Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-])=O)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:23]#[N:24])[CH:6]=[CH:7][CH:8]=1)#[CH:2]>C(O)C>[NH2:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]([C:23]#[N:24])=[C:10]2[NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[CH:2])[CH:4]=1
Reactant: C#Cc1cccc(Nc2c(C#N)cnc3ccc([N+](=O)[O-])cc23)c1
Solvent: CCO
Product: C#Cc1cccc(Nc2c(C#N)cnc3ccc(N)cc23)c1
Reaction time: 2 h
Yield: 96.1 %

Procedure:
A mixture of 2.00 g (6.36 mmol) 4-[(3-ethynylphenyl)amino]-6-nitro-quinoline-3-carbonitrile, 100 ml ethanol, and 7.19 g (31.8 mmol) SnCl2 dihydrate was heated to reflux under N2. Removed heat at 3½ hours and added ice water. Made basic with sodium bicarbonate and stirred for 2 hours. Extracted with chloroform, stirred organic layer with Darco, dried with sodium sulfate, filtered, stripped solvent, and dried in vacuo, giving 1.737 g of yellow-brown solid: mass spectrum (electrospray m/e): M+H=285.2.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[Ba+2].[CH3:9][CH:10]1[CH:14]([C:15]([O:17][CH3:18])=[O:16])[C:13](=O)[CH:12]([CH3:20])[S:11]1>C(O)C>[OH:3][N:2]=[C:13]1[CH:12]([CH3:20])[S:11][CH:10]([CH3:9])[CH:14]1[C:15]([O:17][CH3:18])=[O:16]
Reactant: NO
Reactant: COC(=O)C1C(=O)C(C)SC1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Ba+2]
Solvent: CCO
Product: COC(=O)C1C(=NO)C(C)SC1C

Procedure:
Hydroxylamine hydrochloride, 145 g (2.09 mol), and barium carbonate (J. T. Baker Chemical Company), 219.2 g (1.11 mol), are added to a solution of 89.3 g (0.474 mol) of tetrahydro-2,5-dimethyl-4-oxo-3-thiophenecarboxylic acid, methyl ester (Example C) in 1 L of absolute ethanol. The suspension is stirred and refluxed for sixteen hours, cooled, filtered through Supercell Hyflo® (Johns-Manville), the filtrate evaporated and the residue dissolved in 500 ml of diethyl ether. The diethyl ether solution is washed with 500 ml of water (2 times). The diethyl ether layer is separated, dried over anhydrous Na2SO4 and evaporated to give 83.7 g of tetrahydro-4-(hydroxyimino)-2,5-dimethyl-3-thiophene-carboxylic acid, methyl ester as an orange liquid.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[CH2:8]([O:11][N:12]=[C:13]([C:17]1[N:18]=[C:19]([NH2:22])[S:20][CH:21]=1)[C:14]([OH:16])=[O:15])[C:9]#[CH:10].C(OC(C)C)(C)C>C(O)=O>[CH2:8]([O:11][N:12]=[C:13]([C:17]1[N:18]=[C:19]([NH:22][CH:1]=[O:3])[S:20][CH:21]=1)[C:14]([OH:16])=[O:15])[C:9]#[CH:10]
Reactant: CC(=O)OC(C)=O
Reactant: C#CCON=C(C(=O)O)c1csc(N)n1
Solvent: CC(C)OC(C)C
Solvent: O=CO
Product: C#CCON=C(C(=O)O)c1csc(NC=O)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
Formic acid (107 g) was added to acetic anhydride (239 g) under ice-cooling, and the mixture was stirred for 1 hour at 50° C. and then cooled to 20° C. To the mixture was added 2-(2-propynyloxyimino)-2-(2-aminothiazol-4-yl)acetic acid (syn isomer) (135 g), and the mixture was stirred for 3 hours at ambient temperature. To the mixture was added diisopropyl ether (400 ml) and then the precipitated crystals were collected by filtration, washed with diisopropyl ether and then dried to give 2-(2-propynyloxyimino)-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (118.4 g).
Reaction SMILES: CN([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][N:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=2)[N:7]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH:6]=1)C.[C:26]1([C@H:32]([OH:34])[CH3:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[F:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:7]2[C:8]3=[CH:9][N:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=[C:13]3[C:5]([CH2:4][O:34][C@@H:32]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:33])=[CH:6]2)=[CH:20][CH:21]=1
Reactant: COC(=O)c1cc2c(CN(C)C)cn(Cc3ccc(F)cc3)c2cn1
Reactant: C[C@@H](O)c1ccccc1
Product: COC(=O)c1cc2c(CO[C@H](C)c3ccccc3)cn(Cc3ccc(F)cc3)c2cn1

Procedure:
The title compound was prepared as in example 116, step 1, using methyl 3-[(dimethylamino)methyl]-1-(4-fluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate and (1R)-1-phenylethanol. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.48 (d, J=6.41 Hz, 3H) 4.01 (s, 3H) 4.48-4.59 (m, 3H) 5.34 (s, 2H) 6.97-7.05 (m, 2H) 7.10-7.17 (m, 2H) 7.23 (s, 1H) 7.29-7.42 (m, 5H) 8.47 (s, 1H) 8.72 (s, 1H)
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13]C(C(O)=O)[S:15][CH2:16]2)=[CH:11][CH:10]=1.CN(C=O)C>C(Cl)Cl>[CH3:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH:1]([C:2]([Cl:4])=[O:3])[S:15][CH2:16]2)=[CH:11][CH:10]=1
Reactant: COc1ccc2c(c1)CSC(C(=O)O)C2
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CSC(C(=O)Cl)C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 2.0 M solution of oxalyl chloride (3.57 mL, 7.14 mmol) in CH2Cl2 was added under N2 to a solution of 7-methoxy-isothiochroman-3-carboxylic acid (0.80 g, 3.57 mmol) and a drop of DMF in CH2Cl2 (100 mL). The solution was allowed to stir at room temperature for 3 h and was concentrated under reduced pressure to provide 7-methoxy-isothiochroman-3-carbonyl chloride as a tan oil. The acid halide was used in the next step without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1[C:16]2[C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[O:13][C:12]=2[C:11]([C:21]2[N:26]=[CH:25][N:24]=[C:23]([NH:27][C:28]3[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=3)[CH:22]=2)=[CH:10][CH:9]=1.[CH3:35][N:36]([CH3:46])[C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=1)[C:40](Cl)=[O:41]>N1C=CC=CC=1>[CH:8]1[C:16]2[C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[O:13][C:12]=2[C:11]([C:21]2[N:26]=[CH:25][N:24]=[C:23]([NH:27][C:28]3[CH:29]=[CH:30][C:31]([NH:34][C:40](=[O:41])[C:39]4[CH:43]=[CH:44][CH:45]=[C:37]([N:36]([CH3:35])[CH3:46])[CH:38]=4)=[CH:32][CH:33]=3)[CH:22]=2)=[CH:10][CH:9]=1
Reactant: CN(C)c1cccc(C(=O)Cl)c1
Reactant: Nc1ccc(Nc2cc(-c3cccc4c3oc3ccccc34)ncn2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Product: CN(C)c1cccc(C(=O)Nc2ccc(Nc3cc(-c4cccc5c4oc4ccccc45)ncn3)cc2)c1

Procedure:
To a solution of N-(6-dibenzofuran-4-yl-pyrimidin-4-yl)-benzene-1,4-diamine trifluoroacetic acid (compound A1) (500 mg, 1.1 mmol) in pyridine (10 mL) is added at 10° C. 3-dimethylaminobenzoyl chloride (288 mg, 1.21 mmol) portion wise. After 14 h at ambient temperature the mixture is evaporated and the crude product is purified by crystallization.
Reaction SMILES: C(OC([NH:8][N:9]1[CH2:14][CH2:13][N:12]([S:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([Cl:28])[CH:24]=3)[CH:19]=2)(=[O:17])=[O:16])[CH2:11][C:10]1=[O:29])=O)(C)(C)C.CO.Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[NH2:8][N:9]1[CH2:14][CH2:13][N:12]([S:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([Cl:28])[CH:24]=3)[CH:19]=2)(=[O:16])=[O:17])[CH2:11][C:10]1=[O:29]
Reactant: CC(C)(C)OC(=O)NN1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: NN1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1=O

Procedure:
1-(tert-Butoxycarbonylamino)-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone (575 mg) was combined with methanol (4 ml) and a 4N solution of hydrochloric-acid in ethyl acetate (4 ml) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated and the residue obtained was combined with aqueous sodium bicarbonate, extracted with dichloromethane, dried and concentrated to obtain 1-amino-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone as a colorless solid. A solution of the resultant 1-amino-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone and 1-(4-pyridyl)-4-piperidone (237 mg) in ethanol (30 ml) was dehydrated using a Soxlet extractor packed with molecular sieves 4A while refluxing for 24 hours. The reaction mixture was concentrated and the residue was purified by a column chromatography (dichloromethane: 10% aqueous ammonia-containing methanol=20:1) and crystallized from ether to obtain the title compound (265 mg) as colorless crystals.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[N:15]=[N:16][N:17]([CH2:19][C:20]([O:22]CC)=[O:21])[N:18]=3)=[CH:10][N:9]=2)[CH2:4][CH2:3]1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[N:15]=[N:16][N:17]([CH2:19][C:20]([OH:22])=[O:21])[N:18]=3)=[CH:10][N:9]=2)[CH2:6][CH2:7]1
Reactant: CCOC(=O)Cn1nnc(-c2cnc(N3CCC(O)CC3)nc2)n1
Reactant: Oc1cc(F)ccc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C(O)Cn1nnc(-c2cnc(N3CCC(Oc4cc(F)ccc4Cl)CC3)nc2)n1

Procedure:
The title compound was prepared in a similar manner as that described for Example 3 (step 4) from ethyl {5-[2-(4-hydroxypiperidin-1-yl)pyrimidin-5-yl]-2H-tetrazol-2-yl}acetate, 2-chloro-5-fluorophenol, triphenylphosphine and diethyl azodicarboxylate.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([CH3:31])=[C:20]([C:32](O)=[O:33])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.[NH2:35][C@@H:36]1[CH2:41][CH2:40][C@H:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:38][CH2:37]1>>[C:45]([O:44][C:43](=[O:49])[NH:42][C@H:39]1[CH2:40][CH2:41][C@@H:36]([NH:35][C:32]([C:20]2[C:16]3[N:17]=[CH:18][N:19]=[C:14]([C:7]4[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:15]=3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:30])[CH3:29])[C:21]=2[CH3:31])=[O:33])[CH2:37][CH2:38]1)([CH3:46])([CH3:48])[CH3:47]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: COc1ccc(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)c1
Product: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c5) and commercially available tert-butyl cis-(4-amino-cyclohexyl)-carbamate the title compound is obtained as colorless foam.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=[O:28])[CH2:10][CH:11]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.[CH2:29]([O:31][C:32](=[O:40])[CH2:33][CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)[CH3:30].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>O1CCCC1>[CH2:29]([O:31][C:32](=[O:40])[CH2:33][CH:34]1[CH2:39][CH2:38][N:37]([C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:19]([CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[CH2:10][C:9]([C:4]3[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=3)=[O:28])=[CH:20][CH:21]=2)[CH2:36][CH2:35]1)[CH3:30]
Reactant: CCOC(=O)CC1CCNCC1
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CCOC(=O)CC1CCN(C(=O)c2ccc(C(CC(=O)c3ccc(=O)n(C)c3)c3ccccc3C)cc2)CC1

Procedure:
In analogy to example 207, step 2, 4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-benzoic acid (example 207, step 1) was coupled with 2-(piperidin-4-yl)-acetic acid ethyl ester using BOP reagent in tetrahydrofuran to give the title compound as a light brown foam, MS (ESI+): m/z=529.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[CH2:23][CH2:24][NH2:25].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:25][CH2:24][CH2:23][C:22]2[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=2[F:20])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: NCCc1ccccc1F
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2F)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CNCCc3ccccc3F)cc2F)cn1
Reaction time: 8 h
Yield: 74.9 %

Procedure:
Place 5-(2-fluoro-4-formylphenoxy)pyridine-2-carboxamide (Example 403, Part B) (0.650 g, 2.50 mmol), 2-fluorophenethylamine (0.382 g, 2.75 mmol) and 3 Å molecular sieves in a vial. Add methanol (12 mL), cap and stir overnight. Add NaBH4 (slight excess) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 0% to 10% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound (0.718 g, 75%): TOF MS ES+ 384.2 (M+H)+, HRMS calcd for C21H20N3O2F2 387.2032 (M+H)+, found 387.2032, time 0.52 min; HPLC [YMC-Pro pack C-18 (150×46 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=11.4 min, 100% purity.
Reaction SMILES: [CH3:1]/[C:2](/[NH2:6])=[CH:3]\[C:4]#[N:5].[C:7](OCC)(=[O:10])[C:8]#[CH:9]>CN(C=O)C>[CH3:1][C:2]1[NH:6][C:7](=[O:10])[CH:8]=[CH:9][C:3]=1[C:4]#[N:5]
Reactant: C/C(N)=C\C#N
Reactant: C#CC(=O)OCC
Solvent: CN(C)C=O
Product: Cc1[nH]c(=O)ccc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.1 %

Procedure:
(Synthesis 1991, 894-896.) 3-Aminocrotonitrile (29, 2.9 g, 36 mmol) and ethyl propiolate (30, 3.0 mL, 36 mmol) were dissolved in dry DMF (17 mL). The reaction mixture was stirred for 1 h at room temperature, and the mixture was heated at reflux for 3 d. The precipitate formed after cooling to room temperature was collected, washed with methanol (5 mL), ether (10 mL), and dried to yield 131 (1.5 g, 31%): mp >300° C. 1H NMR (300 MHz, DMSO-d6) δ 12.43 (s, 1H), 7.58 (d, J=9.6 Hz, 1H), 6.23 (d, J=9.6 Hz, 1H), 2.37 (s, 3H).
Reaction SMILES: [O:1]=[C:2]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1)[C:3]([O:5]CC)=O.[NH2:19][CH2:20][CH:21]([OH:23])[CH3:22]>C(O)C>[OH:23][CH:21]([CH3:22])[CH2:20][NH:19][C:3](=[O:5])[C:2]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=1)=[O:1]
Reactant: CCOC(=O)C(=O)Nc1cccc(C(F)(F)F)c1
Reactant: CC(O)CN
Solvent: CCO
Product: CC(O)CNC(=O)C(=O)Nc1cccc(C(F)(F)F)c1
Yield: 98.8 %

Procedure:
Ethyl oxo{[3-(trifluoromethyl)-phenyl]amino}acetate (8.04 g, 30.7 mmol) was dissolved in ethanol (50 ml, 99.5%). To the stirred solution was added 1-amino-2-propanol (racemic, 2.32 g, 31 mmol) in one portion, and the mixture was heated to reflux for 90 minutes. The mixture was allowed to cool and was evaporated to dryness, giving 8.80 g (99%) of N-(2-hydroxypropyl)-N′-[3-(trifluoromethyl)-phenyl]ethanediamide as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][C:7]2[CH:11]=[C:12]([NH2:15])[CH:13]=[CH:14][C:6]1=2.I.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](SC)=[NH:24]>CCO.C([O-])(O)=O.[Na+]>[CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][C:7]2[CH:11]=[C:12]([NH:15][C:23]([C:19]3[S:18][CH:22]=[CH:21][CH:20]=3)=[NH:24])[CH:13]=[CH:14][C:6]1=2
Reactant: CN(C)CCN1CCOc2cc(N)ccc21
Reactant: CSC(=N)c1cccs1
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CN(C)CCN1CCOc2cc(NC(=N)c3cccs3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.3 %

Procedure:
A suspension of N,N-dimethyl-2-(7-nitro-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethanamine (210 mg, 0.836 mmol) and Pd—C (10% wt, 89 mg, 0.084 mmol) in dry EtOH (15 mL) was purged with hydrogen gas. The reaction was stirred at room temperature for 3 hours under hydrogen atmosphere (balloon pressure). The reaction mixture was then filtered through a Celite pad and washed with EtOH (15 mL). The light purple filtrate was concentrated to give crude 4-(2-(dimethylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-amine. A solution of this crude 4-(2-(dimethylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-amine (185 mg, 0.836 mmol) in dry EtOH (10 mL) was treated with methyl thiophene-2-carbimidothioate hydroiodide (477 mg, 1.672 mmol) and stirred overnight at room temperature. The reaction was diluted with saturated NaHCO3 solution (50 mL) and the product was extracted into CH2Cl2 (3×25 mL). The combined organic layers were dried (Na2SO4) and concentrated. The residue was subjected to flash chromatography on silica gel using 2:98 MeOH:CH2Cl2, followed by 5:95 (2M NH3 in MeOH):CH2Cl2, to give a yellow solid (150 mg, 54%). 1H-NMR (DMSO-d6) δ 7.69 (dd, J=3.6, 0.9 Hz, 1H), 7.56 (dd, J=5.1, 0.9 Hz, 1H), 7.07 (dd, J=5.1, 3.9 Hz, 1H), 6.64 (d, J=8.4 Hz, 1H), 6.35-6.26 (m, 4H), 4.14 (t, J=3.9 Hz, 2H), 3.33-3.29 (m, 4H), 2.42 (t, J=6.9 Hz, 2H), 2.19 (s, 6H); ESI-MS (m/z, %): 331 (MH+, 100), 260 (25); ESI-HRMS calculated for C17H23N4OS (MH+): 331.1587, Observed: 331.1594; HPLC purity: 99.0% by area.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:37][N:38]([CH3:48])[C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.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>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:42]2[CH:43]=[CH:44][C:39]([N:38]([CH3:48])[CH3:37])=[CH:40][CH:41]=2)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN(C)c1ccc(B(O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CN(C)c1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Yield: 60.6 %

Procedure:
To a mixture of toluene-4-sulfonic acid-1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (prepared as in Example 43, 0.15 g, 0.28 mmol), 4-(dimethylamino)-phenyl boronic acid (0.12 g, 0.72 mmol) and dichlorobis(triphenylphosphine)palladium (II) (21 mg, 0.03 mmol) in dioxane (3 mL) was added an aqueous sodium carbonate solution (2 M, 0.36 mL). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×30 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 25% ethyl acetate/hexanes) afforded {4-[1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-phenyl}-dimethyl-amine (80 mg, 59%) as a white solid: LC/MS m/e calcd for C28H29N3O2S [M+H]+ 472.63, observed 472.2.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([CH:16]=[CH2:17])[CH:5]=1.[CH:18]([O:22][C:23]1[C:28]([CH:29]=[CH:30][C:31](O)=[O:32])=[CH:27][CH:26]=[C:25]([C:34]([F:37])([F:36])[F:35])[N:24]=1)([CH2:20][CH3:21])[CH3:19]>>[CH:18]([O:22][C:23]1[C:28]([CH:29]=[CH:30][C:31]([NH:2][CH2:3][C:4]2[CH:9]=[C:8]([F:10])[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([C:16]#[CH:17])[CH:5]=2)=[O:32])=[CH:27][CH:26]=[C:25]([C:34]([F:37])([F:35])[F:36])[N:24]=1)([CH2:20][CH3:21])[CH3:19]
Reactant: CCC(C)Oc1nc(C(F)(F)F)ccc1C=CC(=O)O
Reactant: C=Cc1cc(CN)cc(F)c1NS(C)(=O)=O
Agent: Cl
Product: C#Cc1cc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2OC(C)CC)cc(F)c1NS(C)(=O)=O
Yield: 25.6 %

Procedure:
N-(4-Aminomethyl-2-ethenyl-6-fluoro-phenyl)-methanesulfonamide HCl salt (35 mg, 0.13 mmol) was reacted with 3-(2-sec-butoxy-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (22 mg) to give the title compound (10 mg) after purification by column chromatography (Hex/EtOAc=1/1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2=[O:12].[N+:13]([CH3:16])([O-:15])=[O:14]>O>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2([OH:12])[CH2:16][N+:13]([O-:15])=[O:14]
Reactant: C[N+](=O)[O-]
Reactant: O=C1Nc2c(F)cccc2C1=O
Solvent: O
Product: O=C1Nc2c(F)cccc2C1(O)C[N+](=O)[O-]
Temperature: 30 °C
Reaction time: 24 h

Procedure:
7-fluoroisatin (0.082 g) and nitromethane (0.15 ml) were added to water and the reaction mixture was vigorously stirred at a temperature of 30° C. for 24 hours. The obtained product was extracted with ethyl acetate and purified by silica gel column chromatography using ethyl acetate/hexane as eluents to afford pure product.
Reaction SMILES: [F:1][C:2]1([F:21])[CH2:5][N:4]([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12](O)=[O:13])=[N:10][CH:11]=2)[CH2:3]1.[NH2:22][C:23]1([CH2:27][C:28]([NH2:30])=[O:29])[CH2:26][O:25][CH2:24]1>>[NH2:30][C:28](=[O:29])[CH2:27][C:23]1([NH:22][C:12]([C:9]2[CH:8]=[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[C:6]([N:4]3[CH2:3][C:2]([F:1])([F:21])[CH2:5]3)=[CH:11][N:10]=2)=[O:13])[CH2:26][O:25][CH2:24]1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(N2CC(F)(F)C2)cn1
Reactant: NC(=O)CC1(N)COC1
Product: NC(=O)CC1(NC(=O)c2cc(OCC(F)(F)F)c(N3CC(F)(F)C3)cn2)COC1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridine-2-carboxylic acid (Example 223b) and 2-(3-Amino-oxetan-3-yl)-acetamide (CAN 1417638-25-5) as starting material and isolated (42 mg, 31%); MS (ESI, m/z): 425.5 (M+H+).
Reaction SMILES: [CH2:1]([CH:3]1[NH:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:4]1)[CH3:2].C1C=CC=CC=1.[Cl:20][CH:21]([Cl:25])[C:22](Cl)=[O:23]>C(N(CC)CC)C>[CH2:1]([CH:3]1[N:7]([C:22](=[O:23])[CH:21]([Cl:25])[Cl:20])[CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:4]1)[CH3:2]
Reactant: CCC1NCC(c2ccccc2)O1
Reactant: O=C(Cl)C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCC1OC(c2ccccc2)CN1C(=O)C(Cl)Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Twenty-one and three tenths (21.3) ml. of a solution containing 5.3 g. of 2-ethyl-5-phenyl oxazolidine was diluted with 25 ml. of benzene and 3.1 g. of triethylamine was added. The mixture was cooled in a room temperature water bath and 4.4 g. of dichloroacetyl chloride was added dropwise with stirring. The stirring was continued for about 30 minutes after addition was complete. The solution was washed with water, separated, dried over magnesium sulfate and removed under vacuum. There was obtained a yield of 8.7 g. of the title compound, an oil, ND30 =1.5600.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([CH2:12][NH:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:6]2)#[N:2].[Cl:24][CH2:25][C:26](Cl)=[O:27]>C(Cl)Cl>[Cl:24][CH2:25][C:26]([N:13]([CH2:12][CH:7]1[CH2:6][C:5]2[C:9](=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[CH:4]=2)[CH2:8]1)[CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:27]
Reactant: CC(C)(C)OC(=O)NCCNCC1Cc2ccc(C#N)cc2C1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCN(CC1Cc2ccc(C#N)cc2C1)C(=O)CCl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of tert-Butyl (2-{[(5-cyano-2,3-dihydro-1H-inden-2-yl)methyl]amino}ethyl)carbamate (460 mg, 1.5 mmol), chloro-acetyl chloride (180 mg, 1.6 mmol) and TEA (590 mg, 5.8 mmol) in 30 mL DCM was stirred at RT for 12 hours. The mixture was diluted with 50 mL DCM and then washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified via prep-TLC (EA/PE=1:1) to give the title compound. MS m/z: 392 [M+1]+.