Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[N:4]([CH2:25][C:26]([O:28]CC)=[O:27])[C:5]([CH3:24])=[C:6]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[S:16]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)(=[O:18])=[O:17])[C:7]=1[CH3:8])#[N:2].O.[OH-].[Li+].Cl>C1COCC1.CO>[C:1]([C:3]1[N:4]([CH2:25][C:26]([OH:28])=[O:27])[C:5]([CH3:24])=[C:6]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[S:16]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)(=[O:17])=[O:18])[C:7]=1[CH3:8])#[N:2]
Reactant: CCOC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)N2CCCC2)c(C)c1C#N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(Cc2ccccc2S(=O)(=O)N2CCCC2)c(C)n(CC(=O)O)c1C#N
Reaction time: 1 h

Procedure:
To a solution of ethyl 2-(2-cyano-3,5-dimethyl-4-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetate (40.0 mg, 0.093 mmol) in THF (1.1 ml), MeOH (372 μl), and Water (372 μl) at 0° C., was added lithium hydroxide (5.2 mg, 0.217 mmol). The mixture was stirred for 1 hour. This mixture was left standing over the course of 2 days at room temperature. To this mixture, was added HCl (214 μl, 0.214 mmol), then, the mixture was concentrated under vacuum, diluted in dichloromethane (50 ml) and washed with water (20 ml×3). The organic layer was dried, filtered, and evaporated to give 2-(2-cyano-3,5-dimethyl-4-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetic acid as a solid. 1H NMR (CDCl3/400 MHz) δ (ppm) 7.95-7.90 (m, 1H), 7.43-7.37 (m, 1H), 7.34-7.28 (m, 1H), 6.92-6.86 (m, 1H), 4.77 (s, 2H), 4.19 (s, 2H), 3.44-3.33 (m, 4H), 2.07 (s, 3H), 2.02 (s, 3H), 1.98-1.93 (m, 4H). MS m/z: 402.3 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[N:30]1[CH:35]=[CH:34][C:33]([C:36](O)=[O:37])=[N:32][CH:31]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:36]([C:33]4[CH:34]=[CH:35][N:30]=[CH:31][N:32]=4)=[O:37])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccncn1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2ccncn2)c1

Procedure:
Prepared as described in Example 83 using (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 28 mg, 0.07 mmol) and pyrimidine-4-carboxylic acid (9 mg, 0.07 mmol). Yield 12 mg (34%).
Reaction SMILES: C1COCC1.Br[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2.C([Li])CCC.[CH2:22]([Sn:26](Cl)([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH3:25]>CCCCC.CCOCC>[N:13]1[C:14]2[C:9](=[CH:8][C:7]([Sn:26]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:22][CH2:23][CH2:24][CH3:25])=[CH:16][CH:15]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Brc1ccc2ncccc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1ccc2ncccc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63.5 %

Procedure:
To 250 mL of THF was added 14 g (67 mmol) of 6-bromoquinoline and 44 mL (88 mmol) of 2M butyllithium in pentane was added at -70° under argon. The reaction was stirred for 15 minutes and 28.4 g (87.2 mmol) of tributyltin chloride was added at such a rate that the temperature remained below -60° . When addition was complete, the mixture was allowed to warm to -50° at which point the dark orange color characteristic of the anion became light amber. The mixture was stirred for 14 hrs at -70° and poured into ice-water and ether. The layers were separated, the ether layer washed with water, dried with magnesium sulfate, filtered and concentrated. The resultant oil was chromatographed on a silica gel column (30 cm ×6 cm) using 30% ether in hexane to provide 17.8 g (63%) of 6-quinolinyltributylstannane.
Reaction SMILES: [ClH:1].[N:2]1([CH2:8][CH2:9][N:10]2[CH2:15][C:14]3[CH:16]=[C:17](/[CH:20]=[CH:21]/[C:22]([OH:24])=O)[CH:18]=[N:19][C:13]=3[NH:12][C:11]2=[O:25])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1.[CH3:45][NH:46][CH2:47][C:48]1[S:52][C:51]2[CH:53]=[CH:54][CH:55]=[CH:56][C:50]=2[C:49]=1[CH3:57].CNCC1C=CC2C(=CC=CC=2)C=1CCC>>[ClH:1].[CH3:45][N:46]([CH2:47][C:48]1[S:52][C:51]2[CH:53]=[CH:54][CH:55]=[CH:56][C:50]=2[C:49]=1[CH3:57])[C:22](=[O:24])/[CH:21]=[CH:20]/[C:17]1[CH:18]=[N:19][C:13]2[NH:12][C:11](=[O:25])[N:10]([CH2:9][CH2:8][N:2]3[CH2:3][CH2:4][O:5][CH2:6][CH2:7]3)[CH2:15][C:14]=2[CH:16]=1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CN(CCN1CCOCC1)C(=O)N2
Reactant: CNCc1sc2ccccc2c1C
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CN(CCN2CCOCC2)C(=O)N3)sc2ccccc12
Yield: 33 %

Procedure:
According to the procedure of Example 1, except substituting (E)-3-[3-(2-morpholin-4-yl-ethyl)-2-oxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-6-yl]acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, and substituting methyl-(3-methyl-benzo[b]thiophen-2-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, the title compound (140 mg, 33%) was prepared as a off-white solid: 1H NMR (300 MHz, DMSO-d6) δ 10.45 (br s, 1H), 10.14 (s, 1H), 8.41-8.39 (m, 1H), 8.01 (s, 1H), 7.88-7.86 (m, 1H), 7.74-7.73 (m, 1H), 7.56-7.53 (m, 1H), 7.41-7.18 (m, 3H), 6.31 (br s, 1H), 5.11-4.88 (m, 2H), 4.57-4.55 (m, 2H), 3.99-3.96 (m, 2H), 3.75-3.71 (m, 4H), 3.57-3.55 (m, 2H), 3.39-3.37 (m, 2H), 3.15-2.94 (m, 5H), 2.42 (s, 3H); MS (ESI) m/e 506 (M+H)+.
Reaction SMILES: N1C2C=CC=C(N)C=2N=[CH:2]1.[N+:11]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[C:15]=1[NH2:21])([O-:13])=[O:12].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl.[OH-].[Na+]>C(OCC)(OCC)OCC>[N+:11]([C:14]1[C:15]2[NH:21][CH:2]=[N:20][C:16]=2[CH:17]=[CH:18][CH:19]=1)([O-:13])=[O:12]
Reactant: Nc1cccc2[nH]cnc12
Reactant: Nc1cccc([N+](=O)[O-])c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCOC(OCC)OCC
Solvent: O
Product: O=[N+]([O-])c1cccc2nc[nH]c12

Procedure:
EXAMPLE 105 was prepared from 1H-benzoimidazol-4-ylamine (The 1H-benzoimidazol-4-yl-amine was prepared by heating 1.5 g of 3-nitro-benzene-1,2-diamine in 50 mL of triethyl orthoformate with 10 mg of p-toluenesulfonic acid monohydrate at reflux overnight, concentration to dryness under reduced pressure, hydrolysis with refluxing 3N HCl for 1 h and neutralization with NaOH. Then, cooling and collection yielded the 4-nitro-benzimidazole product by filtration. Catalytic reduction using Raney Nickel® in ethanol under 1 atm of hydrogen for 1 h gave 1H-benzoimidazol-4-ylamine as an air sensitive solid) and 4-formyl-piperidine-1-carboxylic acid benzyl ester (prepared from 4-(N-methoxy-N-methyl-carbamoyl)-piperidine-1-carboxylic acid benzyl ester, using the procedures described by S. Nahm and S. W. Weinreb, Tetrahedron Letters, 22:3815–3818(1981)) on a 1 mmol scale by reductive animation in 5 mL of 1,2-dichloromethane using sodium triacetoxyborohydride over 0.5 of Raney Nickel® under 1 atm of hydrogen for 1 h, followed by immediate conversion of the crude, air sensitive triaminopyridine into the imidazo[4,5b]pyridine by heating with 5 mL of 96% formic acid and 2 mL of 37% hydrochloric acid at reflux overnight. The free base was liberated with sodium hydroxide and purified by preparative chromatography, eluting with 90:10 chloroform: methanol: MS (m+1)=365.5.
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[N:13]=2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[C:21](Cl)([O:23]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCOCC1>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([N:11]2[C:21](=[O:23])[NH:1][C:2]3[N:3]=[CH:4][CH:5]=[CH:6][C:7]=3[S:8]2(=[O:10])=[O:9])=[N:13][C:14]=1[CH3:19]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1ccc(NS(=O)(=O)c2cccnc2N)nc1C
Solvent: C1COCCO1
Product: Cc1ccc(N2C(=O)Nc3ncccc3S2(=O)=O)nc1C
Yield: 60.6 %

Procedure:
The title compound (0.4 g, 1.31 mmol) was prepared from 2-amino-N-(5,6-dimethylpyridin-2-yl)pyridine-3-sulfonamide (0.6 g, 2.16 mmol) and triphosgene (0.7 g, 2.36 mmol) in 1,4-dioxane (15 mL) at 80° C. using the methods of (IntA1), step 3.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:33]3[CH:38]=[CH:37][C:36]([CH:39]=O)=[CH:35][CH:34]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12.[CH3:41][O:42][CH2:43][CH2:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:33]3[CH:34]=[CH:35][C:36]([CH2:39][N:48]4[CH2:49][CH2:50][N:45]([CH2:44][CH2:43][O:42][CH3:41])[CH2:46][CH2:47]4)=[CH:37][CH:38]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:27])([F:28])[F:26])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12
Reactant: COCCN1CCNCC1
Reactant: COc1cc(-c2nn(-c3ccc(C=O)cc3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: COCCN1CCN(Cc2ccc(-n3nc(-c4ccc(NC(=O)c5ccc(C(F)(F)F)cc5F)c(OC)c4)c4c(N)ncnc43)cc2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 22.1 %

Procedure:
A mixture of N1-{4-[4-amino-1-(4-formylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-(trifluoromethyl)benzamide (Intermediate 2) (0.075 g, 0.14 mmol), 1-(2-methoxyethyl)-piperazine (0.039 g, 0.27 mmol), and sodium triacetoxyborohydride (0.087 g, 0.41 mmol) in dichloroethane (1.4 mL) was shaken at room temperature for 3 days. Additional portions of 1-(2-methoxyethyl)-piperazine (0.10 mL) and sodium triacetoxyborohydride (0.089 g, 0.41 mmol) were added and the reaction mixture was shaken for 16 h. 1N NaOH (1 mL) was added and the resulting solution was extracted with two portions of dichloromethane (2 mL each). The combined organic portions were concentrated to afford a brown solid which was purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 Å, 25 cm; 20-80% acetonitrile-0.05 M ammonium acetate over 25 min, 21 mL/min); the fraction eluting from 16.9-20.2 min was collected, concentrated, and lyopholized to afford N1-{4-[4-amino-1-(4-{[4-(2-methoxyethyl)piperazino]methyl}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-(trifluoromethyl)benzamide as a white solid (0.021 g, 0.031 mmol): 1H NMR (d6-DMSO, 400 MHz): δH 9.94 (1H, s), 8.34-8.37 (2H, m), 8.14-8.17 (1H, m), 7.98-8.02 (1H, m), 7.89 (1H, d, J=10.4 Hz), 7.74-7.76 (1H, m), 7.34-7.64 (6H, m), 3.96 (3H, s), 3.51 (2H, s), 3.31-3.43 (2H, m), 3.22 (3H, s), and 2.41-2.45 (10H, m); RP-HPLC (Hypersil C18, 5 μm, 100 Å, 15 cm; 5%-100% acetonitrile-0.1 M ammonium acetate over 15 min, 1 mL/min). Rt 11.24 min.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][NH:5][CH2:6][C:7]1([CH3:12])[CH2:11][CH2:10][CH2:9][NH:8]1.Cl[C:18](Cl)([O:20]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][N:5]1[CH2:6][C:7]2([CH3:12])[CH2:11][CH2:10][CH2:9][N:8]2[C:18]1=[O:20]
Reactant: CC1(CNCc2ccccc2Cl)CCCN1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC12CCCN1C(=O)N(Cc1ccccc1Cl)C2
Reaction time: 4 h
Yield: 22 %

Procedure:
To a cold (0° C.) solution of (2-chloro-benzyl)-((rac)-2-methyl-pyrrolidin-2-ylmethyl)-amine (0.5 g, 1 eq) in DCM (15 mL) was added a solution of triphosgene (0.5 eqv) in DCM (5 mL) over a period of 5 minutes followed by the addition of triethylamine (3 eq). The reaction mixture was allowed to stir for 4 h. After the completion of the reaction on TLC, the reaction mixture was quenched with 1M HCl (10 mL) and extracted with DCM (3×50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated using rotary evaporator to give sticky crude, which was then purified with column chromatography (1-2% Methanol:DCM, Mesh Size-100-200 silica, Diameter of column—2.5 cm, Height of silica—approx. 5 inch) to afford the desired product (rac)-2-(2-chloro-benzyl)-7a-methyl-hexahydro-pyrrolo[1,2-c]imidazol-3-one as white solid (22-70%). MS (ES+): 265.5 (MH+))
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]3[CH:24]=[CH:23][C:22]([CH2:25][N:26]([C:33]4[CH:34]=[C:35]([CH:41]=[CH:42][CH:43]=4)[C:36]([O:38]CC)=[O:37])[C:27](=[O:32])[CH2:28][CH2:29][CH2:30][CH3:31])=[CH:21][CH:20]=3)[N:10]=[N:9]2)C=CC=CC=1.[OH-].[Li+]>C(O)(=O)C.O.O1CCOCC1.O>[NH:10]1[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]2[CH:20]=[CH:21][C:22]([CH2:25][N:26]([C:33]3[CH:34]=[C:35]([CH:41]=[CH:42][CH:43]=3)[C:36]([OH:38])=[O:37])[C:27](=[O:32])[CH2:28][CH2:29][CH2:30][CH3:31])=[CH:23][CH:24]=2)=[N:12][N:8]=[N:9]1
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1)c1cccc(C(=O)OCC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 51.7 %

Procedure:
Ethyl 3-[N-[[4-[2-(3-triphenylmethyl-3H-tetrazol-5-yl)phenyl]phenyl]methyl]-N-pentanoylamino]benzoate (0.37 g) synthesized in Example 1a was dissolved in 75% acetic acid-water (8.8 ml), and the mixture was stirred at room temperature for 24 hrs. The reaction mixture was concentrated and dried to give a solid. The residue was dissolved in 75% dioxane-water (8.8 ml), lithium hydroxide (45 mg) was added, and the mixture was stirred at 50° C. for 24 hrs. The reaction mixture was concentrated to give a solid, and the residue was purified by silica gel column chromatography (methylene chloride-methanol:7-3 v/v) to give the object compound (0.12 g, yield 88%).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.Br[CH2:16][C:17]#[N:18]>C(#N)C>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:16][C:17]#[N:18])=[CH:10][CH:9]=1
Reactant: Nc1ccc(O)cc1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: N#CCOc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Cs2CO3 (1629 mg, 5 mmol) was added in one portion to a solution of 4-aminophenol (541 mg, 5 mmol) in acetonitrile (20 mL). The reaction mixture was stirred at room temperature for 30 min and cooled to 0° C. prior to the addition of a solution of bromoacetonitrile (313 μL, 5 mmol) in acetonitrile (10 mL) dropwise. After stirring at room temperature for 48 h (TLC control), the reaction mixture is filtered and the filtrate evaporated to dryness in vacuo. The residue obtained after solvent removal was purified by silica gel column chromatography (hexanes/EtOAc 1:1). The desired product was isolated as yellow-brown oil. Yield: 559 mg, 76%. TLC Rf=0.2 (hexanes/EtOAc 1:1). 1H NMR (CDCl3, 600 MHz): δ 3.56 (br.s, 2H, NH2), 4.66 (s, 2H, CH2), 6.65 (d, J=8.4 Hz, 2H), 6.83 (d, J=8.4 Hz, 2H). 13C NMR (CDCl3, 150 MHz): δ 55.28, 115.60, 116.25, 117.10, 142.42, 149.65. HRMS: Calcd. [M+H]+ m/z 149.0715, Observed 149.0689.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[N:4]([C:14](=[O:16])[CH3:15])[CH2:3]1>[Pd].C1COCC1>[NH2:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([CH3:17])([CH3:1])[CH2:3][N:4]2[C:14](=[O:16])[CH3:15])=[CH:9][CH:8]=1
Reactant: CC(=O)N1CC(C)(C)c2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(=O)N1CC(C)(C)c2ccc(N)cc21
Temperature: 0 °C
Reaction time: 0.13 h

Procedure:
A Parr hydrogenation unit was charged with 1-(3,3-dimethyl-6-nitroindolin-1-yl)-ethanone (450 g, 1.92 mol), THF (1.8 L), and 10% Pd/C (20.3 g). The unit was purged with nitrogen twice then agitated. The unit was pressurized with 50 psi hydrogen and the agitation was continued until absorption ceased. Hydrogen absorption was exothermic. The temperature was maintained below 50° C. during the reaction. The reaction was monitored by GC. After 8 min, the unit was purged with nitrogen. The mixture was filtered through a Celite™ pad and washed the pad with THF (100 mL×1). The filtrate was concentrated under reduced pressure to ¼ total volume and cooled to 0° C. To the mixture was added heptane (800 mL×1) and the mixture was stirred at 0° C. for 45 min. The resulting precipitate was collected by filtration, washed the solid with heptane (150 mL×1), and dried at 50° C. under reduced pressure to give 1-(6-amino-3,3-dimethylindolin-1-yl)ethanone.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([NH:18][CH:19]([CH:27]([OH:54])[CH:28]([NH:36][C:37](=[O:53])[C@H:38]([CH:50]([CH3:52])[CH3:51])[NH:39][C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].N1C=CC=CC=1.[Br:61][CH2:62][C:63](Br)=[O:64].CO>C(Cl)Cl.C(Cl)(Cl)Cl>[Br:61][CH2:62][C:63]([O:54][CH:27]([CH:19]([NH:18][C:16](=[O:17])[C@H:12]([CH:13]([CH3:14])[CH3:15])[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:28]([NH:36][C:37](=[O:53])[C@H:38]([CH:50]([CH3:52])[CH3:51])[NH:39][C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41])[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:64]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NC(Cc1ccccc1)C(O)C(Cc1ccccc1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Reactant: O=C(Br)CBr
Solvent: CO
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NC(Cc1ccccc1)C(OC(=O)CBr)C(Cc1ccccc1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Yield: 54.4 %

Procedure:
The resultant compound of Example 70 (600 mg, 0.81 mmol) was dissolved in 8 mL of methylene chloride and 72 μL (0.9 mmol) of pyridine. The solution was cooled in an ice bath with stirring under a nitrogen atmosphere. α-Bromoacetyl bromide (181 mg, 0.9 mmol) was added in one portion and the ice bath was removed. The reaction mixture was stirred at ambient temperature for 3 h and then diluted with 150 mL of chloroform. The chloroform solution was washed with 150 mL of water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue (644 mg) was taken up in a mixture of chloroform and methanol and adsorbed onto approximately 1.5 g of 40 mesh silica gel in vacuo @40° C. The silica gel with the product adsorbed onto it was applied to a 1.0×40 cm column of 40 mesh silica gel and the column was eluted @~5 p.s.i. sequentially with 100 mL of chloroform and 100 mL of 1% methanol in chloroform to give 378 mg (55% yield) of the title compound; FAB MS M/Z: 859 (M+H)+. The 300 MHz 1NMR spectrum was consistent with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:19])[C:9]([C:11]3[CH:12]=[C:13]([CH:17]=O)[CH:14]=[N:15][CH:16]=3)=[CH:10][C:5]2=[CH:4][CH:3]=1.[CH2:20]([S:22]([NH2:25])(=[O:24])=[O:23])[CH3:21].C1(C)C=CC=CC=1.[BH4-].[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].O.CO>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:19])[C:9]([C:11]3[CH:12]=[C:13]([CH2:17][NH:25][S:22]([CH2:20][CH3:21])(=[O:24])=[O:23])[CH:14]=[N:15][CH:16]=3)=[CH:10][C:5]2=[CH:4][CH:3]=1
Reactant: CCS(N)(=O)=O
Reactant: Cn1c(-c2cncc(C=O)c2)cc2ccc(Cl)nc21
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: CCS(=O)(=O)NCc1cncc(-c2cc3ccc(Cl)nc3n2C)c1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A 25 mL flask was charged with 5-(6-Chloro-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-pyridine-3-carbaldehyde (91 mg, 0.335 mmol), ethane sulfonamide (73.1 mg, 0.670 mmol) and toluene (5 mL). Titanium(IV) isopropoxide (0.147 mL, 0.502 mmol) was added dropwise. The mixture was stirred at 120° C. overnight. The mixture was concentrated in vacuo. The residue was taken up in DCM (5 mL) and MeOH (5 mL) and sodium borohydride (50.7 mg, 1.340 mmol) was added at 0° C. The mixture was stirred at 0° C. for 30 min. Water (1 mL) was added and the mixture was stirred for 5 min, then concentrated in vacuo. DMF (5 mL) was added and the suspension was filtered. The filtrate was purified by Xbridge RP 18 eluting with a 5 to 95% ACN-water gradient to afford ethanesulfonic acid [5-(6-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-pyridin-3-ylmethyl]-amide. ESI-MS: m/z 365.2 (M+H)1H NMR (400 MHz, MeOD) δ ppm 1.38 (t, J=7.3 Hz, 2H), 3.23 (q, J=7.4 Hz, 2H), 4.08-4.17 (m, 2H), 4.59 (dd, J=8.8, 7.3 Hz, 2H), 7.10 (d, J=8.3 Hz, 1H), 7.53 (dd, J=8.6, 2.3 Hz, 1H), 7.63 (d, J=2.3 Hz, 1H), 7.92 (t, J=2.1 Hz, 1H), 8.40 (d, J=2.5 Hz, 1H), 8.56 (d, J=2.0 Hz, 2H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:34]=[CH:33][C:23]([C:24]([NH:26][CH2:27][CH2:28][S:29]([CH3:32])(=[O:31])=[O:30])=[O:25])=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=O)=[C:4]([F:35])[CH:3]=1.Cl.[NH2:37][OH:38].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:21]=[CH:22][C:23]([C:24]([NH:26][CH2:27][CH2:28][S:29]([CH3:32])(=[O:30])=[O:31])=[O:25])=[CH:33][CH:34]=2)[CH2:9]/[C:10](=[N:37]\[OH:38])/[C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[C:4]([F:35])[CH:3]=1
Reactant: Cn1cc(C(=O)CC(c2ccc(C(=O)NCCS(C)(=O)=O)cc2)c2ccc(Cl)cc2F)ccc1=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(/C(CC(c2ccc(C(=O)NCCS(C)(=O)=O)cc2)c2ccc(Cl)cc2F)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, 4-[1-(4-chloro-2-fluoro-phenyl)-3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-propyl]-N-(2-methanesulfonyl-ethyl)-benzamide was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as a colourless foam containing 3% of the corresponding Z isomer, MS (ESI+): m/z=534.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([I:19])[S:18][C:11]=12)[NH2:5].[O:20]=[C:21]1[CH:25]([C:26](O)=[O:27])[CH2:24][CH2:23][NH:22]1.Cl.C(N=C=NCCCN(C)C)C.N1(O)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:26]([CH:25]2[CH2:24][CH2:23][NH:22][C:21]2=[O:20])=[O:27])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([I:19])[S:18][C:11]=12
Reactant: O=C(O)C1CCNC1=O
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C1NCCC1C(=O)Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Temperature: 25 °C
Yield: 44.1 %

Procedure:
A flask was charged with 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)aniline (Example 6, Step A, 150.0 mg, 0.388 mmol), 2-oxopyrrolidine-3-carboxylic acid (100.3 mg, 0.777 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (223.4 mg, 1.17 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (157.5 mg, 1.17 mmol), N-ethyl-N-isopropylpropan-2-amine (0.347 ml, 1.94 mmol) and THF (100 mL). The reaction mixture was stirred at room temperature until the starting material had been consumed (overnight). Then the reaction mixture was partitioned between EtOAc (100 mL) and H2O (100 mL). The phases were separated and the aqueous phase was re-extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (EtOAc/Hexane from 1/4 to 4/1, v/v) to afford product (85.0 mg, 44%). LRMS (APCI pos): >97% purity, 254 nm, m/e 498 (M+1).