Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].CC([N-]C(C)C)C.CO[C:11](=[O:31])[C:12]1[CH:22]=[CH:21][C:15]([C:16]([N:18](C)C)=O)=[C:14]([C:23]2[C:24]([CH3:30])=[N:25][N:26]([CH3:29])[C:27]=2[CH3:28])[CH:13]=1.CN(C[N:36]1[C:40]2=[N:41][C:42]([N:45]3[CH2:50][CH2:49][CH:48]([N:51]([CH3:53])[CH3:52])[CH2:47][CH2:46]3)=[CH:43][CH:44]=[C:39]2[N:38]=[CH:37]1)C>>[CH3:52][N:51]([CH3:53])[CH:48]1[CH2:49][CH2:50][N:45]([C:42]2[N:41]=[C:40]3[NH:36][C:37]([C:11]([C:12]4[CH:22]=[CH:21][C:15]([C:16]#[N:18])=[C:14]([C:23]5[C:24]([CH3:30])=[N:25][N:26]([CH3:29])[C:27]=5[CH3:28])[CH:13]=4)=[O:31])=[N:38][C:39]3=[CH:44][CH:43]=2)[CH2:46][CH2:47]1
Reactant: CN(C)Cn1cnc2ccc(N3CCC(N(C)C)CC3)nc21
Reactant: COC(=O)c1ccc(C(=O)N(C)C)c(-c2c(C)nn(C)c2C)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: Cc1nn(C)c(C)c1-c1cc(C(=O)c2nc3ccc(N4CCC(N(C)C)CC4)nc3[nH]2)ccc1C#N

Procedure:
Following General procedure P (LDA metallation, ketone formation and in situ deprotection) using N,N-Dimethyl-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-terephthalamic acid methyl ester and [1-(3-dimethylaminomethyl-3H-imidazo[4,5-b]pyridin-5-yl)-piperidin-4-yl]-dimethyl-amine to give 4-[5-(4-dimethylamino-piperidin-1-yl)-3H-imidazo[4,5-b]pyridine-2-carbonyl]-2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzonitrile. (84%). HRMS m/z 529.3036 (M+H)+.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20](B5OC(C)(C)C(C)(C)O5)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:31]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].Br[C:33]1[N:34]=[C:35]([CH2:44][C:45]([CH3:48])([OH:47])[CH3:46])[N:36]([CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][O:39]2)[CH:37]=1.[F-].[Cs+]>CN(C=O)C.[Cu]I.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>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[N:12]([CH2:13][CH2:14][O:15][C:16]4[CH:21]=[C:20]([C:33]5[N:34]=[C:35]([CH2:44][C:45]([CH3:48])([OH:47])[CH3:46])[N:36]([CH:38]6[CH2:43][CH2:42][CH2:41][CH2:40][O:39]6)[CH:37]=5)[CH:19]=[CH:18][C:17]=43)[CH:31]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(B3OC(C)(C)C(C)(C)O3)cc1OCC2
Reactant: CC(C)(O)Cc1nc(Br)cn1C1CCCCO1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(-c3cn(C4CCCCO4)c(CC(C)(C)O)n3)cc1OCC2
Temperature: 120 °C
Yield: 149.7 %

Procedure:
To a mixture of 2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (600 mg, 1.42 mmol) and 1-(4-bromo-1-(tetrahydro-pyran-2-yl)-1H-imidazol-2-yl)-2-methyl-propan-2-ol (648 mg, 2.1 mmol) in dry DMF (6 mL) under nitrogen was added CsF (534 mg, 3.53 mmol), CuI (27 mg, 0.14 mmol) and Pd(PPh3)4 (81 mg, 0.07 mmol). The reaction mixture was heated at 120° C. for 20 min in a microwave reactor. It was filtered, concentrated and purified by column chromatography (DCM/MeOH=20:1) to give 1-[4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-1-(tetrahydro-pyran-2-yl)-1H-imidazol-2-yl]-2-methyl-propan-2-ol as brown oil (1.1 g). LCMS: (ESI, m/z)=518 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[C:15]([C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[C:26](=[O:30])[O:25][CH2:24]4)[C:7]=2[O:8][CH2:9][C:10]([O:12]CC)=[O:11])[CH2:3][CH2:2]1.[OH-].[Li+]>O1CCCC1.O>[CH:1]1([CH2:4][O:5][C:6]2[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[C:15]([C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[C:26](=[O:30])[O:25][CH2:24]4)[C:7]=2[O:8][CH2:9][C:10]([OH:12])=[O:11])[CH2:3][CH2:2]1
Reactant: CCOC(=O)COc1c(-c2ccc3c(c2)COC3=O)ccc(OC)c1OCC1CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2ccc3c(c2)COC3=O)c(OCC(=O)O)c1OCC1CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.7 %

Procedure:
To a stirring solution of ethyl 2-(2-(cyclopropylmethoxy)-3-methoxy-6-(1-oxo-1,3-dihydroisobenzofuran-5-yl)phenoxy)acetate (300 mg, 0.726 mmol) in tetrahydrofuran (15 mL) was added lithium hydroxide (152 mg, 3.631 mmol) in water (5 mL) and the reaction mixture was stirred at RT for 4 h. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined ethyl acetate layers were washed with water, dried over sodium sulphate and concentrated under reduced pressure to afford the 2-(2-(Cyclopropylmethoxy)-3-methoxy-6-(1-oxo-1,3-dihydroisobenzofuran-5-yl)phenoxy)acetic acid as a solid (200 mg, 71.5%).
Reaction SMILES: N1(CCO)CCNCC1.BrC1SC(C=O)=CC=1.[OH:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[S:31][C:30]([CH:32]=O)=[CH:29][CH:28]=2)[CH2:23][CH2:22]1.[CH3:34][O:35][C:36]1[CH:37]=[C:38]([CH:42]=[CH:43][C:44]=1[O:45][CH3:46])[CH2:39][C:40]#[N:41]>>[CH3:34][O:35][C:36]1[CH:37]=[C:38](/[C:39](=[CH:32]/[C:30]2[S:31][C:27]([N:24]3[CH2:23][CH2:22][N:21]([CH2:20][CH2:19][OH:18])[CH2:26][CH2:25]3)=[CH:28][CH:29]=2)/[C:40]#[N:41])[CH:42]=[CH:43][C:44]=1[O:45][CH3:46]
Reactant: O=Cc1ccc(N2CCN(CCO)CC2)s1
Reactant: COc1ccc(CC#N)cc1OC
Agent: O=Cc1ccc(Br)s1
Agent: OCCN1CCNCC1
Product: COc1ccc(/C(C#N)=C/c2ccc(N3CCN(CCO)CC3)s2)cc1OC
Yield: 48.9 %

Procedure:
Through the procedure as employed in Production step 1, an amine moiety derived from 1-piperazineethanol (7.81 g) was introduced into 5-bromothiophene-2-carboxaldehyde (3.82 g), to thereby yield 5-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-thiophene-2-carbaldehyde (yield: 3.22 g, 67%). The produced 5-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-thiophene-2-carbaldehyde (1.85 g) was condensed with 3,4-dimethoxybenzyl cyanide (1.37 g) through Method A (production step 2), to thereby yield the target product (yield: 1.51 g, 49%).
Reaction SMILES: CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].[CH3:15][O:16][C:17](=[O:59])[CH2:18][O:19][CH2:20][C:21]#[C:22][CH2:23][C@H:24]1[C:28](=[O:29])[CH2:27][C@@H:26]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[C@@H:25]1[C:38]1[CH:43]=[CH:42][C:41]([CH:44]([O:51][Si:52]([C:55]([CH3:58])([CH3:57])[CH3:56])([CH3:54])[CH3:53])[CH:45]2[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]2)=[CH:40][CH:39]=1.OO.[NH4+].[Cl-]>C1COCC1>[CH3:15][O:16][C:17](=[O:59])[CH2:18][O:19][CH2:20][C:21]#[C:22][CH2:23][C@H:24]1[C@@H:28]([OH:29])[CH2:27][C@@H:26]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[C@@H:25]1[C:38]1[CH:39]=[CH:40][C:41]([CH:44]([O:51][Si:52]([C:55]([CH3:58])([CH3:57])[CH3:56])([CH3:54])[CH3:53])[CH:45]2[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50]2)=[CH:42][CH:43]=1
Reactant: COC(=O)COCC#CC[C@H]1C(=O)C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1c1ccc(C(O[Si](C)(C)C(C)(C)C)C2CCCCC2)cc1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: OO
Agent: [Cl-]
Solvent: C1CCOC1
Product: COC(=O)COCC#CC[C@@H]1[C@@H](c2ccc(C(O[Si](C)(C)C(C)(C)C)C3CCCCC3)cc2)[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1O
Reaction time: 1 h
Yield: 61.9 %

Procedure:
L-selectride (0.76 mL, 0.76 mmol, 1 M/THF) was added to a −78° C. THF (20 mL) solution of 10-3 (415 mg, 0.63 mmol). The reaction was stirred for 1 h and then 3% H2O2 (14 mL) was added. The resulting mixture was stirred at room temperature for 45 min. and then saturated NH4Cl solution (60 mL) was added. The resulting mixture was extracted with ethyl acetate (3×40 mL) and the combined ethyl acetate solution was washed with brine. The solution was then dried (Na2SO4), filtered and evaporated. Purification by flash chromatography on silica gel (25% ethyl acetate/hexanes) gave the title alcohol (255 mg, 0.39 mmol, 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[O:12][C:11](=[O:13])[N:10]([CH:14]([CH3:24])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([OH:23])[CH:17]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Br[C:26](Br)([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[O:12][C:11](=[O:13])[N:10]([C@H:14]([CH3:24])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]4[O:22][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])([C:32]([O:34][CH2:35][CH3:36])=[O:33])[O:23][C:18]=4[CH:17]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Br)(Br)C(=O)OCC
Reactant: CC(Cc1ccc(O)c(O)c1)N1CC(c2cccc(Cl)c2)OC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1(C(=O)OCC)Oc2ccc(C[C@@H](C)N3C[C@@H](c4cccc(Cl)c4)OC3=O)cc2O1

Procedure:
In accordance with the above preferred reaction scheme 2-(3-chlorophenyl)-2-hydroxyethylamine 1, and 3,4-dimethoxyphenylacetone 2 are reacted with sodium cyanoborohydride in methanol, giving 3-chloro-alpha-(((2-(3,4-dimethoxyphenyl)-1-methylethyl)amino)methyl) benzenemethanol 3which is reacted with carbonyl diimidazole and triethylamine in tetrahydrofuran, followed by separation of isomers, giving cyclized derivative 4 which is reacted with boron tribromide in dichloromethane, giving (R*, R*)-(±)-5-(3-chlorophenyl)-3-(2-(3,4-dihydroxyphenyl)-1-methylethyl)2-oxazolidinone 5. Compound 5 is then reacted with diethyl dibromomalonate and anhydrous potassium carbonate in acetone, giving (R*,R*)-(±)-5-(2-(5-(3-chlorophenyl)-2-oxo-3-oxazolidinyl)propyl)-1, 3-benzodioxole-2,2-dicarboxylic acid, diethyl ester 6 which is then reacted first with sodium hydroxide in ethanol and then with hydrogen chloride gas in methanol, giving the product (R*,R*)-(±) 5-(2-((2-(3-chlorophenyl) 2-hydroxyethyl)-amino)propyl)-2,3-benzodioxole-2,2-dicarboxylic acid, dimethyl ester 7.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([O:24]CC)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[Li].O>C(O)C.O1CCCC1>[CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([OH:24])=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
A mixture of intermediate 26, ethyl 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4] oxazine-2-carboxylate, (2.93 g, 8.2 mmol) and LiOH.H2O (0.84 g, 20 mmol) in 4:1 ethanol/tetrahydrofuran (50 mL) was stirred for 2 h at ambient temperature then concentrated under vacuum. The resulting yellow residue was treated with 1N HCl (25 mL) providing a precipitate that was filtered and dried under vacuum to yield the title compound as a white powder (2.68 g, 99% yield). 1H NMR (500 MHz, CDCl3) δ ppm: 7.54-7.48 (2H, m), 7.37-7.27 (3H, m), 5.44 (2H, s), 4.05-3.93 (4H, m), 1.60 (6H, s).). HRMS (M+H) calcd for C17H19N2O5: 331.1294; found: 331.1308. Anal calcd for C17H18N2O5: C, 61.81; H, 5.49; N, 8.48; found: C, 61.84; H, 5.36; N, 8.25.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=O)[C:5]2=[CH:11][C:12]=1[Cl:13].[C:14]([CH:19]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:16][CH2:17][CH3:18])=[O:15]>C(Cl)(Cl)Cl>[CH2:17]([O:16][C:14]([CH:19]=[C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[C:12]([Cl:13])[CH:11]=2)[C:9](=[O:10])[O:8]1)=[O:15])[CH3:18]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1OC(=O)c2cc(Cl)c(Cl)cc21
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C=C1OC(=O)c2cc(Cl)c(Cl)cc21
Yield: 70.8 %

Procedure:
A solution of 4,5-dichlorophthalic anhydride (10.0 g) and (carbethoxymethylene)triphenylphosphorane (16.0 g) in chloroform (450 ml) was refluxed for 16 hours. Evaporation of chloroform and chromatography of the residue over silica gel gave the product (9.34 g).
Reaction SMILES: C1(C)C=CC(S([N:10]2[CH2:25][CH2:24][CH2:23][N:22](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:21][CH2:20][N:19](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:18][CH2:17][N:16](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:15][CH2:14][N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:12][CH2:11]2)(=O)=O)=CC=1.OS(O)(=O)=O.C(O)C>C(OCC)C>[NH:10]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: Cc1ccc(S(=O)(=O)N2CCCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: CCOCC
Product: C1CNCCNCCNCCNCCNC1
Temperature: 100 °C
Reaction time: 69 h
Yield: 15 %

Procedure:
A mixture of 1,4,7,10,13-penta(p-toluenesulfonyl)-1,4,7,10,13-pentaazacyclohexadecane prepared as in Example 1D (30 g, 0.030 mole) and concentrated H2SO4 (100 ml) was heated at 100° C. with stirring under a dry argon atmosphere for 69 h. To the resulting brown solution, ethanol (200 mL) was added dropwise with stirring at 5° C., followed by ethyl ether (500 ml). The tan solid was filtered and washed thoroughly with ethyl ether. The solid was then dissolved in H2O (75 ml), the pH was adjusted to 10 with 10N NaOH, and the solution was extracted with CHCl3 (6×200 ml). The extracts were combined and dried (Na2SO4), and the solvent was removed in vacuo. The resulting yellow solid was purified by recrystallization from hexane to give 1.0 g (15% yield) of the product as colorless needles: mp 109-110.5° C.; 1H NMR (CDCl3)δ 1.72 (quint, J=5.4 Hz, 2 H), 1.76 (br s, 5 H), 2.73 (m, 20 H); Anal. calcd. for C11H27N5: C, 57.60; H, 11.86; N, 30.53. Found: C, 57.77; H, 12.35; N, 30.57.
Reaction SMILES: C([O:5][C:6](=[O:27])[CH:7]=[C:8]([CH3:26])[CH:9]=[CH:10][CH:11]=[C:12]([CH3:25])[CH:13]=[CH:14][C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[C:17]([CH3:23])[C:16]=1[CH3:24])CCC.[Cl-].CC1C(C)=C(C)C=C(C)C=1C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OC(=O)C=C(C)C=CC=C(C=O)C)CCC>>[CH3:24][C:16]1[C:17]([CH3:23])=[C:18]([CH3:22])[CH:19]=[C:20]([CH3:21])[C:15]=1[CH:14]=[CH:13][C:12]([CH3:25])=[CH:11][CH:10]=[CH:9][C:8]([CH3:26])=[CH:7][C:6]([OH:27])=[O:5]
Reactant: CCCCOC(=O)C=C(C)C=CC=C(C)C=Cc1c(C)cc(C)c(C)c1C
Agent: CCCCOC(=O)C=C(C)C=CC=C(C)C=O
Agent: Cc1cc(C)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(C)c1C
Agent: [Cl-]
Product: CC(C=Cc1c(C)cc(C)c(C)c1C)=CC=CC(C)=CC(=O)O

Procedure:
By the procedure of Example 14, 9-(2,3,4,6-tetramethylphenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid butyl ester is manufactured from 2,3,4,6-tetramethyl-benzyl-triphenylphosphonium chloride by reaction with 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid butyl ester. From this product, there is produced by the procedure of Example 15 9-(2,3,4,6-tetra-methyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid of melting point 201°-202° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH:12]=2)[CH:5]=[C:4]([Cl:20])[N:3]=1>[Rh]>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH2:9]2)[CH:5]=[C:4]([Cl:20])[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(Cl)nc(Cl)c2)C1
Agent: [Rh]
Product: CC(C)(C)OC(=O)N1CCC(c2cc(Cl)nc(Cl)c2)C1
Yield: 95.6 %

Procedure:
A mixture of tert-butyl 3-(2,6-dichloro-4-pyridyl)-2,5-dihydropyrrole-1-carboxylate (126 mg, 0.399 mmol) and 5% Rh/C (20 mg) in absolute alcohol (12 mL) was purged with N2, then primed with H2 (balloon)/vacuum (3×), stirred under H2 balloon for o/n. It was purged with N2, filtered through Celite, washed the Celite with MeOH, concentrated in vacuo gave 121 mg (95.4%) of product as clear gum. It was carried on without further purification. LC-MS: m/z=318 (M+H+).
Reaction SMILES: O1CCCC1.[CH2:6]([O:10][C:11]1[CH:12]=[C:13]([CH2:17][C:18](Cl)=[N:19][OH:20])[CH:14]=[CH:15][CH:16]=1)[CH2:7][CH2:8][CH3:9].[C:22]([C:24]1[C:25]([NH2:30])=[N:26][CH:27]=[CH:28][CH:29]=1)#[CH:23].C(N(CC)CC)C>O>[CH2:6]([O:10][C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=1)[CH2:17][C:18]1[CH:23]=[C:22]([C:24]2[C:25]([NH2:30])=[N:26][CH:27]=[CH:28][CH:29]=2)[O:20][N:19]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCOc1cccc(CC(Cl)=NO)c1
Reactant: C#Cc1cccnc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCOc1cccc(Cc2cc(-c3cccnc3N)on2)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 25.8 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (3-butoxy-phenyl)-acetohydroximoyl chloride (150 mg, 0.621 mmol) described in Manufacturing Example 65-1-4 and 3-ethynyl-pyridin-2-ylamine (47 mg, 0.396 mmol) described in Manufacturing Example 1-2-3 was added triethylamine (216 μL, 1.55 mmol) at room temperature, which was stirred for 2 hours at 50° C. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=4:1-2:1) to obtain the title compound (33 mg, 8%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][C:6]=2[CH:19]=1.[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C.C([Li])CCC>C1COCC1>[CH3:16][C:15]([O:14][C:12]([N:8]1[CH2:7][C:6]2[CH:19]=[C:2]([B:20]([OH:25])[OH:21])[CH:3]=[CH:4][C:5]=2[O:11][CH2:10][CH2:9]1)=[O:13])([CH3:18])[CH3:17]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(Br)cc2C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOc2ccc(B(O)O)cc2C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
A solution of 1,1-dimethylethyl 7-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (30.0 g, 91.4 mmol) and triisopropyl borate (22.4 g, 119 mmol) in THF (300 mL) was cooled to −78° C., and a 2.5 M solution of n-butyllithium in hexanes (47.6 mL, 119 mmol) was added dropwise over 40 min at this temperature. The reaction mixture was stirred at −78° C. for an additional 30 min, then quenched by dropwise addition of 2 N hydrochloric acid (80 ml), and allowed to warm up to room temperature. Ethyl acetate (100 mL) and water (100 mL) were added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layers were washed with water, dried over sodium sulfate, and concentrated. Hexane (200 mL) was added to the residue and the mixture was stirred overnight. The precipitate was filtered, washed several times with hexane, and dried to give (4-{[(1,1-dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)boronic acid (23.4 g, 87%) as a colorless solid. MS (EI) for C14H20BNO5: 294 (MH+).
Reaction SMILES: [CH2:1]([N:4]1[C:8]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)=[C:7]([CH:17]([CH3:19])[CH3:18])[N:6]=[C:5]1[CH2:20]OCC1C=CC=CC=1)[CH:2]=[CH2:3].B(Cl)(Cl)[Cl:30].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:1]([N:4]1[C:8]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)=[C:7]([CH:17]([CH3:19])[CH3:18])[N:6]=[C:5]1[CH2:20][Cl:30])[CH:2]=[CH2:3]
Reactant: ClB(Cl)Cl
Reactant: C=CCn1c(COCc2ccccc2)nc(C(C)C)c1Sc1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=CCn1c(CCl)nc(C(C)C)c1Sc1cccc(Cl)c1
Temperature: -40 °C
Yield: 13 %

Procedure:
(2)In 5 ml of methylene chloride was dissolved 470 mg (1.13 mmol)of 1-allyl-2-benzyloxymethyl-5-(3-chlorophenylthio)-4-isopropyl-1H-imidazole (17g), with cooling to -40° C., 0.7 ml (1.36 mmol)of methylene chloride solution of boron trichloride (1.94 molar)was addled with stirring, and the mixture was stirred for 30 minutes. To this reaction mixture, a saturated aqueous solution of sodium bicarbonate was added for neutralization, methylene chloride layer was washed with water and dried over sodium sulfate. The solvent was concentrated under reduced pressure and the residue was fractionated by silica gel chromatography (ethyl acetate:methylene chloride=1:4). From the first fraction, 50 mg (yield 13%)of 1-allyl-2-chloromethyl-5-(3-chlorophenylthio)-4-isopropylimidazole (28a)was obtained as oil, and then, 155 mg (yield 43%)of Compound I-17 was obtained. mp 84-86° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7](Cl)=[N:8][OH:9])=[N:4][O:5][N:6]=1.Cl.Cl.[NH2:13][CH2:14][CH2:15][NH:16][S:17]([CH3:20])(=[O:19])=[O:18].C(N(CC)CC)C>C(O)C>[NH2:1][C:2]1[C:3]([C:7](=[N:8][OH:9])[NH:13][CH2:14][CH2:15][NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[N:4][O:5][N:6]=1
Reactant: Nc1nonc1C(Cl)=NO
Reactant: CS(=O)(=O)NCCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CS(=O)(=O)NCCNC(=NO)c1nonc1N
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100.9 %

Procedure:
4-Amino-N-hydroxy-1,2,5-oxadiazole-3-carboximidoyl chloride (9.7 g, 60 mmol) was stirred in ethanol (460 mL) and N-(2-aminoethyl)methanesulfonamide dihydrochloride (19 g, 109 mmol) was added slowly in portions and the temperature rose to 25° C. After cooling back to 0° C., triethylamine (53 mL, 380 mmol) was added dropwise over 15 minutes and the reaction was stirred for an additional 15 minutes. The solution was washed with water (300 mL) and brine (300 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to give the desired product (16 g, 100%). LCMS calculated for C6H13N6O4S (M+H)+: m/z=265.1. 1H NMR (400 MHz, DMSO-d6): δ 10.16 (s, 1H), 9.07 (m, 1H), 7.18 (m, 1H), 6.37 (s, 2H), 3.36 (m, 2H), 3.15 (m, 2H), 2.87 (s, 3H).
Reaction SMILES: [CH3:1][S:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][S:15]([NH2:18])(=[O:17])=[O:16])=[N:5][N:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25]([N:29]=[C:30]=[O:31])[CH2:26][CH2:27][CH3:28]>CC(=O)CC>[CH2:25]([NH:29][C:30]([NH:18][S:15]([CH2:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[O:7][C:3]([S:2][CH3:1])=[N:4][N:5]=1)(=[O:17])=[O:16])=[O:31])[CH2:26][CH2:27][CH3:28]
Reactant: CSc1nnc(-c2ccccc2CS(N)(=O)=O)o1
Reactant: CCCCN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCNC(=O)NS(=O)(=O)Cc1ccccc1-c1nnc(SC)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
A suspension containing 16 g of the sulfonamide of Example 3, 7.7 g of potassium carbonate and 6.7 g of n-butylisocyanate in 130 of 2-butanone was refluxed for 4 hours, then stirred overnight at room temperature. After concentrating the mixture in vacuo, the residue was diluted with about 150 ml of water and the solution was washed 1×100 ml of ethyl ether. The aqueous layer was acidified with concentrated hydrochloric acid (red to litmus paper) and the resulting suspension was filtered, then suction-dried overnight to give 20 g of the subject compound; m.p. 156°-159°. IR (nujol): 1680 cm-1 (C=O).