c1ccccc1
Agent: [Na]
Product: O=C(Oc1cc(CSc2nc3ccncc3[nH]2)cc(OC(=O)c2ccccc2)c1)c1ccccc1

Procedure:
The synthesis of this compound proceeded in the same fashion as Example 15 using 1.66 g (0.011 mol) of 2-mercapto-1H-imidazo[4,5-c]pyridine, 0.28 g (0.012 g atom) of sodium and 4.51 g (0.011 mol) of 5-bromomethyl-benzene-1,3-diol dibenzoate. The crude material (4.2 g) when subjected to HPLC gave pure product (m.p. 209°-212° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1.Cl.[NH2:19][C@H:20]([C:22]([NH2:24])=[O:23])[CH3:21].[BH3-]C#N.[Na+]>>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][NH:19][C@@H:20]([CH3:21])[C:22]([NH2:24])=[O:23])=[CH:9][CH:8]=1.[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[N:19][C@@H:20]([CH3:21])[C:22]([NH2:24])=[O:23])=[CH:9][CH:8]=1
Reactant: O=Cc1ccc(OCc2cccc(F)c2)cc1
Reactant: C[C@H](N)C(N)=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: C[C@H](N=Cc1ccc(OCc2cccc(F)c2)cc1)C(N)=O
Product: C[C@H](NCc1ccc(OCc2cccc(F)c2)cc1)C(N)=O

Procedure:
(S)-2-[4-(3-Fluorobenzyloxy)benzylamino]propanamide (Ia) is prepared by reacting 4-(3-fluorobenzyloxy)benzaldehyde (10 mmol), prepared as described in Example 22.1 a), and L-alaninamide hydrochloride (1.37 g, 11 mmol) followed by reduction with NaBH3CN (0.50 g, 8 mmol). After working up the reaction mixture and purification by flash-chromatography, (S)-2[4-(3-fluorobenzyloxy)benzalamino]propanamide is isolated as white solid in 68.7% yield. The product has HPLC purity of 96.2 (area %, see Example 25A) and a content of (S)-2-[3-(3-fluorobenzyl)-4-(3-fluorobenzyloxy)-benzylamino]propanamide (IIa) of 0.15% by weight (see Example 25B).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]([CH3:31])[C:10]([NH:12][CH2:13][C:14]2[C:15]([C:24]3[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=3)=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].[BH4-].[Na+]>C(O)C.C(OCC)(=O)C.[NiH6-5]Cl>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([CH:9]([CH3:31])[C:10]([NH:12][CH2:13][C:14]2[C:15]([C:24]3[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=3)=[N:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2cccc(C#N)c2)c1
Agent: Cl[NiH6-5]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2cccc(CN)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 5.9 %

Procedure:
To a stirred solution of 2-(3-cyanophenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (217 mg, 5.13 mmol) in dry ethanol (15 mL), cooled to 0° C., were added nickel(II) chloride hexahydride (121 mg, 5.13 mmol). Sodium borohydride (136 mg, 35.9 mmol) was added in small portions over 10 min. The reaction mixture was allowed to warm to room temperature and left to stir for a further 1 h. The purple residue was dissolved in ethyl acetate (50 mL) and extracted with saturated NaHCO3. The organic layer was dried over magnesium sulfate and the solvent removed in vacuo to yield 2-(3-(aminomethyl)phenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (130 mg, 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([Br:13])[C:6]([CH2:14]Br)=[CH:5]2.[CH3:16][O:17][P:18]([O:21]C)[O:19][CH3:20]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([Br:13])[C:6]([CH2:14][P:18]([O:19][CH3:20])([O:17][CH3:16])=[O:21])=[CH:5]2
Reactant: COP(OC)OC
Reactant: Clc1cc2cc(CBr)c(Br)nc2cc1Cl
Product: COP(=O)(Cc1cc2cc(Cl)c(Cl)cc2nc1Br)OC

Procedure:
A mixture of 6,7-dichloro-2-bromo-3-bromomethylquinoline (0.74 g, 2 mmol) and trimethylphosphite (5 ml) was heated at 80°-90° C. for 2-3h. Then the excess trimethylphosphite was removed in vacuo at 70°-80° C. and the oily residue was made crystalline by treating with hexane-ethyl ether (1:1). The crystalls were collected, washed with toluene and dried in vacuo to give 0.65 g of 6,7-dichloro-3-dimethylphosphonomethyl-2-bromoquinoline.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:11]([C:13]1[CH:18]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:16]=[CH:15][C:14]=1[O:23][C@@H:24]([CH3:29])[C:25]([F:28])([F:27])[F:26])=[O:12])[CH2:5]2.[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:22][S:19]([C:17]1[CH:16]=[CH:15][C:14]([O:23][C@@H:24]([CH3:29])[C:25]([F:26])([F:28])[F:27])=[C:13]([C:11]([N:6]2[CH2:5][C:4]3[C:8](=[CH:9][CH:10]=[C:2]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:3]=3)[CH2:7]2)=[O:12])[CH:18]=1)(=[O:20])=[O:21]
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1Cc2ccc(I)cc2C1)C(F)(F)F
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1Cc2ccc(-c3ccccc3)cc2C1)C(F)(F)F
Temperature: 120 °C
Yield: 50 %

Procedure:
To a solution of 0.19 mmol (5-Iodo-1,3-dihydro-isoindol-2-yl)-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone (Example C3) in 1 ml DMF under argon was added successively 0.018 mmol tetrakistriphenylphosphine, 0.28 mmol phenyl boronic acid and 0.56 mmol potassium carbonate. The reaction mixture was heated at 120° C. for 2 hours then cooled to room temperature and filtered. The filtrate was evaporated to dryness and the residue was treated with sat. NaCl. The resulting mixture was extracted 3 times with dichloromethane. The organics phases were dried over sodium sulfate and evaporated. The crude compound was purified on a 10 g of Si-Amine cartridge: n-Heptane/Ethylacetate to provide the title compound (50%). Off-white solid. MS (m/e): 490.0 [M+H]+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[N:24][NH:23][C:22]4=[O:26])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[H-].[Na+].CN(C)C=O.[CH3:34][C@@H:35](O)[CH2:36]C.Br[C:40]1[CH:45]=C[C:43]([S:46]([O-:49])(=[O:48])=[O:47])=[CH:42][CH:41]=1>O>[CH3:34][C:35]1([CH3:36])[CH:5]2[CH2:6][CH2:7][C@@:8]1([CH2:43][S:46]([OH:49])(=[O:48])=[O:47])[C:3](=[O:2])[CH2:4]2.[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[N:24][N:23]([C@@H:40]([CH3:45])[CH2:41][CH3:42])[C:22]4=[O:26])=[CH:17][CH:16]=3)[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: O=S(=O)([O-])c1ccc(Br)cc1
Reactant: COc1ccc(N2CCN(c3ccc(-n4cn[nH]c4=O)cc3)CC2)cc1
Reactant: CC[C@@H](C)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Product: CC[C@H](C)n1ncn(-c2ccc(N3CCN(c4ccc(OC)cc4)CC3)cc2)c1=O
Temperature: 80 °C
Reaction time: 3 h
Yield: 37.7 %

Procedure:
A mixture of 3.5 g of 2,4-dihydro-4-[4-[4-(4-methoxyphenyl)-1-piperazinyl ]-phenyl]-3H-1,2,4-triazol-3-one, 0.6 g of a sodium hydride dispersion 50% and 100 ml of N,N-dimethylformarnide was stirred for 3 hours at 80° C. After the addition of 3.5 g of (R)-2-butanol 4-bromobenzenesulfonate (ester) (intermediate (3)), stirring was continued for 6 hours at this temperature. After cooling, water was added The crystallized product was filtered off and taken up in trichloromethane. The undissolved part was filtered off. The remaining solution was dried and purified by column chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 4methyl-2-pentanone. The product was filtered off and converted into the (S)-7,7dimethyl-2-oxobicyclo[2.2.1]heptane-1-methanesulfonate salt in 2-propanone. The salt was filtered off and recrystallized from 1-butanol. The product was filtered off and dried, yielding 1.2 g (13.7%) of (+)-(S)-2,4-dihydro-4-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one (S)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-1-methanesulfonate (1:2); mp. 192.0° C.; [α]D20=+28.410° (conc.=1% in ethanol) (interm. 5).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][N:5]=1.[Cl:11][C:12]1[C:13](F)=[CH:14][C:15]([F:21])=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=1>CN(C=O)C.CCOC(C)=O>[Cl:3][C:4]1[CH:9]=[C:8]([O:10][C:13]2[CH:14]=[C:15]([F:21])[C:16]([N+:18]([O-:20])=[O:19])=[CH:17][C:12]=2[Cl:11])[CH:7]=[CH:6][N:5]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(F)cc1F
Reactant: Oc1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Cl)c(Oc2ccnc(Cl)c2)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45.5 %

Procedure:
A suspension of sodium hydride (60% in mineral oil) (0.620 g, 15.5 mmol) in dry DMF (30 mL) under argon was treated portion wise with 2-chloro-4-hydroxypyridine (1.34 g, 10.3 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min, and then slowly warmed to RT. A solution of 5-chloro-2,4-difluoronitrobenzene (2 g, 10.3 mmol) in DMF (4.4 mL) was added to the suspension, and the mixture was heated at 90° C. for 15 h under argon. The mixture was cooled to RT, diluted with EtOAc (100 mL), washed with 10% aq LiCl (3×100 mL) and brine (2×100 mL), dried (MgSO4), concentrated to dryness, and purified by silica gel chromatography (EtOAc/hexanes) to yield 2-chloro-4-(2-chloro-5-fluoro-4-nitrophenoxy)pyridine as a bright yellow oil (1.42 g, 45% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.56 (dd, 1H), 8.35 (dd, 1H), 7.88 (dd, 1H), 7.32 (dd, 1H), 7.18 (m, 1H); MS (ESI) m/z: 303.0 (M+H+).
Reaction SMILES: Cl.C([O:4][CH2:5][CH2:6][O:7][NH:8][C:9]([C:11]1[C:16]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=2[F:25])=[CH:15][C:14](=[O:26])[N:13]([CH3:27])[CH:12]=1)=[O:10])=C.CCO.[OH-].[Na+]>CCOC(C)=O.C1COCC1>[OH:4][CH2:5][CH2:6][O:7][NH:8][C:9]([C:11]1[C:16]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=2[F:25])=[CH:15][C:14](=[O:26])[N:13]([CH3:27])[CH:12]=1)=[O:10]
Reactant: C=COCCONC(=O)c1cn(C)c(=O)cc1Nc1ccc(Br)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cn1cc(C(=O)NOCCO)c(Nc2ccc(Br)cc2F)cc1=O
Reaction time: 1 h
Yield: 75.9 %

Procedure:
1 N HCl solution (0.36 mL) was added to a stirred solution of 4-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (2-vinyloxyethoxy)-amide (0.077 g, 0.181 mmol) in a 1:1 mixture of EtOH:THF (6 mL). After 1 hour, the pH of the reaction mixture was adjusted to 5 to 7 with 2 N NaOH solution. The reaction mixture was diluted with EtOAc, washed with water, dried (MgSO4) and concentrated. Trituration with diethyl ether yielded 55 mg (76%) clean desired product as a white solid. MS APCI (−) m/z 398, 400 (M−, Br pattern) detected: 1H NMR (400 mHz, DMSO-d6)<11.65 (s, 1H), 9.41 (s, 1H), 8.13 (s, 1H), 7.68 (d, 1H), 7.43 (m, 3H), 4.74 (t, 1H), 3.91 (t, 2H), 3.62 (m, 2H), 3.36 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C:12]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:11](=[O:18])[NH:10][CH2:9]2)=[CH:4][CH:3]=1.O=[CH:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].C1COCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C:12]3([CH2:13][CH2:14][N:15]([CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:16][CH2:17]3)[C:11](=[O:18])[NH:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C1NC[C@@H](c2ccc(F)cc2)C12CCNCC2
Reactant: CC(C)(C)OC(=O)NCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCN1CCC2(CC1)C(=O)NC[C@H]2c1ccc(F)cc1
Reaction time: 8 h
Yield: 33.5 %

Procedure:
A mixture containing 0.25 g (1.0 mmol) of (S)-4-(4-fluorophenyl)-2,8-diazaspiro[4.5]decan-1-one, 0.2 g (1.41 mmol) of tert-butyl 2-oxoethylcarbamate, 2 mL of THF, 1 mL of DCM, and 1 g (2.5 mmol) of MP-sodium triacetoxyborohydride resin was rotated overnight. The reaction mixture was filtered and the solvents were removed under reduced pressure. The residue was subjected to silica gel chromatography to give 131 mg (33%) of (S)-tert-butyl 2-(4-(4-fluorophenyl)-1-oxo-2,8-diazaspiro[4.5]decan-8-yl)ethylcarbamate as a colorless oil: 1HNMR (400 MHz, CD3OD) δ ppm 7.35-7.32 (m, 2H), 7.12-7.07 (m, 2H), 3.68 (dd, 1H, J=10.4 and 7.6 Hz), 3.57 (dd, 1H, J=10.4 and 6.4 Hz), 3.32-3.28 (m, 3H), 3.11-3.08 (m, 2H), 2.87-2.84 (m, 3H), 2.02-1.80 (m, 4H), 1.41 (s, 9H), and 1.34-1.27 (m, 2H); LCMS m/z: 392.3 (M+H)+.
Reaction SMILES: CC(C)=[O:3].C(C(C)=O)C.[Br:10][C:11]1[CH:16]=[C:15]([Br:17])[CH:14]=[C:13]([Br:18])[C:12]=1[O-:19].[Na+:20]>O>[OH-:3].[Na+:20].[Br:10][C:11]1[CH:16]=[C:15]([Br:17])[CH:14]=[C:13]([Br:18])[C:12]=1[O-:19].[Na+:20]
Reactant: CC(C)=O
Agent: [Na+]
Agent: [O-]c1c(Br)cc(Br)cc1Br
Solvent: O
Solvent: CCC(C)=O
Product: [OH-]

Procedure:
It has been found that a liquid ketone such as acetone or methyl ethyl ketone when present in this reaction mixture tends to ensure that the desired tris(2,4,6-tribromophenoxy)-s-1,3,5-triazine product is formed in high purity. In experiments wherein a refluxing mixture of water and an alkanol (methanol), was used as the reaction medium for step d), it was found that some of the chloro groups in the cyanuric chloride reacted with the methanol to form bis-(tribromophenoxy)-methoxy-s-1,3,5-triazine as an impurity. On the other hand, when acetone or methyl ethyl ketone was used as the organic solvent in step d), the chloro groups were found to react exclusively with the sodium 2,4,6-tribromophenolate despite of the presence of a large amount of water in the reaction mixture which was carried over from the prior bromination step and the prior use of aqueous NaOH to form the sodium 2,4,6-tribromophenolate.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1.C([O-])(=O)C.[Na+]>C(O)C.C(OCC)(=O)C>[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccc(S)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Sc2ccc(N)cc2)c([N+](=O)[O-])c1
Yield: 96.4 %

Procedure:
A solution of methyl 4-chloro-3-nitrobenzoate (1.00 g, 4.638 mmol) in anhydrous ethanol (40 mL) was treated with 4-aminothiophenol (0.813 g, 6.494 mmol) and anhydrous sodium acetate (1.90 g, 23.19 mmol) at room temperature under a nitrogen atmosphere, at reflux for 2 hours. The reaction was cooled, diluted with ethyl acetate (100 mL), and washed with water (3×50 mL) and brine (50 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated by rotary evaporation. The resulting orange solid was triturated with ethyl ether/hexanes (1:1 v/v, 3×30 mL), and dried in vacuo to afford the title compound (1.36 g, 4.469 mmol, 96%). 1H NMR (300 MHz, DMSO-D6) δ ppm 3.87 (s, 3 H) 5.80 (s, 2 H) 6.70 (d, J=8.46 Hz, 2 H) 7.00 (d, J=8.46 Hz, 1 H) 7.23 (d, J=8.46 Hz, 2 H) 8.05 (dd, J=8.46, 1.84 Hz, 1 H) 8.64 (d, J=1.84 Hz, 1 H). MS (ESI+) m/z 305 (M+H)+.
Reaction SMILES: NC1N=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[C:12]4[C:20]([NH:21][CH:22]([CH:26]5[CH2:28][CH2:27]5)[CH:23]5CC5)=[N:19][CH:18]=[C:17]([C:29]([NH2:31])=[O:30])[C:13]=4[NH:14][C:15]=3[CH:16]=2)=CN=1.C([C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1)#C.C(=O)([O-])[O-:41].[Cs+].[Cs+]>CS(C)=O.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.Cl[Pd]Cl>[OH:41][C:26]([CH3:27])([CH3:28])[CH:22]([NH:21][C:20]1[C:12]2[C:11]3[CH:10]=[CH:9][C:8]([C:5]#[C:6][C:34]4[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=4)=[CH:16][C:15]=3[NH:14][C:13]=2[C:17]([C:29]([NH2:31])=[O:30])=[CH:18][N:19]=1)[CH3:23]
Reactant: NC(=O)c1cnc(NC(C2CC2)C2CC2)c2c1[nH]c1cc(-c3cnc(N)nc3)ccc12
Reactant: O=C([O-])[O-]
Reactant: C#Cc1cccnc1
Agent: Cl[Pd]Cl
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC(Nc1ncc(C(N)=O)c2[nH]c3cc(C#Cc4cccnc4)ccc3c12)C(C)(C)O
Temperature: 120 °C

Procedure:
A mixture of 1-[(2-hydroxy-1,2-dimethylpropyl)amino]-7-iodo-5H-pyrido[4,3-b]indole-4-carboxamide (prepared according to Examples 11 and 35, 50 mg, 0.11 mmol), 3-ethynylpyridine (18 mg, 0.17 mmol), cesium carbonate (74 mg, 0.23 mmol), and dichlorobis(tricyclohexylphosphine)palladium(II) (8.4 mg, 0.011 mmol) in DMSO (1.1 mL) was purged with nitrogen for 5 min, heated to 120° C. for 12 h, cooled to room temperature, diluted with EtOAc, and washed with water and brine. The organic layer was dried, concentrated, and purified by flash chromatography to afford the title compound. LRMS (APCI) calc'd for (C24H23N5O2) [M+H]+, 414.2. found 414.1.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:9][CH2:8][NH:7][C:6]1=[O:10])(=[O:4])=[O:3].C[Si](C)(C)[Cl:13].C(N(CC)CC)C.[O:23]1[CH2:28]COCC1>>[Cl:13][C:28]([N:7]1[CH2:8][CH2:9][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[C:6]1=[O:10])=[O:23]
Reactant: C1COCCO1
Reactant: CS(=O)(=O)N1CCNC1=O
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(C(=O)Cl)C1=O
Reaction time: 8 h

Procedure:
16.4 parts by weight of 1-methylsulphonyl-imidazolid- 2-one in dioxane were boiled for 3 days with 27 parts by weight of trimethylchlorosilane and 20 parts by weight of triethylamine. The triethylamine hydrochloride which precipitated was filtered off, 11 parts by weight of phosgene were added to the filtrate and the mixture was left to stand overnight at room temperature. It was then evaporated to dryness and the residue recrystallized from boiling acetone.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:21][CH3:22])[CH:4]1[S:8][C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[N+:18]([O-])=O)=[N:6][CH2:5]1.O.NN>C(O)C.O1CCCC1.[C].[Pd]>[CH3:22][O:21][CH:3]([O:2][CH3:1])[CH:4]1[S:8][C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[NH2:18])=[N:6][CH2:5]1
Reactant: COC(OC)C1CN=C(c2cc3cccc([N+](=O)[O-])c3[nH]2)S1
Agent: [Pd]
Agent: NN
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: COC(OC)C1CN=C(c2cc3cccc(N)c3[nH]2)S1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 76 %

Procedure:
To a solution of 2-[5-(dimethoxymethyl)-4,5-dihydro-1,3-thiazol-2-yl]-7-nitro-1H-indole (16.25 g) in ethanol (200 mL) and tetrahydrofuran (100 mL) was added 10% palladium carbon (50% containing water, 2 g) under nitrogen atmosphere, and hydrazine monohydrate (14.5 mL) was added dropwise at room temperature. The reaction mixture was stirred at 80° C. for 20 min, and allowed to cool to room temperature. The palladium carbon was removed by the filtration, and the filtrate was concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (11.2 g, yield 76%) as yellow crystals from a fraction eluted with ethyl acetate-hexane (50:50, volume ratio). MS: 292 (MH+).