Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1([C:6]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[O:7])C=CN=C1.[O:13]1[CH2:17][CH2:16][CH2:15][CH:14]1[CH2:18][CH2:19]C(O)=O>ClCCl>[N:8]1([C:6](=[O:7])[CH2:19][CH2:18][CH:14]2[CH2:15][CH2:16][CH2:17][O:13]2)[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)CCC1CCCO1
Solvent: ClCCl
Product: O=C(CCC1CCCO1)n1ccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
Di-(1H-imidazol-1-yl)methanone (0.554 g, 3.42 mmol) was added in small portions to a stirred solution of 3-(tetrahydrofuran-2-yl)propanoic acid (0.469 g, 3.25 mmol) in dichloromethane (3 mL) at room temperature under argon. The reaction mixture is stirred at room temperature for 2 hours. The mixture was washed twice with water, dried over MgSO4 and concentrated resulting a quantitative yield of 1-(1H-imidazol-1-yl)-3-(tetrahydrofuran-2-yl)propan-1-one (632 mg, 100%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)[CH:19]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:43][C:44]1[C:45](F)=[CH:46][C:47]([F:71])=[C:48]([S:50]([N:53]([CH2:60][C:61]2[CH:66]=[CH:65][C:64]([O:67][CH3:68])=[CH:63][C:62]=2[O:69][CH3:70])[C:54]2[N:59]=[CH:58][CH:57]=[CH:56][N:55]=2)(=[O:52])=[O:51])[CH:49]=1>CS(C)=O>[Cl:43][C:44]1[CH:49]=[C:48]([S:50]([N:53]([CH2:60][C:61]2[CH:66]=[CH:65][C:64]([O:67][CH3:68])=[CH:63][C:62]=2[O:69][CH3:70])[C:54]2[N:55]=[CH:56][CH:57]=[CH:58][N:59]=2)(=[O:51])=[O:52])[C:47]([F:71])=[CH:46][C:45]=1[O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:16])([F:17])[F:15])=[CH:12][CH:13]=2)=[CH:4][C:3]=1[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)[CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(-c3cc(-c4ccc(C(F)(F)F)cc4)ccc3O)ccn2)CC1
Reactant: COc1ccc(CN(c2ncccn2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2ncccn2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(-c4ccc(C(F)(F)F)cc4)cc3-c3ccnc(N4CCN(C(=O)OC(C)(C)C)CC4)c3)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 84.6 %

Procedure:
tert-Butyl 4-(4-(4-hydroxy-4′-(trifluoromethyl)biphenyl-3-yl)pyridin-2-yl)piperazine-1-carboxylate (Preparation 114, 240 mg, 0.480 mmol) was dissolved in dimethyl sulfoxide (3 mL) and then potassium carbonate (133 mg, 0.962 mmol) followed by 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-2-yl)benzenesulfonamide (Preparation 13, 219 mg, 0.480 mmol) were added. The reaction mixture was stirred at room temperature for 20 hours. The reaction was then partitioned between ethyl acetate (15 mL) and 2M HCl (5 mL). The organic layer was separated and dried over anhydrous MgSO4, filtered and evaporated. The residue was purified by flash chromatography on silica gel (gradient: 5-60% ethyl acetate in heptane) to give the title compound (380 mg, 84%) as a yellow foam.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][N:4]=[C:5]([NH2:17])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])[N:11]=1.Cl[C:21]1[N:26]=[CH:25][CH:24]=[CH:23][N:22]=1>C(#N)C>[F:19][C:2]([F:1])([F:18])[CH2:3][N:4]=[C:5]([NH2:17])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:21]2[N:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[N:11]=1
Reactant: Clc1ncccn1
Reactant: NCCCCc1csc(NC(N)=NCC(F)(F)F)n1
Solvent: CC#N
Product: NC(=NCC(F)(F)F)Nc1nc(CCCCNc2ncccn2)cs1
Yield: 51 %

Procedure:
A mixture of 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-aminobutyl)thiazole (0.45 g.) and 2-chloropyrimidine (0.18 g.) was heated under reflux in acetonitrile (5 ml.) for 16 hours. The reaction mixture was then evaporated to dryness and the residue purified by medium pressure liquid chromatography on silica gel using chloroform/methanol/ammonia 1900:100:5 v/v/v as eluant. The appropriate fraction was evaporated to dryness and the residue recrystallised from acetonitrile to give 2-(4-[2-(2-[2,2,2-trifluoroethyl]guanidino)thiazol-4-yl]butylamino)pyrimidine (0.29 g.), m.p. 173°-175°.
Reaction SMILES: [O:1]([C:8]1[C:9]([NH2:14])=[N:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:15]Br.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[Br:15][C:12]1[CH:13]=[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]([NH2:14])=[N:10][CH:11]=1
Reactant: Nc1ncccc1Oc1ccccc1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Nc1ncc(Br)cc1Oc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
A 3 L flask was charged with 3-phenoxypyridin-2-amine (63.6 g, 342 mmol) and CHCl3 (1500 mL). The reaction was cooled to 0° C. and bromine (21.0 mL, 410 mmol) was added dropwise. The reaction was stirred for 1 hour. Another 1 mL of bromine was added and the reaction was poured into saturated aqueous NaHCO3 (1500 mL) and extracted with CH2Cl2. The organic layer was dried with sodium sulfate and 25 g charcoal. The mixture was filtered through Celite and concentrated in vacuo. The residue was dissolved in CH2Cl2 and passed through a plug of silica (1 L) eluting with 30% EtOAc/Hexanes to afford 5-bromo-3-phenoxypyridin-2-amine (64.02 g, 70.70% yield).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C@@H:7]([NH:10]S(C(C)(C)C)=O)[CH2:8][CH3:9])[O:4][N:3]=1.[ClH:17].O1CCOCC1>CO>[ClH:17].[Br:1][C:2]1[CH:6]=[C:5]([C@@H:7]([NH2:10])[CH2:8][CH3:9])[O:4][N:3]=1
Reactant: CC[C@H](NS(=O)C(C)(C)C)c1cc(Br)no1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC[C@H](N)c1cc(Br)no1
Reaction time: 2.5 h

Procedure:
To a solution of 2-methyl-propane-2-sulfinic acid [(S)-1-(3-bromo-isoxazol-5-yl)-propyl]-amide (17.5 mg, 0.0566 mmol) in MeOH (1 mL) was added a 4 M solution of HCl in dioxane (0.70 mL, 0.28 mmol) dropwise. After 2.5 hours, the mixture was concentrated in vacuo to afford the title compound which was used with out purification. MS m/z 188.24 (M-53), 190.20 (M+2-53).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:19]([F:20])=[C:18](Cl)[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.C([Li])CCC.[I:27]I>O1CCCC1.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:19]([F:20])=[C:18]([I:27])[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Fc1c(-c2ccc3c(c2)OCO3)nc2ccccc2c1Cl
Reactant: II
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Fc1c(-c2ccc3c(c2)OCO3)nc2ccccc2c1I
Reaction time: 3 h
Yield: 48.8 %

Procedure:
To a −78° C. solution of 2-benzo[1,3]dioxol-5-yl-4-chloro-3-fluoro-quinoline (from step A, 0.073 g, 0.24 mmol) in tetrahydrofuran (2 mL) was added butyl lithium (0.36 mL, 2.5 M in hexane, 0.6 mmol). The resulting reaction mixture was stirred for 3 h., after which a solution of iodine (0.06 g, 0.24 mmol) in 0.8 mL of THF was added. The reaction mixture was stirred for an additional 2 h. and diluted with water (20 mL). The aqueous layer was extracted with ethyl acetate (2×25 mL). The combined organic layers were dried over sodium sulfate, concentrated and purified via silica gel column chromatography to give the title compound (0.046 g, 48%). MS (ES) 393.8 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1.C1C(=O)N([Br:27])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:27][CH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1ccccc1Oc1ccc(C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)Cc1ccccc1Oc1ccc(CBr)cc1
Yield: 51.5 %

Procedure:
A solution of the product of Step B (50 mg, 0.205 mmol) NBS (33 mg, 0.9 eq) and AIBN (5 mg, catalytic amount) in CCl4 (2 mL) was heated to reflux for 2 hours, and then concentrated in vacuo. The residue was chromatographed on a flash silica column (20×140 mm) eluted with 5% ethyl acetate/hexane to yield 32 mg (48%) of product (Rf =0.17, 5% ethyl acetate/hexane).
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([OH:17])=O)=[CH:12][CH:13]=2)[CH:8]=[C:7]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[N:6]=1)([CH3:3])[CH3:2].[CH3:25][S:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:28])=[O:27]>>[CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([N:32]3[CH2:33][CH2:34][N:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:30][CH2:31]3)=[O:17])=[CH:12][CH:13]=2)[CH:8]=[C:7]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[N:6]=1)([CH3:2])[CH3:3]
Reactant: Cc1cc(Nc2cc3cc(C(=O)O)ccc3c(OC(C)C)n2)n[nH]1
Reactant: CS(=O)(=O)N1CCNCC1
Product: Cc1cc(Nc2cc3cc(C(=O)N4CCN(S(C)(=O)=O)CC4)ccc3c(OC(C)C)n2)n[nH]1

Procedure:
Similar procedure as described in example 384 was used, starting from 1-Isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-6-carboxylic acid and 1-Methanesulfonyl-piperazine to give [1-Isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-yl]-(4-methanesulfonyl-piperazin-1-yl)-methanone. LC-MS: m/e 473 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][CH2:7][N:8]2[CH2:14][CH2:13][CH2:12][CH:11]([N:15]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=4)[C:18](=O)[C:16]3=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.O>O1CCCC1>[F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][CH2:7][N:8]2[CH2:14][CH2:13][CH2:12][CH:11]([N:15]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=4)[CH:18]=[CH:16]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)N(C1CCCN(CCc3ccc(F)cc3)CC1)C(=O)C2=O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2ccn(C3CCCN(CCc4ccc(F)cc4)CC3)c2c1
Temperature: 25 °C
Reaction time: 11 h

Procedure:
1-(4-Fluorophenethyl)-4-(6-methoxyisatin-1-yl)homopiperidine (0.4 g) was dissolved in tetrahydrofuran (1.0 ml). Under nitrogen atmosphere, a 2.0 M solution (4.0 ml) of borane-tetrahydrofuran complex in tetrahydrofuran was added dropwise thereinto in a water bath followed by heating under reflux for 3 hr. The reaction solution was ice cooled and water was added thereto. Next, the reaction solution was partitioned between water and ethyl acetate and the organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in pyridine (5.0 ml) and stirred at room temperature for 11 hr. After adding water, the reaction solution was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Then the resulting residue was purified by NH-silica gel column chromatography (hexane/ethyl acetate system) to give 1-(4-florophenethyl)-4-(6-methoxyindol-1-yl)homopiperidine as a yellow oil. Then this product was treated as in Production Example 64 to give the free title compound (0.095g) asayellowoil (yield: 27.2%).
Reaction SMILES: [N:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([OH:17])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:18]([C:27]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)(O)[C:28]#[CH:29])[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[CH2:18]([C:27]1([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[O:17][C:9]2[CH:8]=[C:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:16]3[C:11]([C:10]=2[CH:29]=[CH:28]1)=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1
Reactant: Oc1cc(N2CCCCC2)c2ccccc2c1
Reactant: C#CC(O)(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(CC2(Cc3ccc(OC)cc3)C=Cc3c(cc(N4CCCCC4)c4ccccc34)O2)cc1
Reaction time: 1.5 h

Procedure:
1-Chloro-4-piperidino-2-naphthol (3.0 g;0.0115 mol), prepared as in 1(a) above, dissolved in 1.25M aqueous NaOH (100 ml) was stirred and heated to 75°-80° C. To the solution was added (50/50) Raney Nickel (14.0 g) portionwise over 1 hour. The mixture was stirred for 1.5 h, cooled then filtered through celite with washing (3×2M NaOH). The filtrate was neutralised with conc. HCl and extracted into CH2Cl2, dried and evaporated to yield crude 4-piperidino-2-naphthol (1.46 g;56%) as a red-orange oil. Purification by flash chromatography over silica (CH2Cl2) gave 4-piperidino-2-naphthol (of structure 4a below) as a red oil. ##STR16## (c) A mixture of 4-piperidino-2-naphthol (1.00 g; 0.0044 mol) , prepared as described in 1(b) above, 1,1-dianisylprop-2-yn-1-ol(1.18 g;0.0044 mol), acidic alumina Brockmann 1 (4 g) and toluene (40.0 ml) was heated and stirred for 1.5 h, cooled and filtered. The filtrate was washed with 2M NaOH then water, dried and evaporated to give a red gum. Purification of the gum by flash chromatography over silica (20% ethylacetate in hexane) affored an orange gum which upon trituration with pet. ether (40-60)/diethyl ether yielded 3,3-dianisyl-6-piperidino -3H-naphtho[2,1-b]pyran (of structure 5a below) as an off-white solid (5% yield), m.pt. 114°-119° C. ##STR17##
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([NH:14][C:15]1[CH:36]=[CH:35][C:18]([CH2:19][N:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:22]([CH2:29][C:30]([O:32]CC)=[O:31])=[N:21]3)=[CH:17][CH:16]=1)=[O:13])[CH:6]=[CH:5]2.O.[OH-].[Li+].O.Cl>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([NH:14][C:15]1[CH:36]=[CH:35][C:18]([CH2:19][N:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:22]([CH2:29][C:30]([OH:32])=[O:31])=[N:21]3)=[CH:17][CH:16]=1)=[O:13])[CH:6]=[CH:5]2
Reactant: CCOC(=O)Cc1nn(Cc2ccc(NC(=O)c3ccc4cc(F)ccc4c3)cc2)c2ccccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1nn(Cc2ccc(NC(=O)c3ccc4cc(F)ccc4c3)cc2)c2ccccc12
Yield: 92.4 %

Procedure:
Ethyl 2-[1-[4-(6-fluoro-2-naphthamido)benzyl]-1H-indazol-3-yl]acetate (262 mg, 0.544 mmol) was dissolved in tetrahydrofuran (10 mL), and in an ice bath 10 mL aqueous solution dissolving lithium hydroxide monohydrate (114 mg, 2.71 mmol) was added. It was reacted at room temperature for 3 h, and the reaction was monitored to be complete by TLC. Water was added into the system, and adjusted to pH≈3-4 with diluted hydrochloric acid. A solid precipitated, which was filtered and dried to obtain a white solid 228 mg, at a yield of 92.5%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.Cl[CH2:13][CH2:14][N:15]([CH2:23][CH2:24]Cl)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[Na+]>C(O)CCC>[CH2:16]([N:15]1[CH2:23][CH2:24][N:1]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)[CH2:13][CH2:14]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCCN(CCCl)Cc1ccccc1
Reactant: Nc1cccc2cccnc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Product: c1ccc(CN2CCN(c3cccc4cccnc34)CC2)cc1
Temperature: 85 °C
Yield: 45.7 %

Procedure:
A solution of 8-amino-quinoline (12.91 g, 89 mmol) and bis(2-chloroethyl)-benzylamine (25.95 g, 112 mmol) in n-butanol (65 ml) was allowed to heat at 85° C. for 11 hours. The mixture was poured into 50% sodium hydroxide, extracted with methylene chloride and water. The organic layer was dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under vacuum. Chromatography (methanol-methylene chloride) afforded 12.34 g of product as a solid: mp 116.5-118° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:12](OC(=O)C)(=[O:14])[CH3:13]>CC(O)=O>[C:12]([NH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6])(=[O:14])[CH3:13]
Reactant: COC(=O)c1ccnc(N)c1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1ccnc(NC(C)=O)c1
Yield: 76.9 %

Procedure:
To a solution of methyl 2-aminoisonicotinate (0.5 g, 3.29 mmol) in AcOH (6.6 mL) at room temperature was added acetic anhydride (0.37 mL, 3.94 mmol), and the mixture was refluxed for 1 hour. The mixture was cooled and transferred to a 100 mL round-bottom, where the product was precipitated out of solution by slowly adding water (˜6 mL). The suspension was then filtered and washed with water. The solid was dried in vacuo overnight, furnishing Intermediate 62A (0.491 g, 76% yield) as a light yellow solid. HPLC: Rt=1.927 min. (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min. gradient, monitored at 220 nm). MS (ES): m/z=195.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.76 (1H, s), 8.57 (1H, s), 8.48 (1H, d, J=5.04 Hz), 7.51 (1H, dd, J=5.04, 1.51 Hz), 3.88 (3H, s), 2.11 (3H, s).
Reaction SMILES: Cl.[F:2][C:3]([F:29])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl[C:31]([O:33][CH3:34])=[O:32]>>[CH3:34][O:33][C:31]([N:12]1[CH2:13][CH2:14][C@H:9]([O:8][CH2:7][C:6]2[CH:21]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:23]=[C:4]([C:3]([F:2])([F:28])[F:29])[CH:5]=2)[C@H:10]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:11]1)=[O:32]
Reactant: COC(=O)Cl
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Agent: Cl
Product: COC(=O)N1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](c2ccccc2)C1
Yield: 67 %

Procedure:
The compound (0.15 g) obtained in Example 1 and methyl chloroformate (0.040 ml) were reacted and treated in the same manner as in the method described in Example 2 to obtain the title compound as colorless oil (0.11 g, 67%).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[I:15]I.Cl>O.C(OCC)(=O)C>[Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([I:15])[N:3]=1
Reactant: II
Reactant: Oc1cccnc1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Oc1ccc(I)nc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.4 %

Procedure:
2-Bromo-pyridin-3-ol (5 g) is dissolved in water (150 ml) and thereto are added sodium carbonate (6.15 g) and iodine (7.65 g) and the mixture is stirred at room temperature for 2 hours. Thereto are added a 1N-hydrochloric acid and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (hexane:ethyl acetate=9:1→3:1) to give 2-bromo-6-iodo-pyridin-3-ol (4.52 g). MS (m/z): 300/302 [M+H]+
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])=[O:9].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([Sn](C)(C)C)=[CH:18][CH:17]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C)C=O>[C:12]([NH:11][S:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:19]1[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=1)(=[O:10])=[O:9])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1Br
Reactant: Cc1ccc([Sn](C)(C)C)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Temperature: 90 °C
Reaction time: 5 h
Yield: 74 %

Procedure:
2-Bromo-N-(tert-butyl)benzenesulfonamide (from Step A) (1.00 g, 3.92 mmol), p-tolyltrimethyltin (from Step B) (1.95 g, 6.67 mmol), bis(triphenylphosphine)palladium(II) chloride (Aldrich) (165 mg, 0.235 mmol) and dimethylformamide (25 ml) were heated with stirring under nitrogen at 90° C. for 5 hours. The black suspension was cooled to room temperature, then filtered through a pad of Celite which was washed with tetrahydrofuran. The colorless filtrate was evaporated to dryness then chromatographed (silica gel, 10% ethyl acetate-hexane) to give the title compound (0.88 g, 74%) as a white solid; 1H NMR (300 MHz, CDCl3) δ8.16 (d, J=7.9 Hz, 1H), 7.60-7.37 (m, 4H), 7.36-7.24 (m, 3H), 3.57 (s, 1H), 2.42 (s, 3H), 0.99 (s, 9H).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].[CH2:26]([O:28][C:29]1[CH:34]=[CH:33][C:32](I)=[CH:31][C:30]=1[CH3:36])[CH3:27].C([Mg]Cl)(C)C>C1COCC1>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4](=[O:5])[C:32]3[CH:33]=[CH:34][C:29]([O:28][CH2:26][CH3:27])=[C:30]([CH3:36])[CH:31]=3)=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CCOc1ccc(I)cc1C
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCOc1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)cc1C

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 120 mg (0.30 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1 mL THF and 172 mg (0.66 mmol) of 1-ethoxy-4-iodo-2-methyl-benzene in 1 mL THF with 0.34 mL 2M isopropylmagnesium chloride. Yield: 53 mg of a white powder. LC-MSD, m/z for C25H21BrN2O3 [M+H]+=477.0, 479.0; HPLC retention time: 2.6 min.
Reaction SMILES: CN([CH:4]=[C:5]1[C:11](=O)[C:10]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:9]=2[NH:8][C:7](=[O:18])[CH2:6]1)C.Cl.[CH:20]1([C:23]([NH2:25])=[NH:24])[CH2:22][CH2:21]1>>[CH:20]1([C:23]2[N:24]=[CH:4][C:5]3[CH2:6][C:7](=[O:18])[NH:8][C:9]4[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:10]=4[C:11]=3[N:25]=2)[CH2:22][CH2:21]1
Reactant: CN(C)C=C1CC(=O)Nc2ccc(F)cc2C1=O
Reactant: N=C(N)C1CC1
Agent: Cl
Product: O=C1Cc2cnc(C3CC3)nc2-c2cc(F)ccc2N1
Yield: 88 %

Procedure:
Analogous to Scheme 1, from 4-[(dimethylamino)methylene]-7-fluoro-3,4-dihydro-1H-benzazepine-2,5-dione and cyclopropanecarboxamidine hydrochloride. Yield: 88%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].S([O-])([O-])(=O)=O.[CH3:13][C:14]1[NH:18][CH:17]=[N:16][C:15]=1[CH2:19][S:20][CH2:21][CH2:22][NH+:23]=[C:24]([NH2:26])S.[CH3:27][C:28]1[NH:32][CH:31]=[N:30][C:29]=1[CH2:33][S:34][CH2:35][CH2:36][NH+:37]=[C:38]([NH2:40])S>>[CH3:13][C:14]1[NH:18][CH:17]=[N:16][C:15]=1[CH2:19][S:20][CH2:21][CH2:22][N:23]=[C:24]([NH2:26])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:38]([NH2:40])=[N:37][CH2:36][CH2:35][S:34][CH2:33][C:29]1[N:30]=[CH:31][NH:32][C:28]=1[CH3:27]
Reactant: Cc1[nH]cnc1CSCC[NH+]=C(N)S
Reactant: NCCCCCN
Agent: O=S(=O)([O-])[O-]
Product: Cc1[nH]cnc1CSCCN=C(N)NCCCCCNC(N)=NCCSCc1nc[nH]c1C

Procedure:
The reaction of 1,5-diaminopentane (0.43 g) with S-methyl-N-[2-((5-methyl-4-imidazolyl)methylthio)ethylthiouronium sulphate (2.52 g) by the method described in Example 5 afforded the title compound which was isolated as the dipicrate (1.8 g) m.p. 115-120°.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([CH:18]=[CH2:19])[C:4]=1[C:20]([O:22][CH3:23])=[O:21].OO.C(=O)(O)[O-:28].[Na+]>C(O)C>[F:24][CH:2]([F:1])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([CH:18]2[CH2:19][O:28]2)[C:4]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: C=Cc1c(C(=O)OC)c(C(F)F)nc(C(F)(F)F)c1C(=O)OCC
Reactant: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1C1CO1
Temperature: 70 °C
Yield: 19 %

Procedure:
A stirred mixture of 14.0 g (0.039 mole) of product of Example 99, 105 ml of ethanol, 70 ml (0.60 mole) of 30% hydrogen peroxide, and 2.9 g (0.033 mole) of sodium bicarbonate is heated at 70° C. for 3 hours. The reaction mixture is cooled and concentrated in vacuo to approximately 30 ml then extracted with 75 ml of methylene chloride. The methylene chloride solution is washed with 300 ml of water. The aqueous layer is extracted twice with 75 ml of methylene chloride. The combined methylene chloride extracts were dried over magnesium sulfate and concentrated. The residue is purified by HPLC using 8% ethyl acetate/cyclohexane as eluent to give a yellow solid which after recrystallization from hexane/ether gave 2.32 g of the desired product as a white solid; m.p. 57.5°-59° C.