Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][C:25]=1[N+:34]([O-:36])=[O:35]>C1COCC1>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH:1][CH2:2][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:20])[CH3:21])[CH:14]=[CH:15][CH:16]=3)[CH2:7][CH2:6]2)(=[O:32])=[O:31])=[CH:26][C:25]=1[N+:34]([O-:36])=[O:35]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNS(=O)(=O)c3ccc(Cl)c([N+](=O)[O-])c3)CC2)c1

Procedure:
Prepared by Procedure Q1 (THF) and Scheme AT using N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 4-chloro-3-nitrobenzenesulfonyl chloride: ESMS m/e: 523.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.Cl.[CH3:18][NH2:19].Cl>O.C(N(CC)CC)C.CN(C)C=O.C(Cl)Cl>[CH3:18][NH:19][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: CN
Reactant: Cc1ccc(C(=O)O)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 64.2 %

Procedure:
3.00 g of 4-methylbenzoic acid was suspended in a mixed solvent of 30 mL of methylene chloride and 20 μL of N,N-dimethylformamide, to which 2.9 mL of oxalyl chloride was added dropwise at room temperature, and this suspension was stirred for 5.5 hours at room temperature. Then, 1.79 g of monomethylamine hydrochloride was added to the reaction mixture, to which 15.4 mL of triethylamine was added dropwise in an ice bath, and the mixture was stirred for one hour at room temperature. The reaction mixture, to which water was added, was adjusted to pH 3 with 6M hydrochloric acid, and then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; chloroform:acetone=5:1] to yield 2.11 g of N,4-dimethylbenzamide as light orange solid.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH:4]([C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]([CH3:35])[CH:27]=1)[CH2:5][C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[N:8]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[N:7]=1.[Li+].[OH-]>>[CH3:25][O:24][C:21]1[CH:20]=[CH:19][C:18]([N:8]2[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)=[CH:10][C:6]([CH2:5][CH:4]([C:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]([CH3:35])[CH:27]=3)[C:3]([OH:36])=[O:2])=[N:7]2)=[CH:23][CH:22]=1
Reactant: COC(=O)C(Cc1cc(-c2ccc(C)cc2)n(-c2ccc(OC)cc2)n1)c1cn(C)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Product: COc1ccc(-n2nc(CC(C(=O)O)c3cn(C)c4ccccc34)cc2-c2ccc(C)cc2)cc1
Yield: 49 %

Procedure:
3-[1-(4-Methoxy-phenyl)-5-β-tolyl-1-H-pyrazol-3-yl]-2-(1-methyl-1H-indol-3-yl)-propionic acid. The title compound was prepared by Method 2 from (1-methyl-1H-indol-3-yl)-acetic acid methyl ester (0.10 g, 0.49 mmol), 3-bromoethyl-1-(4-methoxy-phenyl)-5-p-tolyl-1H-pyrazole (89 mg, 0.25 mmol), sodium hydride (19 mg, 0.49 mmol) and DMF (4.0 mL), giving 3-[1-(4-methoxy-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-2-(1-methyl-1H-indol-3-yl)-propionic acid methyl ester, which was not isolated. The ester was converted to the acid in situ by adding 2.5 mL (4.9 mmol) LiOH solution giving 57 mg (49%) of 3-[1-(4-methoxy-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-2-(1-methyl-1H-indol-3-yl)-propionic acid. HPLC: Rt=3.23 (Method B). MS (ES+): mass calculated for C29H27N3O3, 465.21; m/z found 466.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 12.15 (brs, 1H), 7.64 (d, J=7.9 Hz, 1H), 7.40 (d, J=8.2 Hz, 1H), 7.32 (s, 1H), 7.17-7.10 (m, 5H), 7.05-7.03 (m, 3H), 6.93 (d, J=8.9 Hz, 2H), 6.38 (s, 1H), 4.22 (dd, J=9.1, 5.9 Hz, 1H), 3.76 (s, 6H), 3.44 (dd, J=14.7, 9.2 Hz, 1H), 3.04 (dd, J=5.9, 14.7 Hz, 1H), 2.27 (s, 3H).
Reaction SMILES: [Li].N.[CH:3]#[CH:4].[O:5]=[C:6]1[C:12]([CH3:14])([CH3:13])[CH2:11][C:9](=[O:10])[CH:8]=[C:7]1[CH3:15]>>[CH3:15][C:7]1[C:6]([OH:5])([C:3]#[CH:4])[C:12]([CH3:14])([CH3:13])[CH2:11][C:9](=[O:10])[CH:8]=1
Reactant: CC1=CC(=O)CC(C)(C)C1=O
Reactant: C#C
Agent: N
Agent: [Li]
Product: C#CC1(O)C(C)=CC(=O)CC1(C)C

Procedure:
Lithium (15 g, 2.2 mol) in small pieces is added within one hour to 900 ml of ammonia at -35° C. Acetylene is conducted through the mixture until the blue color has disappeared and a grey suspension results. Ketoisophorone (150 g, 1 mol) is then added dropwise. The ammonia is evaporated within 12 hours. An orange colored residue remains. Subsequently, 1 liter of ice/water is added, the mixture is treated while stirring with ether and then with 2N HCl and thereafter made acid with conc. HCl. The phases are separated and the aqueous phase is extracted four times with ether. The ether extracts are washed twice with water and with saturated sodium chloride solution, dried, filtered and concentrated. In this manner there are obtained 166 g of crude 3,5,5-trimethyl-4-hydroxy-4-ethynylcyclohex-2-en-1-one. This crude product is dissolved almost completely in 500 ml of ether and then cooled to -25°. In this manner there are obtained 86.2 g (48%) of crystalline 3,5,5-trimethyl-4-hydroxy-4-ethynylcyclohex-2-en-1-one. The mother liquor is dissolved in 140 ml of isopropyl ether and cooled to 0°. In this manner there are obtained a further 25 g (14%) of crystals of the desired compound.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([C:18]([OH:20])=O)=[CH:16][N:17]=3)[CH:14]=2)=[CH:5][CH:4]=1.[NH2:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([NH:30]O)=[NH:29])=[CH:26][N:25]=1>>[F:22][C:2]([F:21])([F:1])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([C:18]4[O:20][N:30]=[C:28]([C:27]5[CH:32]=[CH:33][C:24]([NH2:23])=[N:25][CH:26]=5)[N:29]=4)=[CH:16][N:17]=3)[CH:14]=2)=[CH:7][CH:8]=1
Reactant: N=C(NO)c1ccc(N)nc1
Reactant: O=C(O)c1cnc2ccc(-c3ccc(C(F)(F)F)cc3)cn12
Product: Nc1ccc(-c2noc(-c3cnc4ccc(-c5ccc(C(F)(F)F)cc5)cn34)n2)cn1

Procedure:
The title compound was prepared from 6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine-3-carboxylic acid (example C.35) (153 mg, 0.5 mmol) and 6-amino-N-hydroxy-nicotinamidine (example B.4) (114 mg, 0.75 mmol) according to general procedure II. Obtained after flash chromatography on silica gel (ethyl acetate) and further purification by crystallization (MeOH/diethyl ether) as a white solid (27 mg, 13%). MS (ISP) 423.3 [(M+H)+]; mp 258° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([CH2:14][O:15][C:16]([C:30]2[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[C:32]([C:40]([F:43])([F:42])[F:41])[CH:31]=2)([C:26](OC)=[O:27])[CH2:17][O:18]CC2C=CC=CC=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[BH4-].[Li+].[ClH:52]>O1CCCC1>[ClH:52].[C:44]1([C:11]2([CH2:14][O:15][C:16]([C:30]3[CH:35]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:33]=[C:32]([C:40]([F:43])([F:41])[F:42])[CH:31]=3)([CH2:26][OH:27])[CH2:17][OH:18])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: COC(=O)C(COCc1ccccc1)(OCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC(CO)(OCC1(c2ccccc2)CCNCC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The oil from step (a) above was dissolved in anhydrous tetrahydrofuran (50 ml) and lithium borohydride (0.140 g, 6.5 mmol) was added. The reaction was stirred at 25° C. for 30 minutes and quenched with saturated aqueous ammonium chloride solution (75 ml) and extracted into ethyl acetate (75 ml). The organic layer was dried over (MgSO4) and removed in vacuo. The residue was dissolved in ethanol (15 ml) and hydrogenated at 50 psi over Pd(OH)2 (0.150 g) for 16 h. The catalyst was filtered and the solvent evaporated. The residue was chromatographed on silica eluting with ethyl acetate. The oil obtained was treated with ethereal HCl and left standing for 16 h. The solid formed was filtered off and washed with ether to obtain the title compound. 1H NMR (DMSO-d6) δ 7.99 (1 H, s), 7.75 (2H, s), 7.48 (4H, m), 7.35 (1H. m), 3.85 (4H, s), 3.47 (2H, s), 3.33 (2H, br d), 2.97 (2H, br t), 2.56 (2H, br d), 2.10 (2H, br t). MS (Cl+) 478 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][C@@H:8]([NH2:11])[CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12](O)(=O)C.C(N)=N>C(O)C>[CH2:7]([C@@H:8]1[CH2:9][NH:10][CH:12]=[N:11]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC[C@H](N)Cc1ccccc1
Reactant: CC(=O)O
Agent: N=CN
Solvent: CCO
Product: C1=N[C@H](Cc2ccccc2)CN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
To a solution of (2R)-3-phenyl-1,2-propanediamine (0.20 g, 1.33 mmol) in ethanol (5 ml) was added formamidine acetate (0.15 g, 1.45 mmol) and the mixture was stirred overnight at room temperature. The solvent was evaporated, sodium hydroxide (2N, 5 ml) was added and the mixture was extracted 3 times with dichloromethane (10 ml). The combined organic layers were dried over magnesium sulfate and evaporated. The residue was purified by chromatography (column: Isolute® Flash-NH2 from Separtis; eluent:ethyl acetate/methanol=90:10) to yield a colorless oil (0.20 g, 92%); MS (ISP): 161.4 ((M+H)+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[N:11]([S:19]([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[CH3:30][C:31]1[O:35][C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[N:33][C:32]=1[CH2:42][CH2:43]OS(C)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[N:11]([S:19]([C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:43][CH2:42][C:32]2[N:33]=[C:34]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[O:35][C:31]=2[CH3:30])=[CH:26][CH:27]=1)(=[O:21])=[O:20])[C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13]
Reactant: Cc1oc(-c2ccccc2)nc1CCOS(C)(=O)=O
Reactant: COC(=O)c1ccc(Cl)cc1N(C(=O)OC(C)(C)C)S(=O)(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cl)cc1N(C(=O)OC(C)(C)C)S(=O)(=O)c1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1

Procedure:
A mixture of the title E compound, 2-[(4-hydroxybenzenesulfonyl)-(t-butoxycarbonyl)-amino]-4-chloro-benzoic acid methyl ester (300 mg, 0.73 mmol), the title F compound, methanesulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl ester (246 mg, 0.87 mmol) and cesium carbonate (475 mg, 1.46 mmol) is stirred in DMF at 60° C. overnight. The mixture is cooled and the product is taken up in EtOAc. The solution is washed with brine, dried over anhydrous magnesium sulfate, and concentrated to give the crude product which is purified by flash chromatography on silica gel using an EtOAc (15%)-hexane (85%) mixture as the eluent to afford 4-chloro-2-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzenesulfonyl-(t-butoxycarbonyl)amino}benzoic acid methyl ester as a white foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([S:22][CH2:23][CH2:24][CH2:25][C:26]([NH:28][C@H:29]([C:45]([O:47][CH3:48])=[O:46])[CH2:30][CH2:31][CH2:32][CH2:33][NH:34]C(OCC3C=CC=CC=3)=O)=[O:27])[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[BrH:49]>C(O)(=O)C.C(OCC)C>[BrH:49].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[C:11]([S:22][CH2:23][CH2:24][CH2:25][C:26]([NH:28][C@H:29]([C:45]([O:47][CH3:48])=[O:46])[CH2:30][CH2:31][CH2:32][CH2:33][NH2:34])=[O:27])[NH:12][C:13]=2[C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[CH:7][CH:8]=1
Reactant: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)CCCSc1nc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)[nH]1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: COC(=O)[C@H](CCCCN)NC(=O)CCCSc1nc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)[nH]1
Reaction time: 1 h
Yield: 95 %

Procedure:
The N2-[4-[4,5-bis(4-methoxyphenyl)-1H-imidazol-2-ylthio]-1-oxobutyl]-N6-[(phenylmethoxy)carbonyl]-L-lysine, methyl ester (1.60 g, 0.0023 mol) was dissolved in hydrogen bromide 30 wt. % solution in acetic acid (20 ml) under a nitrogen atmosphere at ambient temperature. The reaction mixture was stirred for 1 hour, and diluted with ethyl ether to precipitate a gum. This residue was triturated with ethyl ether to give the title compound (1.58 g, 0.00224 mol, 95% yield) as an off white powder, mp 165°-70°. 1H NMR (DMSO-d6) δ8.38 (d, 1H), 7.80-7.70(bs, 3H), 7.39(d, 4H), 7.03(d, 4H), 4.26-4.23(m, 1H), 3.79(s, 6H), 3.6(s, 3H), 3.30-3.26(t, 2H), 2.79-2.73(m, 2H), 2.36-2.31(t, 2H), 1.93-1.86(m, 2H), 1.70-1.31(m, 6H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:25])[S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:26]1[S:27][CH2:28][C@@H:29]([C:31](O)=[O:32])[N:30]=1)=[CH:9]2.[NH4+].[N:35]1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C)C=O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:25])[S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)(=[O:17])=[O:18])[CH:14]=1)[NH:11][C:10]([C:26]1[S:27][CH2:28][C@@H:29]([C:31]([NH2:35])=[O:32])[N:30]=1)=[CH:9]2
Reactant: On1nnc2ccccc21
Reactant: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=N[C@H](C(=O)O)CS3)cc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=N[C@H](C(N)=O)CS3)cc2c1
Yield: 37.4 %

Procedure:
A solution of (4R)-2-{5-(2-methoxyethoxy)-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazole-4-carboxylic acid (0.15 g), 1H-1,2,3-benzotriazol-1-ol ammonium salt (0.072 g), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.090 g) and triethylamine (0.086 mL) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 3 hr. The reaction mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with ethyl acetate to give the title compound (0.056 g, yield 37%) as colorless crystals.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:10][C:11]([N:13]1[C@@H:17]([CH:18]([CH3:20])[CH3:19])[C@@:16](O)([C:21]([F:24])([F:23])[F:22])[O:15]C1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl-].[NH4+]>COC(C)(C)C.[Cl-].[Zn+2].[Cl-]>[CH2:3]([O:10][C:11](=[O:12])[NH:13][C@@H:17]([CH:18]([CH3:19])[CH3:20])[C@H:16]([OH:15])[C:21]([F:24])([F:22])[F:23])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)[C@@H]1N(C(=O)OCc2ccccc2)CO[C@]1(O)C(F)(F)F
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: COC(C)(C)C
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)[C@H](O)C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 65.5 %

Procedure:
To a solution of zinc chloride (2.0 g, 0.015 mol) and sodium borohydride (1.1 g, 0.029 mol) in t-butyl methyl ether (80 ml) was added dropwise a solution of (4S,5S)-5-hydroxy-4-isopropyl-5-trifluoromethyl-1,3-oxazolidine-3-carboxylic acid benzyl ester (5.0 g, 0.015 mol) obtained in Example 2 in t-butyl methyl ether (20 ml), and the mixture was stirred at room temperature for 15 hours. To the reaction solution was added a saturated aqueous ammonium chloride solution (80 ml), and the mixture was extracted with ethyl acetate (50 ml). The extract was washed with a saturated brine, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and thereto were added each 25 ml of methanol and water, and potassium carbonate (3.1 g), and the mixture was stirred for one hour. The reaction solvent was evaporated under reduced pressure, and thereto was added water (50 ml). The mixture was extracted three times with ethyl acetate (each 50 ml). The extract was washed with a saturated brine, and the organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The precipitated crystals were collected by filtration and washed with hexane to give the desired compound (3.0 g, yield: 87%).
Reaction SMILES: [CH2:1]([C:3]1[NH:8][C:7](=[O:9])[C:6]([C:10]#[N:11])=[C:5]([CH3:12])[CH:4]=1)[CH3:2].[BH4-].[Na+].NCCNCCN.C(O)(C(F)(F)F)=O>CO.[Ni](Cl)Cl>[NH2:11][CH2:10][C:6]1[C:7](=[O:9])[NH:8][C:3]([CH2:1][CH3:2])=[CH:4][C:5]=1[CH3:12]
Reactant: CCc1cc(C)c(C#N)c(=O)[nH]1
Agent: Cl[Ni]Cl
Agent: NCCNCCN
Agent: [BH4-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCc1cc(C)c(CN)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
To a stirred solution of 6-ethyl-4-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (1.462 g, 9.01 mmol) in Methanol (50 mL), cooled to 0° C. were added di-tertbutoxycarbonyl anhydride (4.19 mL, 18.03 mmol) and nickel(II) chloride.hexahydrate (0.214 g, 0.901 mmol). Sodium borohydride (2.387 g, 63.1 mmol) was added portionwise over 30 min, then the mixture was allowed to warm to room temperature and stirred overnight. Additional sodium borohydride (2.387 g, 63.1 mmol) was added and the reaction stirred overnight again. Diethylenetriamine (0.979 mL, 9.01 mmol) was added, and the reaction mixture was stirred for 30 min. at room temperature. The solvent was evaporated, and the residue was dissolved in ethyl acetate (20 mL) and extracted with sodium bicarbonate (2×10 mL). The organics were dried over sodium sulfate, and concentrated. The residue was dissolved in chloroform (25 mL) and TFA (3.47 mL, 45.1 mmol) was added. The reaction was heated to 50° C. for 3 h, then cooled to room temperature and concentrated. The reaction mixture was concentrated in vacuo and the crude product was purified by reverse phase HPLC (eluent; 0-30% gradient ACN in H2O, 0.1% TFA) to afford the title compound (TFA salt, 1.37 g, 54.1% yield) as a white solid. LC-MS (ES) m/z=167 [M+H]+. 1H NMR (400 MHz, DMSO-d) δ ppm 1.12 (t, J=7.58 Hz, 3H), 2.20 (s, 3H), 2.44 (q, J=7.58 Hz, 2H), 3.78-3.83 (m, 2H), 6.01 (s, 1H), 7.75-7.9 (br s, 3H), 11.86 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)[CH:5]=[C:4]([Cl:15])[N:3]=1.Cl.[F:17][C:18]1[CH:19]=[N:20][C:21]([C@@H:24]([NH2:26])[CH3:25])=[N:22][CH:23]=1>>[Cl:15][C:4]1[N:3]=[C:2]([NH:26][C@H:24]([C:21]2[N:22]=[CH:23][C:18]([F:17])=[CH:19][N:20]=2)[CH3:25])[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)[CH:5]=1
Reactant: C[C@H](N)c1ncc(F)cn1
Reactant: Cc1cc(Nc2cc(Cl)nc(Cl)n2)n[nH]1
Agent: Cl
Product: Cc1cc(Nc2cc(Cl)nc(N[C@@H](C)c3ncc(F)cn3)n2)n[nH]1

Procedure:
Following a similar procedure to that of Example 9, the title compound was synthesized from 2,6-dichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Method 17) and (5)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7). m/z 348.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([OH:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.C(O)C.[OH-].[Ba+2:37].[OH-]>C(#N)C>[CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([OH:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.[Ba:37]
Reactant: [Ba+2]
Agent: Cc1nnc(C(=O)NC(C)(C)c2nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n2C)o1
Agent: [OH-]
Solvent: CCO
Solvent: CC#N
Product: [Ba]
Temperature: 62.5 °C
Reaction time: 18 h

Procedure:
Raltegravir (100 gm), ethanol (600 ml), acetonitrile (400 ml) and barium hydroxide (42 gm) were added at 25 to 30° C. The contents were heated to 60 to 65° C. to obtain a solution. The solution was cooled to 25 to 30° C. and stirred for 18 hours at 25 to 30° C. The solid obtained was collected by filtration and dried to obtain 108 gm of raltegravir barium.
Reaction SMILES: [CH3:1][CH:2]([N:4]([CH2:21][C:22]1[C:30]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[N:24](COCC[Si](C)(C)C)[CH:23]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15])=[CH:10][CH:9]=1)=[O:6])[CH3:3].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:3][CH:2]([N:4]([CH2:21][C:22]1[C:30]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([S:14]([C:17]([F:19])([F:20])[F:18])(=[O:16])=[O:15])=[CH:12][CH:13]=1)=[O:6])[CH3:1]
Reactant: CC(C)N(Cc1cn(COCC[Si](C)(C)C)c2ncccc12)C(=O)Nc1ccc(S(=O)(=O)C(F)(F)F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)N(Cc1c[nH]c2ncccc12)C(=O)Nc1ccc(S(=O)(=O)C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
To a solution of 1-propan-2-yl-3-{4-[(trifluoromethyl)sulfonyl]phenyl}-1-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]urea (167 mg, 0.29 mmol) in 1 mL THF was added 1 M tetrabutylammonium fluoride in THF (1.46 mL, 1.46 mmol). The reaction was heated to reflux for 1 h then treated with additional 1M tetrabutylammonium fluoride in THF (0.73 mL, 0.73 mmol). The solution was heated to reflux for 16 h, cooled to ambient temperature, and partitioned between saturated NaHCO3 and ethylacetate. The organics were washed with water and brine, then dried over Na2SO4, filtered and concentrated. The residue was purified on a Gilson reverse phase preparatory instrument, followed by purification by silica gel chromatography (CH2Cl2/MeOH followed by ethylacetate/hexanes) to give 1-(1-methylethyl)-1-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-3-{4-[(trifluoromethyl)sulfonyl]phenyl}urea. 1H NMR (400 MHz, CD3 OD): δ 8.19 (dd, J=4.8, 1.5 Hz, 1 H); 8.12 (dd, J=7.9, 1.5 Hz, 1 H); 7.90 (d, J=8.9 Hz, 2 H); 7.77 (d, J=9.0 Hz, 2 H); 7.33 (s, 1 H); 7.11 (dd, J=7.9, 4.8 Hz, 1 H); 4.79 (s, 2 H); 4.53-4.47 (m, 1 H); 1.25 (d, J=6.7 Hz, 6 H). LCMS [M+H]+=441.1.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][CH2:8][CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1.N1(O[C:29]2[C:37]([F:38])=[CH:36][C:32]([C:33]([NH2:35])=[O:34])=[C:31]([NH:39][C:40]3[CH:45]=[C:44]([O:46][CH3:47])[CH:43]=[C:42]([O:48][CH3:49])[CH:41]=3)[N:30]=2)C2C=CC=CC=2N=N1.[Cl-].[Na+]>C(OCC)(=O)C.O.CN1CCCC1=O>[CH3:49][O:48][C:42]1[CH:41]=[C:40]([NH:39][C:31]2[N:30]=[C:29]([NH:7][CH2:8][CH2:9][C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[NH:12][CH:11]=3)[C:37]([F:38])=[CH:36][C:32]=2[C:33]([NH2:35])=[O:34])[CH:45]=[C:44]([O:46][CH3:47])[CH:43]=1
Reactant: COc1cc(Nc2nc(On3nnc4ccccc43)c(F)cc2C(N)=O)cc(OC)c1
Reactant: NCCc1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1cc(Nc2nc(NCCc3c[nH]c4ccccc34)c(F)cc2C(N)=O)cc(OC)c1
Temperature: 90 °C
Reaction time: 7 h
Yield: 43.8 %

Procedure:
Potassium carbonate (27 mg) and tryptamine (32 mg) were added to an N-methylpyrrolidone (1 ml) solution containing 6-(1H-1,2,3-benzotriazol-1-yloxy)-2-(3,5-dimethoxyphenylamino)-5-fluoronicotinamide (41 mg), followed by stirring at 90° C. for 7 hours. The reaction mixture was cooled to room temperature, and potassium carbonate (14 mg) and tryptamine (16 mg) were added, followed by stirring at 90° C. for 7 hours. The reaction mixture was cooled to room temperature, and then water, sodium chloride, and ethyl acetate were added. The organic layer was collected and dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform:methanol=10:0 to 20:1), diisopropylether was added, solid matter was collected by filtration, and a light brown solid of 2-(3,5-dimethoxyphenylamino)-5-fluoro-6-(2-(1H-indole-3-yl)ethylamino)nicotinamide (19 mg) was thus obtained.