Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]3[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[S:23]1[C:27](B(O)O)=[CH:26][C:25]2[CH:31]=[CH:32][CH:33]=[CH:34][C:24]1=2.C([O-])([O-])=O.[K+].[K+].O>COCCOC.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>[S:23]1[C:27]([C:2]2[CH:3]=[C:4]([N:8]3[C:16]4[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=4[C:10]4[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]3=4)[CH:5]=[CH:6][CH:7]=2)=[CH:26][C:25]2[CH:31]=[CH:32][CH:33]=[CH:34][C:24]1=2
Reactant: OB(O)c1cc2ccccc2s1
Reactant: Cc1ccc2c(c1)c1c(n2-c2cccc(Br)c2)CCN(C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2-c2cccc(-c3cc4ccccc4s3)c2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), benzo[b]thien-2-ylboronic acid (100 mg, 0.557 mmol) and K2CO3 (116 mg, 0.845 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh3)4 (16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 5-(3-(benzo[b]thiophen-2-yl)phenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (TFA salt, CD3OD) d (ppm): 7.8-7.91 (m, 3H), 7.78 (s, 2H), 7.61-7.7 (t, 1H), 7.3-7.4 (m, 4H), 7.18 (d, 1H), 7.02 (d, 1H), 4.8 (d, 1H), 4.4 (d, 1H), 3.81 (m, 1H), 3.5 (m, 1H), 3.2 (m, 1H), 3.18 (s, 3H), 3.01 (m, 1H), 2.41 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([C:27]1[N:28]=[N:29][N:30]([CH3:32])[N:31]=1)[C@H:8]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]#[N:17])[C:10]2[CH:18]=[C:19]([C:23]([F:26])([F:25])[F:24])[C:20]([CH3:22])=[CH:21][C:9]1=2.[N:42]([Sn](CCCC)(CCCC)CCCC)=[N+:43]=[N-:44]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:37][C:36]([F:39])([F:38])[C:34]1[CH:33]=[C:5]([CH:4]=[C:3]([C:2]([F:40])([F:1])[F:41])[CH:35]=1)[CH2:6][N:7]([C:27]1[N:28]=[N:29][N:30]([CH3:32])[N:31]=1)[C@H:8]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]2[N:42]=[N:43][NH:44][N:17]=2)[C:10]2[CH:18]=[C:19]([C:23]([F:24])([F:25])[F:26])[C:20]([CH3:22])=[CH:21][C:9]1=2
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: Cc1cc2c(cc1C(F)(F)F)N(CC#N)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cc2c(cc1C(F)(F)F)N(Cc1nn[nH]n1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Temperature: 100 °C

Procedure:
To a solution of (S)-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-acetonitrile (0.1 mmol) in toluene (6 mL), add azidotributyltin (0.1 mmol) and heat at 100° C. After heating for 14 h, cool to room temperature and dilute with ethyl acetate (20 mL). Wash the reaction with concentrated sodium fluoride (2×20 mL), dry the organic phase over sodium sulfate, filter, and remove solvent under vacuum. Chromatograph the product over silica gel, eluting with methanol/dichloromethane (0.5-5%), to afford the title compound as a colorless foam. MS (ES+): 633 (M+H).
Reaction SMILES: O=[C:2]1[N:10]2[C:6]([NH:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)=[C:5]([C:15]#[N:16])[C:4]2[CH2:17][CH2:18][S:19][CH2:20][C:3]1=2.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:2]1[N:10]2[C:6](=[N:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)[C:5]([C:15]#[N:16])=[C:4]2[CH2:17][CH2:18][S:19][CH2:20][C:3]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1c2c(c(=O)n3c1[nH]c1ccccc13)CSCC2
Product: N#Cc1c2c(c(Cl)n3c1nc1ccccc13)CSCC2

Procedure:
Phosphorus oxychloride (50 ml) was added to 12-oxo-3,4,6,12-tetrahydro-1H-thiopyrano[4′,3′:4,5]pyrido[1,2-a]benzimidazole-5-carbonitrile (16 g), followed by heating under reflux for 3 hours. The reaction liquid was concentrated under reduced pressure and the residue was poured into ice-water. The precipitate was collected by filtration and washed with water to obtain 12-chloro-3,4-dihydro-1H-thiopyrano[4′,3′:4,5]pyrido[1,2-a]benzimidazole-5-carbonitrile (18 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][C:7]([C:15]([OH:17])=O)([CH2:8]3)[CH2:6]1)[CH2:12]2)=[O:4].C(Cl)[Cl:19].C(Cl)(=O)C(Cl)=O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][C:7]([C:15]([Cl:19])=[O:17])([CH2:8]3)[CH2:6]1)[CH2:12]2)=[O:4]
Reactant: COC(=O)C12CC3CC(CC(C(=O)O)(C3)C1)C2
Reactant: ClCCl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: COC(=O)C12CC3CC(CC(C(=O)Cl)(C3)C1)C2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
3-Methoxycarbonyladamantane-1-carboxylic acid (1.0 eq) was suspended in a solution of CH2Cl2 containing a catalytic amount of DMF. This mixture was then cooled to 0° C. and oxalyl chloride (3.0 eq) was added. After 15 minutes, the reaction mixture was allowed to warm to room temperature and stirred at this temperature for 30 minutes, and then warmed to reflux for 1 hour. During the reflux period, the reaction became homogenous. The reaction mixture was then cooled and concentrated at reduced pressure. The residue was taken-up in diethyl ether and filtered. The filtrate was concentrated at reduced pressure to yield the title intermediate as a yellow liquid.
Reaction SMILES: [O:1]=[CH:2]/[CH:3]=[CH:4]/[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:23]=[CH:24]/[CH:25]=[CH:26]/[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([N:23]2[CH:24]=[CH:25][C@H:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@H:3]([CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[C:2]2=[O:1])(=[O:21])=[O:22])=[CH:18][CH:19]=1
Reactant: COc1ccc(S(=O)(=O)N=C/C=C/c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)/C=C/C=O
Product: COc1ccc(S(=O)(=O)N2C=C[C@H](c3ccccc3)[C@H](CC(=O)OC(C)(C)C)C2=O)cc1

Procedure:
The title compound was prepared according to the general procedure from tert-butyl trans-4-oxo-2-butenoate and trans-N-(4-methoxybenzenesulfonyl)-3-phenylprop-2-en-1-imine using 10 mol % 9 as the catalyst in 70% yield white solid. [α]D20 (c 1.07, CHCl3)=+90.4; mp=139-142° C.; 1H NMR (400 MHz, CDCl3) 8.03 (dd, 21-1, J=6.9, 2.1 Hz), 7.16-7.13 (m, 2H), 7.05-7.00 (m, 4H), 6.60 (dd, 2H, J=8.2, 1.0 Hz), 5.59 (dd, 1H, J=8.1, 6.6 Hz), 3.92 (s, 3H), 3.66 (t, 1H, J=6.9 Hz), 3.49-3.43 (m, 1H), 2.57 (dd, 1H, J=17.3, 6.1 Hz), 1.94 (dd, 1H, J=17.3, 7.5 Hz), 1.41 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 171.0, 169.0, 164.3, 136.9, 131.4, 129.2, 128.9, 128.0, 127.8, 124.5, 114.2, 113.6, 81.1, 56.0, 44.2, 41.9, 32.5, 28.2; IR (thin film) ν 3086, 2976, 1715, 1594, 1496, 1364, 1264, 1167, 1080 cm−1; HRMS (ESI) calcd for C24H27NO6S [M+Na]+ 480.1451, found 480.1456; 97% ee (3S,4S)-isomer as determined by HPLC (AS-H, 9:1 hexanes/i-PrOH), tr (3S,4S)=19.4 min, tr (3R,4R)=14.1 min.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[N:5]([CH2:11][C:12]#[CH:13])[C:4](=[O:14])[C:3]=1[NH:15][C:16](=O)[C:17]#[C:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>CN(C)C=O>[CH3:28][O:27][C:21]1[CH:20]=[C:19]([C:18]#[C:17][C:16]2[NH:15][C:3]3[C:4](=[O:14])[N:5]([CH2:11][C:12]#[CH:13])[C:6](=[O:10])[N:7]([CH2:8][CH3:9])[C:2]=3[N:1]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: C#CCn1c(=O)c(NC(=O)C#Cc2ccc(OC)c(OC)c2)c(N)n(CC)c1=O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CN(C)C=O
Product: C#CCn1c(=O)c2[nH]c(C#Cc3ccc(OC)c(OC)c3)nc2n(CC)c1=O
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 82.6 %

Procedure:
To a solution of 3-(3,4-dimethoxyphenyl)propynoic acid (6-amino-1-ethyl-3-prop-2-ynyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl)amide (3.2 g, 8.0 mmol) in 15 ml of dry dimethylformamide was added phosphorous pentoxide (6 g). The mixture was stirred at 100° C. for 10 min and subsequently cooled to room temperature. The product was precipitated by adding water (ca. 100 ml), filtered under reduced pressure, washed thoroughly with water and dried at 70° C., yielding light yellow 8-(3,4-dimethoxyphenylethynyl)-3-ethyl-1-prop-2-ynyl-3,7-dihydro-purine-2,6-dione (2.5 g, 82%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([F:9])[C:7]=1F.[NH3:14]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([F:9])[C:7]=1[NH2:14]
Reactant: N
Reactant: Fc1cc(C(F)(F)F)cc(F)c1F
Solvent: C1CCOC1
Product: Nc1c(F)cc(C(F)(F)F)cc1F

Procedure:
In a stainless steel autoclave, 500 g of 3,4,5-trifluoro-benzotrifluoride are introduced, 2,000 ml of tetrahydrofuran are added, and 150 g of liquid ammonia are forced in. The autoclave is heated to 120° to 130° C. for 5 hours with stirring, then cooled, and the pressure is released at 20° C. In addition to the solvent and the starting material, 272 g of 3,5-difluoro-4-amino-benzotrifluoride of a boiling point of 58° to 60° C. at 16 mbar are obtained by distillation.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=3[CH3:37])[CH2:19][C:20]([C:22]3[CH:27]=[CH:26][C:25](=[O:28])[N:24]([CH3:29])[CH:23]=3)=O)=[CH:14][CH:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[NH2:39][OH:40].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=3[CH3:37])[CH2:19]/[C:20](=[N:39]\[OH:40])/[C:22]3[CH:27]=[CH:26][C:25](=[O:28])[N:24]([CH3:29])[CH:23]=3)=[CH:14][CH:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Oc2ccc(Cl)c(C(=O)O)c2)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(Oc2ccc(Cl)c(C(=O)O)c2)cc1

Procedure:
In analogy to example 151, step 3, 2-chloro-5-{4-[1-(4-chloro-2-methyl-phenyl)-3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-propyl]-phenoxy}-benzoic acid was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound containing less than 10% of the corresponding Z isomer as a colourless solid, MS (ESI−): m/z=549.2 [M−H]−.
Reaction SMILES: CO[C:3]([C:5]1[C:10]([Br:11])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].[NH2:12][C:13]1[S:14][CH:15]=[C:16]([CH3:18])[N:17]=1>>[CH3:18][C:16]1[N:17]=[C:13]([NH:12][C:3]([C:5]2[C:10]([Br:11])=[N:9][CH:8]=[CH:7][N:6]=2)=[O:4])[S:14][CH:15]=1
Reactant: Cc1csc(N)n1
Reactant: COC(=O)c1nccnc1Br
Product: Cc1csc(NC(=O)c2nccnc2Br)n1

Procedure:
The title compound, MS: m/e=301.0 (M+H+), was prepared in accordance with the general method of example 1, step 2 from 3-bromo-pyrazine-2-carboxylic acid methyl ester (Example A) and 2-amino-4-methylthiazole.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([CH3:15])=[CH:10][C:9]=1[NH:16][C:17](=[O:33])[CH2:18][C:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[CH:21]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:14][C:12]1[C:11]([CH3:15])=[CH:10][C:9]2[NH:16][C:17](=[O:33])[CH2:18][C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=4)[CH:21]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(NC(=O)CC(=O)c2cccc(-c3ccncc3)c2)c(NC(=O)OC(C)(C)C)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(cc1Cl)N=C(c1cccc(-c3ccncc3)c1)CC(=O)N2

Procedure:
The title compound was prepared from {5-chloro-4-methyl-2-[3-oxo-3-(3-pyridin-4-yl-phenyl)-propionylamino]-phenyl}-carbamic acid tert-butyl ester (Example M63) (0.36 g, 0.75 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white light solid (269 mg, 99%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([OH:29])=O)=[C:22]([F:30])[CH:21]=2)[CH:7]=[N:8][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH3:2].[CH3:31][N:32]([CH3:47])[CH2:33][CH2:34][O:35][C:36]1[CH:37]=[C:38]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[NH2:39].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>N1C=CC=CC=1>[CH3:31][N:32]([CH3:47])[CH2:33][CH2:34][O:35][C:36]1[CH:37]=[C:38]([NH:39][C:27](=[O:29])[CH2:26][C:23]2[CH:24]=[CH:25][C:20]([C:6]3[CH:7]=[N:8][C:9]([O:10][CH2:11][C:12]4[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=4)=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=3)=[CH:21][C:22]=2[F:30])[CH:40]=[C:41]([C:43]([F:44])([F:45])[F:46])[CH:42]=1
Reactant: CN(C)CCOc1cc(N)cc(C(F)(F)F)c1
Reactant: CCOc1cc(-c2ccc(CC(=O)O)c(F)c2)cnc1OCc1ccc(OC)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: c1ccncc1
Product: CCOc1cc(-c2ccc(CC(=O)Nc3cc(OCCN(C)C)cc(C(F)(F)F)c3)c(F)c2)cnc1OCc1ccc(OC)cc1
Temperature: 27 °C
Reaction time: 0.5 h
Yield: 64.2 %

Procedure:
To a solution of 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (100 mg, 0.243 mmol) and 3-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)aniline (60.3 mg, 0.243 mmol) in pyridine (2 mL) was added T3P® (0.5 mL, 0.243 mmol) at 27° C. under N2. The mixture was stirred at 27° C. for 30 min. LCMS showed the reaction was completed. Then the mixture was put onto ice (10 mg). The precipitate was filtered and redissolved in DCM (5 mL). The solution was washed with water (5 mL×2), and the combined organic extracts were dried over Na2SO4, filtered and concentrated. The residue was suspended in PE/EA (2:1, v/v, 8 mL) and stirred for 10 min. The solid was filtered, and washed with PE/EA (2:1, v/v, 10 mL) and dried in vacuo to give an off-white solid of N-(3-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (100 mg, 0.156 mmol, 64.1% yield). TLC (PE/EA=1:1, Rf=0.3): 1H NMR (400 MHz, CD3OD) δ 7.97-7.92 (m, 1H), 7.76 (br. s., 1H), 7.48-7.37 (m, 7H), 7.04 (s, 1H), 6.91 (d, J=8.6 Hz, 2H), 5.36 (s, 2H), 4.14 (q, J=7.1 Hz, 4H), 3.86-3.78 (m, 5H), 2.97 (br. s., 8H), 1.42 (t, J=6.9 Hz, 4H). ES-LCMS m/z 642 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([N:11]2[CH2:14][CH:13]([OH:15])[CH2:12]2)[S:9][CH:10]=1)=[O:5])[CH3:2].[Si:16](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N1C=CN=C1.C(O)C>CN(C)C=O>[Si:16]([O:15][CH:13]1[CH2:12][N:11]([C:8]2[S:9][CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]=2)[CH2:14]1)([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1csc(N2CC(O)C2)n1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Reaction time: 0.17 h
Yield: 85.5 %

Procedure:
To a solution of 1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)-3-hydroxyazetidine (8.5 g, 37.2 mmol) (obtained as described in Reference Example 1(2)) in dimethylformamide (255 ml) were added t-butyldiphenylsilyl chloride (19.4 ml, 74.5 mmol) and imidazole (5.07 g, 74.5 mmol) in an ice bath. After stirring the mixture in an ice bath for 10 minutes, the resulting mixture was stirred at room temperature for 2.5 hours. After checking the completion of the reaction, ethanol (2.59 ml) was added to the reaction mixture in an ice bath and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (6:1→2:1) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)azetidine (14.85 g, yield 86%) as a pale brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:14][C:15]([N:17]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:18])=[O:16])[CH2:10][C:11](O)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].C(N1C=CN=C1)(N1C=CN=C1)=O.[BH4-].[Na+]>CCOC(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:10][CH2:11][OH:12])[CH2:14][C:15]([N:17]([CH3:18])[CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:16])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(Cc1ccccc1)C(=O)CC(CC(=O)O)c1ccc(Cl)c(Cl)c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CN(Cc1ccccc1)C(=O)CC(CCO)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.6 %

Procedure:
3,4-Dichloro-beta-[2-[(phenylmethyl)methylamino]-2-oxoethyl]benzenepropanoic acid (6.9 g) in EtOAc (150 mL) was treated with carbonyldiimidazole (4.4 g) and N,N-dimethylaminopyridine (0.22 g). The resulting solution was stirred at room temperature for 15 minutes and then heated at 50° C. for 1 hour. The reaction mixture was cooled to 0° C. and treated with a solution of NaBH4 (4.46 g) in H2O (75 mL), warmed slowly to room temperature and stirred for 12 hours. The reaction mixture was then diluted with EtOAc (250 mL) and washed with 1N HCl (250 mL), H2O (250 mL) and dried over MgSO4, filtered and concentrated under reduced pressure to yield the title compound (6.29 g).
Reaction SMILES: C([BH3-])#N.[Na+].[F:5][C:6]1[CH:7]=[CH:8][C:9]([O:22][CH3:23])=[C:10]2[C:15]=1[O:14][CH2:13][C@H:12]([NH:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[CH2:11]2.[CH:24](=O)[CH2:25][CH3:26].C(O)(=O)C>CO>[F:5][C:6]1[CH:7]=[CH:8][C:9]([O:22][CH3:23])=[C:10]2[C:15]=1[O:14][CH2:13][C@H:12]([N:16]([CH:17]([CH2:18][CH3:19])[CH2:20][CH3:21])[CH2:24][CH2:25][CH3:26])[CH2:11]2
Reactant: CCC=O
Reactant: CCC(CC)N[C@H]1COc2c(F)ccc(OC)c2C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(C(CC)CC)[C@H]1COc2c(F)ccc(OC)c2C1
Reaction time: 18 h
Yield: 94.4 %

Procedure:
Sodiumcyanoborohydride (1.3 g, 20.7 mmol) was added during 10 min. to a stirred solution of (R)-8-fluoro-5-methoxy-3-(N-3-pentylamino)chroman (3.69 g, 13.8 mmol) and propionaldehyde (5 ml, 69.3 mmol) in 100 ml dry MeOH. The pH was adjusted with acetic acid to pH 6. The solution was stirred in room temp. for 18 hours and propionaldehyde (1 ml, 13.7 mmol) was added. After stirring at room temp. for 3.5 hours the solution was concentrated, and the residue was partitionated between 100 ml 2M NH3 and 200 ml ether. Extraction with 2×200 ml ether and drying of the combined organic layers (Na2SO4) gave after evaporation a crude product. Purification by flash chromatography on silica with hexane:acetone 20:1 gave 4.03 g of (R)-8-fluoro-5-methoxy-3-(N-3-pentyl-N-n-propylamino)chroman as an uncolored oil. [α]D22 -83° (c 1.08 in MeOH).
Reaction SMILES: CS(O)(=O)=O.CS(O)(=O)=O.[NH2:11][C:12]1[C:19](=[O:20])[N:15]2[CH2:16][CH2:17][CH2:18][N:14]2[C:13]=1[NH2:21].[NH2:22][C:23]1[CH:24]=[C:25]([OH:31])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30].N.OO>O.C(O)C>[NH2:21][C:13]1[N:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19](=[O:20])[C:12]=1/[N:11]=[C:26]1/[C:25]([OH:31])=[CH:24][C:23](=[NH:22])[C:28]([O:29][CH3:30])=[CH:27]/1
Reactant: COc1ccc(O)cc1N
Reactant: Nc1c(N)n2n(c1=O)CCC2
Agent: CS(=O)(=O)O
Agent: N
Agent: OO
Solvent: CCO
Solvent: O
Product: COC1=C/C(=N\c2c(N)n3n(c2=O)CCC3)C(O)=CC1=N

Procedure:
0.05 mmol of 2,3-diamino-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazol-1-one dimethane sulfonate was dissolved in a mixture of water and ethanol (7.5 ml/1.5 ml). This solution was admixed with 0.05 mmol of 3-amino-4-methoxyphenol, then with 1.8 ml of concentrated aqueous ammonia, then with 9 ml of hydrogen peroxide.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[S:14][C:15]=2[Br:16])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[NH2:28][CH2:29][CH2:30][CH2:31][OH:32]>C(Cl)Cl>[Br:16][C:15]1[S:14][C:13]([S:17](=[O:19])(=[O:18])[NH:28][CH2:29][CH2:30][CH2:31][OH:32])=[CH:12][C:11]=1[C:7]1[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=1[CH3:10]
Reactant: NCCCO
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Cl)sc2Br)s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)NCCCO)sc2Br)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
4-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]-5-bromothiophene-2-sulfonyl chloride, prepared as in Step III of Example 23 (300 mg; 0.72 mmol; 1 eq), is dissolved in anhydrous DCM (20 ml). The reaction is put under nitrogen. Triethylamine (0.5 ml; 3.61 mmol; 5 eq) and 3-amino-1-propanol (0.27 ml; 3.61 mmol; 5 eq) are added successively and the reaction mixture is stirred for 1 hour at room temperature. It is washed with water, NaHCO3 sat., brine and dried over MgSO4, affording the title compound (230 mg; 70%).
Reaction SMILES: [NH3:1].[N:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[N:14][C:13]([CH3:16])=[N:12]2)=[C:7]([O:17][CH3:18])[CH:6]=1)=[C:3]=[S:4]>>[CH3:18][O:17][C:7]1[CH:6]=[C:5]([NH:2][C:3]([NH2:1])=[S:4])[CH:10]=[CH:9][C:8]=1[N:11]1[CH:15]=[N:14][C:13]([CH3:16])=[N:12]1
Reactant: COc1cc(N=C=S)ccc1-n1cnc(C)n1
Reactant: N
Product: COc1cc(NC(N)=S)ccc1-n1cnc(C)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87 %

Procedure:
Step F (4): Methanolic ammonia (1.0 M, 100 mL, 100 mmol) was added to a flask charged with 1-(4-isothiocyanato-2-methoxyphenyl)-3-methyl-1H-1,2,4-triazole (3.91 g, 15.88 mmol) in a ice-water bath. After the addition was complete, the resulting slurry was stirred for 10 min and then allowed to warm to rt. After 24 h, the reaction mixture was concentrated to dryness in vacuo to afford 1-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)thiourea (4.18 g, 13.81 mmol, 87% yield) as a white solid. LC-MS (M+H)+ 264.0.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:9])[C:7]#[CH:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[Br:12]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>CO>[C:1]([NH:5][C:6](=[O:9])[C:7]#[C:8][Br:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrBr
Reactant: C#CC(=O)NC(C)(C)C
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)NC(=O)C#CBr
Temperature: 25 °C
Yield: 67.5 %

Procedure:
0.50 g of N-(tert-butyl)propiolamide was dissolved in 15 ml of methanol, to which 0.17 g of sodium hydroxide was added. 0.64 g of bromine was added dropwise to the mixture while stirring at a room temperature. 50 ml of 5%-aqueous solution of sodium thiosulfate was added to the reaction solution to extract with dichlormethane. The extracted solution was dried and concentrated. The residue was then purified by column chromatography (silica gel, eluent: ethyl acetate/hexane =1/5). Subsequently, 0.55 g of N-(tert-butyl)-3-bromopropiolamide was obtained by means of recrystallization from dichlormethane/hexane.